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Posts Tagged ‘BRCA1’


BRCA 1 and 2 and Early Detection of Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

BRCA1 and BRCA2: Cancer Risk and Genetic Testing

http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet

Recommendations for Follow-up Care of Individuals With an Inherited Predisposition to Cancer II. BRCA1 and BRCA2

Wylie Burke, Mary Daly, Judy Garber, Jeffrey Botkin,  Mary Jo Ellis Kahn, et al.

JAMA. 1997;277(12):997-1003. http://dx.doi.org:/10.1001/jama.1997.03540360065034

Objective.  —To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations in the BRCA1 or BRCA2 genes.

Participants.  —A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by National Human Genome Research Institute (previously the National Center for Human Genome Research).

Evidence.  —Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to breast and ovarian cancer were identified using MEDLINE (National Library of Medicine) and from bibliographies of articles thus identified. Indexing terms used were “genetics” in combination with “breast cancer,” “ovarian cancer,” and “screening,” or “surveillance” in combination with “cancer family” and “BRCA1” and “BRCA2.” For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force.

Consensus Process.  —The task force developed recommendations through discussions over a 14-month period.

Conclusions.  —Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with BRCA1 mutations and early breast cancer screening for those with BRCA2 mutations. No recommendation is made for or against prophylactic surgery (eg, mastectomy, oophorectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking, and case reports have documented the occurrence of cancer following prophylactic surgery. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.

Two Percent of Men with Early-Onset Prostate Cancer Harbor Germline Mutations in the BRCA2 Gene

Stephen M. Edwards1*Zsofia Kote-Jarai1*Julia Meitz1Rifat Hamoudi2Questa Hope1, et al.

  • Cancer Research UK/British Prostate Group UK Familial Prostate Cancer Study Collaborators, 
  • British Association of Urological Surgeons Section of Oncology,, 

AJHG Volume 72, Issue 1, January 2003, Pages 1–12

doi:10.1086/345310  Get rights and content

Under an Elsevier user license

Studies of families with breast cancer have indicated that male carriers ofBRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were ≤55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%–5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer–susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives.

Introduction

Many studies have demonstrated that prostate cancer (PRCA) exhibits significant familial aggregation, particularly at a young age (reviewed by Eeles et al. 1999). Segregation analyses have suggested that this familial clustering is consistent with the existence of high-penetrance prostate-cancer–susceptibility alleles. Despite this, linkage searches in families with multiple cases of PRCA have been inconclusive. Loci on chromosomes 1q24, 1q42, 1p36, Xq27, and 17p11 have been mapped (Smith et al. 1996; Berthon et al. 1998; Xu et al. 1998; Gibbs et al. 1999), and the specific candidate genesHPC1 (Carpten et al. 2002 [RNASEL; MIM 601518 and MIM 180435]) and HPC2(Tavtigian et al. 2001 [MIM 605367]) have been identified as high-risk PRCA genes, but none has thus far been definitively confirmed.

One other gene that has been implicated in PRCA predisposition is BRCA2 (MIM 600185). The association with this gene was first suggested by studies in Iceland: Arason et al. ( 1993) found an excess risk of PRCA in families with multiple cases of breast cancer in Iceland, the majority of which have subsequently been shown to segregate a singleBRCA2 mutation, 999del5 (Thorlacius et al. 1996). Johannesdottir et al. ( 1996) found that 2.7% of patients with PRCA who were aged <65 years carried this mutation, compared with ∼0.5% of the general population. Sigurdsson et al. ( 1997) estimated a PRCA relative risk of 4.6 in male first-degree relatives of patients with breast cancer in families segregating the 999del5 mutation. This association has been supported by a large collaborative study from the Breast Cancer Linkage Consortium (BCLC 1999). This study, based on 173 families harboring BRCA2 mutations, estimated a relative risk of 4.65 (95% CI 3.48–6.22) for PRCA in male BRCA2 gene carriers. The estimated relative risk rose to 7.33 in patients diagnosed before the age of 65 years. In contrast, studies based on the Ashkenazi Jewish founder mutation 6174delT have not found a strong association between this mutation and PRCA risk (Struewing et al. 1997; Lehrer et al. 1998; Hubert et al. 1999; Nastiuk et al. 1999; Wilkens et al. 1999; Vazina et al. 2000). There is consistent evidence for loss of heterozygosity of the BRCA2 region in PRCAs, particularly those at an advanced stage (Cooney et al. 1996; Melamed et al. 1997; Edwards et al. 1998; Watanabe et al. 1998; Hyytinen et al. 1999).

In a previous study (Gayther et al. 2000), we screened for BRCA2 mutations in 38 patients with PRCA who had a family history of the disease. Deleterious mutations were found in 2 of the 16 patients who received diagnoses before the age of 60 years (at ages 52 and 56 years), whereas no mutations were found among the 22 older patients (who received diagnoses at or after the age of 60 years), providing further evidence of an increased risk of PRCA at young ages in BRCA2 mutation carriers. To establish the contribution ofBRCA2 mutations to early-onset PRCA, we have now screened a total of 263 men diagnosed at ages ≤55 years, who were unselected for family history.

Material and Methods

Patients

Patients were recruited through the Cancer Research UK/British Prostate Group (formerly “CRC/BPG”) UK Familial Prostate Cancer Study and the British Association of Urological Surgeons Section of Oncology, over the period 1992–1999. Three hundred and twelve patients who received diagnoses before the age of 56 years were identified through records of participating clinicians. This represents ∼50% of patients who received diagnoses in the United Kingdom over the corresponding period. Patients were enrolled regardless of family history. Seven (2.2%) of the patients invited to participate had died before being approached, 4 (1.3%) declined to participate, and a further 37 (11.9%) did not provide a questionnaire or blood sample, leaving 264 patients to be analyzed.

All but one of the patients in the study had disease that was classified as adenocarcinoma of the prostate. The one exception was the youngest patient in the study, diagnosed at age 24 years with a low grade sarcoma. This patient was excluded from these analyses. The remaining 263 patients received diagnoses between the ages of 32 and 55 years (mean 51 years). Eleven (4%) of the patients from this group were of black African or Caribbean descent, and the remainder were white. Details of prostate and other cancers in first-degree relatives of the patients were obtained by questionnaire.

DNA Isolation

Lymphocytes were collected from patients and were stored in EDTA at −70°C until required. Lymphocyte DNA was extracted by routine methods (Edwards et al. 1997).

PCR

PCR and thermocycling was conducted as described by Edwards et al. (2001). Forty-fiveBRCA2 primer pairs (M. Stratton and S. Gayther, personal communication) were used. The longer exons were amplified as subfragments and were numbered accordingly; there are four fragments for exon 10 (10.01–10.04), 17 fragments for exon 11 (11.01–11.17), and two fragments each for exons 14 and 27. Exons 5/6 and 23/24 were amplified in the same fragment. Primer sequences and PCR conditions are available from the authors’ Web site.

Mutation Screening

Samples were analyzed by fluorescent mutation detection (F-MD) as described by Edwards et al. (2001). PCR products were mixed robotically (as many as 12 fragments per sample), which allowed the entire BRCA2 gene of an individual to be screened in four lanes of an ABI 377. Heteroduplexes were identified by the presence of more than one peak (band shift) for a specific PCR product. Where band shifts were found, the mixed and unmixed PCR products were rerun on F-MD for confirmation. When PCR fragments were too weak or contained nonspecific amplimers, they were not placed in a post-PCR multiplex mix; these fragments were run on F-MD separately.

Sequencing

After confirmation of a band shift, the sample was reamplified by PCR from stock DNA, and sequencing was conducted to characterize mutations through use of an ABI Prism dRhodamine Terminator Cycle Sequencing Ready Reaction Kit and an ABI377 Genetic Analyzer, with both forward and reverse PCR primers.

Nomenclature

Sequence variants were categorized as either “deleterious,” “polymorphisms,” or “variants of uncertain significance” (VUS). Since no amino-acid substitutions in BRCA2have been shown to be clearly disease associated, the category of deleterious mutations was restricted to those that result in a truncated protein (frameshift insertion or deletion, nonsense mutation, or known pathogenic splice-site alteration). Polymorphisms were those with reported population frequencies >1%. All other missense variants in the coding and noncoding regions were categorized as VUS (Frank et al. 2002; Breast Cancer Information Core [BIC] Web site).

Statistical Methods

Confidence intervals for the prevalence of BRCA2 mutations among patients with PRCA were computed under the assumption that (given that the prevalence was relatively small) the number of mutations followed a Poisson distribution and, hence, that the variance of the log(prevalence) was given by the reciprocal of the number of observed mutations. Estimates of BRCA2 prevalence in the general population were derived from two previous studies (Peto et al. 1999; Antoniou et al. 2002). Confidence limits for the prevalence estimate in the Peto et al. ( 1999) article were derived using a similar Poisson assumption based on the observed number of mutations; confidence limits for the estimate in the Antoniou et al. ( 2002) study are given in that article. These estimates were combined into a single inverse variance-weighted estimate. Confidence limits for the relative risk of PRCA in BRCA2 mutation carriers were computed by assuming that the variance of the log(relative risk) was the sum of the variances of the log(prevalence) in patients with PRCA and the log(prevalence) in the general population.

Results

Mutation Detection (F-MD) and Sequencing

Examples of band shifts seen by F-MD are shown in figure 1. Five frameshift mutations were identified, in patients aged 47, 48, 52, 52, and 53 years at PRCA diagnosis (table 1). In addition, we found one splice-site mutation (IVS17-1g→c), in a 44-year-old patient. This mutation would be expected to result in skipping of exon 18 and has been reported six times previously as a splice-site mutation, on the BIC Web site. We have therefore classified this as a deleterious mutation. The sequence electropherograms of these mutations are shown in figure 2. All of the truncating mutations were found in white patients. Twenty-two variants of uncertain significance (VUS) in 24 patients (table 2) and 26 polymorphisms (table 3) were also identified.

Figure 1.

F-MD traces of deleterious alterations. Heteroduplexes are seen as band shifts from normal (N) and mutant (M) amplimers on F-MD gels. When band shifts were detected, samples were repeated at least once.

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Table 1.

Deleterious Alterations Found in 263 Patients with Early-Onset Prostate Cancer

The longer exons were amplified as subfragments and were numbered accordingly; see the “Material and Methods” section for explanation. Intronic (I) sequences were present at the beginning and ends of shorter coding sequences.

B In first- and second-degree relatives.

C This mutation was also found by Gayther et al. (2000).

D  PRY 086 also had another missense mutation 3′ to the deletion 8365A→G (T2713A).

Table options

Figure 2.

Electropherograms of mutations. Left column, normal sequence. Right column, mutant sequence. The arrow (↓) shows the position of the mutation.

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Table 2.

BRCA2 VUS Found in Patients with Early-Onset Prostate Cancer

A The longer exons were amplified as subfragments and were numbered accordingly; see the “Material and Methods” section for explanation. Intronic (I) sequences were present at the beginning and ends of shorter coding sequences.

B  P/CAF (transcriptional coactivator protein), HAT (histone acetylase transferase), BRC (30 amino acid repeats)

C Amino acid conservation was scored by the BESTFIT program (Wisconsin Computing Group) as 100% identical, >50% (indicates amino acid pairs having matrix scores >0.5), <50% (indicates positive scores <0.5%), or 0% (no similarity) (Connor et al. 1997).

D Values in parentheses represent the number of times there is an entry for the given mutation in the BIC database. UV = unclassified variant equivalent to VUS – variants of unknown significance, S = splice site, Myr = Myriad Genetics.

E Two A2717S mutations were detected separately in two patients; one of these patients received a diagnosis of brain cancer at age 77 years.

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Table 3.

BRCA2 Polymorphisms Found in Patients with Early-Onset Prostate Cancer

A The longer exons were amplified as subfragments and were numbered accordingly; see the “Material and Methods” section for explanation. Intronic (I) sequences were present at the beginning and ends of shorter coding sequences.

B Data on global heterozygosity were obtained from Wagner et al. (1999). UV = unclassified variant equivalent to VUS, P = polymorphism.

C Listed as “UV” on BIC; however, we consider this to be a polymorphism. Wagner et al. (1999) also state this.

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Family History of Cancer

Figure 3.

Pedigrees of patients with PRCA who have deleterious mutations. The index patient is indicated with an arrow. Sites of cancer and ages at diagnosis and years of birth (if available) are shown. All trees have had details of other unaffected individuals altered to preserve anonymity. These changes do not alter the inference of the study.

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Of the six patients with protein-truncating mutations, one had a family history of PRCA. Two (PRY 086 and PRY 012) had a family history of breast/ovarian cancer (fig. 3). The sister of PRY086 was diagnosed with ovarian cancer, and four of his female relatives were diagnosed with breast cancer (three before age 60 years). A paternal aunt of PRY012 received a breast cancer diagnosis at age 68 years. Three of the mutation carriers had no family history of breast or ovarian cancer or PRCA.

Discussion

We have analyzed the entire coding region of the BRCA2 gene in a total of 263 patients with PRCA who received diagnoses at or before the age of 55 years, and we have found six protein truncating mutations (2.3%; 95% CI 0.8%–5.0%). This is likely to be an underestimate of the true frequency, since, like other mutation screening methods, our method will not have been able to detect large deletions or rearrangements, and some of the missense variants may be disease causing. The BCLC has estimated that 78% of families that show linkage to BRCA2 have demonstrable truncating mutations in the gene (D. Easton, personal communication). On the basis of this sensitivity, we estimate the overall prevalence of BRCA2 mutations in early-onset PRCA to be 2.9% (95% CI 1.0%–6.4%).

Patients in this series were selected solely on the basis of age at diagnosis, without regard to family history or disease severity. Among patients identified by participating clinicians, >80% of patients were included, and only seven had died before they could be included. Thus, although some selection bias cannot be ruled out, this series should be reasonably representative of early-onset PRCA in general.

Comparison of our prevalence estimate with the prevalence of BRCA2 mutations in the general population can provide an estimate of the relative risk of early-onset PRCA in carriers. The frequency of BRCA2 mutations in the general U.K. population has not been estimated directly but has been estimated indirectly from the frequency of mutations in patients with early-onset breast cancer. In separate studies, Antoniou et al. ( 2002) estimated a carrier frequency of 0.14% (95% CI 0.07%–0.28%) and Peto et al. ( 1999) estimated a frequency of 0.12% (0.07%–0.20%). On the basis of the average of these two estimates, the relative risk of early-onset PRCA is ∼23-fold (95% CI 9–57). This is significantly higher than the 7.3-fold estimated from the BCLC study, for patients diagnosed before age 65 years (P=.025), consistent with an increasing trend in relative risk with early age at diagnosis (although both estimates have wide confidence limits). The estimated cumulative risks of PRCA by age 55 and 65 years in the general population are ∼0.06% and 1.50%, respectively, on the basis of recent England and Wales cancer registration rates (Parkin et al. 1992). We therefore estimate the absolute risk of PRCA in BRCA2 carriers to be ∼1.3% by age 55 years and 10% by age 65 years.

Thompson et al. (2001) found that the risk of PRCA was lower in carriers of BRCA2mutations in the ovarian cancer cluster region (OCCR; nucleotides 3035–6629) than in carriers of other mutations (relative risk 0.48). Mutations in this region, which is coincident with the BRC repeat domain (Bignell et al. 1997) responsible for RAD51 binding, are also associated with a reduced risk of breast cancer but a higher risk of ovarian cancer. In this regard, it is interesting to note that all six mutations found in our study lie outside the OCCR.

The positional effect noted above would also be consistent with the apparently weaker association found in studies of the Ashkenazi Jewish founder mutation 6174delT, which lies within the OCCR. Another factor may be the high prevalence of screen-detected disease in the United States. The BCLC (1999) noted that the relative risk was higher in families from Europe than those from North America, suggesting that BRCA2predisposes predominantly to symptomatic rather than screen-detected disease.

Of the six patients with deleterious BRCA2 mutations, one (PRY 042) had a family history of PRCA. The overall contribution of BRCA2 mutations to the familial aggregation of PRCA is small, however. Forty-eight patients in the study (18%) had a first-degree relative with PRCA ( table 4), of which at most one quarter would occur at population incidence rates (the familial risk of PRCA in first-degree relatives is at least fourfold at ages younger than 60 years; reviewed by Eeles et al. [ 1999]). Therefore, we estimate thatBRCA2 mutations account for ∼6% (2/[75%×48]) of the excess familial risk of the disease. From a clinical viewpoint, therefore, a family history of PRCA alone would not be a strong indication for BRCA2 mutation screening. On the other hand, only two patients in the study had first-degree relatives with both breast cancer diagnosed before age 60 years and ovarian cancer, one of whom had an identified mutation. Therefore, in this situation, a family history of early-onset breast cancer/ovarian cancer was, as expected, a strong predictor of BRCA2 mutation positivity. The ascertainment by early onset of PRCA was, however, the greatest predictor of BRCA2 mutation positivity with respect to PRCA susceptibility.

Table 4.

Family History of Prostate Cancer and Other Cancers (Data Available for 263 Patients)

No. of Patients Frequency (%)
Patients with PRCA family history:
 In one first-degree relative 35a 13.3
 In two first-degree relatives 6 2.3
 In three or more first-degree relatives  7  2.6
  Total 48 18.2
Patients with breast and/or ovarian cancer family history:
 Ovarian cancer in one first-degree relative 11 4.2
 Ovarian cancer in two first-degree relatives 2 .7
 Ovarian cancer in three or more first-degree relatives  1  .4
  Total 14 5.3
 Breast cancer in one first-degree relative aged <60 years 15b 5.7
 Breast cancer in two first-degree relatives aged <60 years 3 1.1
 Breast cancer in three or more first-degree relatives aged <60 years  1  .4
  Total 19 7.2
 Breast cancer diagnosed at age <60 years and ovarian cancer in first-degree relatives 2b .7
Patients with prostate and breast cancer family history:
 Breast cancer diagnosed at age <60 years and PRCA in first-degree relatives 6 2.3
Patients with any other cancer family history:
 Any cancer in one first-degree relative 79c 30.0
 Any cancer in two first-degree relatives 38 14.4
 Any cancer in three or more first-degree relatives  35 13.3
  Total 152 57.7

A Includes PRY 042 (6710delACAA), who has a brother with PRCA.

B Includes PRY 086 (8525delC), who has four relatives with breast cancer and one with ovarian cancer.

C Includes PRY 012 (2558insA), who has a first-degree relative with laryngeal cancer.

Table options

In addition to the frameshift mutations, we found 24 VUS (22 distinct variants, 2 of which were observed twice; see table 2). Twenty of these (19 distinct variants) were nonsynonymous missense mutations in the coding region, and 4 were sequence variants in the 5′-UTR and intronic regions. Of the 19 nonsynonymous VUS, 6 have not been reported to the BIC database. The overall frequency of VUS (9%) is similar to the frequency of 13% found by Myriad Genetics’ sequencing of 10,000 individuals (Frank et al. 2002) and suggests that the majority of these variants are not disease associated. It is possible that a subset of the variants is deleterious, but, unfortunately, the significance of an individual missense variant is very difficult to assess. Variants may be evaluated on the basis of segregation with disease in families, population frequency, conservation across species, and predicted functional significance, but these are rarely definitive. We note that 13 of the 22 VUS are 100% conserved between human and mouse (overall amino acid identity between the human and mouse BRCA2 is ∼60%; see table 2). Three of these (I1275M, L1457F, and N1730Y) are within the BRC repeat domain. Two of the VUS found are 100% conserved between human, mouse, and pufferfish (exon 18 D2665G and A2717S). As an illustration of the difficulties in classifying these variants, the Y42C variant detected in our study severely compromises the transcriptional activating function of the BRCA2 protein, on the basis of a yeast functional assay (Milner et al. 1997), suggesting that it may be disease associated. However, the variant has been observed to occur concurrently with other deleterious mutations and not to segregate with disease in families with breast cancer (Myriad Genetics, personal communication), demonstrating that the variant cannot be a high-risk mutation. It is, of course, possible that some of these variants or polymorphisms confer a more moderate risk of PRCA, as has been demonstrated for the N372H polymorphism and breast cancer (Healey et al.2000).

The inconclusive nature of genetic linkage studies in PRCA suggests that the genetics of the disease are highly complex, and therefore, if mutations in other candidate PRCA susceptibility genes exist at frequencies similar to BRCA2, high-throughput mutation screening may be required to identify them. This study has demonstrated that BRCA2 mutations, which are individually rare in the population, are responsible for a significant fraction of early-onset PRCA cases outside of families with multiple cases of breast-ovarian cancer, and therefore, BRCA2 is currently the only high-risk gene for which definitive evidence of susceptibility to PRCA, from multiple studies, is available.

References

    • Antoniou et al., 2002
    • AC Antoniou, PDP Pharoah, G McMullan, NE Day, MR Stratton, J Peto, BJ Ponder, DF Easton
    • A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes
    • Brit J Cancer, 86 (2002), pp. 76–83
    • View Record in Scopus

|

Full Text via CrossRef

|

Citing articles (280)

    • Arason et al., 1993
    • A Arason, RB Barkardottir, V Egilsson
    • Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer
    • Am J Hum Genet, 52 (1993), pp. 711–717
    • View Record in Scopus

|

Citing articles (91)

    • Berthon et al., 1998
    • P Berthon, A Valeri, A Cohen-Akenine, E Drelon, T Paiss, G Wohr, A Latil, et al.
    • Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43
    • Am J Hum Genet, 62 (1998), pp. 1416–1424
    • Article

|

 PDF (287 K)

|

View Record in Scopus

|

Full Text via CrossRef

|

Citing articles (280)

|

Full Text via CrossRef

|

Citing articles (122)

    • Carpten et al., 2002
    • J Carpten, N Nupponen, S Isaacs, R Sood, C Robbins, J Xu, M Faruque, et al.
    • Germline mutations in the ribonuclease L gene in families showing linkage with HPC1
    • Nat Genet, 30 (2002), pp. 181–184
    • View Record in Scopus

|

Full Text via CrossRef

|

Citing articles (346)

    • Connor et al., 1997
    • F Connor, A Smith, R Wooster, M Stratton, A Dixon, E Campbell, TM Tait, T Freeman, A Ashworth
    • Cloning, chromosomal mapping and expression pattern of the mouse Brca2 gene
    • Hum Mol Genet, 6 (1997), pp. 291–300
    • View Record in Scopus

|

Full Text via CrossRef

|

Citing articles (43)

    • Cooney et al., 1996
    • KA Cooney, JC Wetzel, SD Merajver, JA Macoska, TP Singleton, KJ Wojno
    • Distinct regions of allelic loss on 13q in prostate cancer
    • Cancer Res, 56 (1996), pp. 1142–1145
    • View Record in Scopus

|

Citing articles (122)

    • Edwards et al., 1997
    • SM Edwards, DP Dearnaley, A Ardern-Jones, RA Hamoudi, DF Easton, D Ford, R Shearer, A Dowe, RA Eeles
    • No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group
    • Br J Cancer, 76 (1997), pp. 992–1000
    • View Record in Scopus

|

Full Text via CrossRef

|

Citing articles (22)

    • Edwards et al., 1998
    • SM Edwards, WD Dunsmuir, CE Gillett, SR Lakhani, C Corbishley, M Young, RS Kirby, DP Dearnaley, A Dowe, A Ardern-Jones, J Kelly, N Spurr, DM Barnes, RA Eeles
    • Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer. CRC/BPG UK Familial Prostate Cancer Study Collaborators
    • Int J Cancer, 78 (1998), pp. 1–7
    • View Record in Scopus

|

Full Text via CrossRef

|

Citing articles (20)

Ovarian Cancer

http://www.cancernetwork.com/ovarian-cancer

ntraoperative Hyperthermic Intraperitoneal Chemotherapy in Patients With Advanced Ovarian Cancer
Review Article | September 15, 2015 | Oncology Journal, Gynecologic Cancers, Ovarian Cancer
By Anton Oseledchyk, MD and Oliver Zivanovic, MD, PhD
Reviews
Clinical Trials of Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: Unanswered Questions
The Legacy of Intraperitoneal Therapy in Ovarian Cancer: Why Are We Never Satisfied With the Answer

Table. Ongoing Prospective Clinical Trials Evaluating the Role of HIPE…
Ovarian cancer, because it is largely confined to the peritoneal cavity, has a unique tumor biology and metastatic spread pattern. Its metastatic potential comes from detached tumor cells in the peritoneal cavity that re-attach to the mesothelial lining of the peritoneal surface. It is proposed that these micrometastases without neovasculature, as well as floating malignant cells, are drivers of early recurrence, since they can be neither resected nor adequately treated by systemic chemotherapy. This represents the major rationale for local treatment by means of postoperative intraperitoneal (IP) chemotherapy, which is the standard of care in the United States in patients with advanced-stage ovarian cancer who have minimal residual disease following cytoreductive surgery. An alternative loco-regional treatment strategy is the “HIPEC” procedure—hyperthermic IP chemoperfusion that is performed during the operation immediately following completion of gross tumor resection, and which provides improved tissue penetration and distribution of the chemotherapeutics. However, prospective data are limited and an outcomes benefit has yet to be shown. Here we discuss the advantages and pitfalls of HIPEC, as well as current data and ongoing prospective trials.

Introduction
Ovarian cancer causes more deaths than any other gynecologic malignancy, accounting for 14,180 deaths in the United States annually, and with a prevalence of 21,290 new cases estimated for 2015.[1] Cure rates vary between 20% and 30%, with most patients experiencing recurrence of their disease within the first 3 years. The reason for the poor prognosis is that the majority of patients (60% to 70%) present at an advanced stage (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV).[2,3] Beyond stage, histology, and grade, a high prognostic value is attributed to the amount of postoperative residual tumor.[4-7] Optimal cytoreduction, defined as residual tumor < 1 cm after surgical debulking, is associated with considerable improvement in overall survival (OS) and progression-free survival (PFS). More recent publications have demonstrated that a complete resection of tumor with only microscopic tumor residuals will improve the prognosis to a median OS of 64 months.[8] The goal of current cytoreductive surgery should therefore be to attempt a complete resection of all visible tumor, and it is preferable that such surgery be performed at centers with high levels of specialization and expertise.[4,9] Even so, and despite improvements in surgical technique, most patients will die from ovarian cancer regardless of their increased disease-free interval, making the improvement of chemotherapy regimens imperative.
Cisplatin’s remarkable activity in ovarian cancer was discovered in the early 1980s, followed by the introduction of the less toxic but equally active second-generation platinum agent carboplatin in the early 1990s. Both agents were predominantly used in combination regimens along with cyclophosphamide or an anthracycline—until the introduction of the taxanes in the late 1990s led to today’s gold standard of chemotherapy that combines carboplatin and paclitaxel in a 3-week cycle.[10]

Biologically, ovarian cancer behaves in a unique way. After undergoing an epithelial-mesenchymal transition, cancer cells simply detach from the main tumor bulk and are carried by the physiologic peritoneal circulation throughout the peritoneal cavity, either as single cells or as multicellular spheroids—something one could call “passive” metastasis.[11] The cells do not undergo several steps of intravasation and extravasation to form metastases as in hematologically spreading tumor types. In fact, ovarian cancer cells seem to selectively invade the mesothelium of the peritoneal surface, forming micrometastases that are adequately supplied solely by means of diffusion until they reach a size of 1 mm2.[12,13] Consequently, because of the lack of vascularization, it is likely that neither micrometastases nor free-floating cancer cells can be addressed adequately by either surgery or systemic chemotherapy. Intraperitoneal (IP) treatment modalities attempt to close this therapeutic gap.

IP Chemotherapy: Rationale
In 1978, Dedrick et al hypothesized that because the peritoneal surface forms a barrier between the peritoneal compartment and the blood compartment, it would be possible for significantly higher concentrations of chemotherapeutic agents to be delivered to the peritoneal cavity, with only limited systemic toxicity[14]; this hypothesis set the stage for the introduction of modern IP treatments. Any drug that shows a high response rate as systemic therapy for ovarian cancer comes under consideration for IP administration. However, there are important pharmacokinetic differences between the different drugs used for IP therapy; these play a role in drug selection and therefore must be mentioned. There is a correlation between molecular size and the ratio of the drug level in the peritoneal cavity to the drug level in plasma. For example, peak paclitaxel concentrations in the peritoneal cavity exceed plasma concentrations by 1,000-fold and persist in the peritoneal cavity for over 24 hours due to the large size of the paclitaxel molecule compared with cisplatin; the latter shows only a 12-fold higher concentration in the peritoneal compartment compared with the concentration in serum.[15] The significantly higher IP drug concentration might reduce the effect of chemotherapy resistance by simply achieving higher intracellular concentrations and, in the case of cisplatin, by overpowering the mechanisms of decreased drug influx that result from loss of copper transporter 1, increased absorption of cisplatin in the cytoplasm by glutathione and metallothionein, increased drug efflux by ATP7A/ATP7B and glutathione S-conjugate export GS-X pumps, improved DNA repair, and insufficient DNA binding.[16]

Most studies of IP chemotherapy in ovarian cancer have involved cisplatin, because of positive results with this agent in murine models and more experience with it as a systemic therapy. However, recent prospective studies were able to demonstrate the feasibility of IP carboplatin application,[17,18] which is an appealing alternative to cisplatin because of its lesser side effects, especially less polyneuropathy and nephrotoxicity.

IP paclitaxel infusion showed dose-limiting toxicity (abdominal pain) at 175 mg/m2 in a phase I trial.[19] Subsequent studies of a weekly IP regimen at 60 mg/m2 showed acceptable toxicity,[20,21] with the result that a phase II trial combining IP cisplatin and IP paclitaxel was performed,[22] demonstrating both feasibility and a high median OS. Because of the positive results, the combination of IP cisplatin and IP paclitaxel was tested as the study arm in the phase III Gynecologic Oncology Group (GOG) 172 trial described further on in detail. It is unclear whether the increased adverse effects of paclitaxel are Cremophor EL–related, since the hydrophobic paclitaxel requires it as a vehicle. It has been shown that Cremophor EL can have biologic effects such as severe anaphylactic hypersensitivity reactions, abnormal lipoprotein patterns, and peripheral neuropathy.[23] The use of water-soluble taxanes, such as docetaxel or the albumin-bound nab-paclitaxel, might prevent these adverse effects in the future.

IP Chemotherapy: Clinical Significance
GOG 104, the first phase III trial to evaluate the role of IP treatment, showed a significant improvement in OS: 49 months in the IP cisplatin treatment group vs 41 months in patients who received intravenous (IV) treatment only.[24] Because the participants in this study were recruited in the pre-paclitaxel era, survival rates were rather low compared with the rates in current adjuvant chemotherapy studies. In the subsequent GOG 114 trial, patients were randomly assigned to receive either 6 cycles of cisplatin and paclitaxel IV therapy or 6 cycles of the combination of paclitaxel IV plus cisplatin IP after 2 previous cycles of carboplatin (area under the curve [AUC], 9),[25] with significant improvement in median PFS (28 months vs 22 months) and close to significant improvement in median OS (63 months vs 52 months) favoring the IP regimen. The most recently published phase III trial, GOG 172, randomly assigned patients—after primary debulking of stage III ovarian, fallopian tube, or peritoneal cancer with postoperative residual tumor < 1 cm—to receive either IV paclitaxel, 135 mg/m2 over 24 hours, on day 1 and IV cisplatin, 75 mg/m2, on day 2, or IV paclitaxel, 135 mg/m2 over 24 hours, on day 1 and IP cisplatin, 100 mg/m2 over 24 hours, on day 2, followed by IP paclitaxel, 60 mg/m2, on day 8 of a 3-week cycle. The investigators showed a significantly increased PFS and OS of 23.8 months vs 18.3 months and 65.5 months vs 49.7 months, respectively, favoring the IP regimen. Based on these results, the National Cancer Institute issued an alert encouraging the incorporation of IP therapy into the care of women with advanced ovarian cancer in the United States.[26]

However, the strong effect of the IP regimens in GOG 114 and GOG 172 may have been due to the higher dosing in the IP treatment arms: 2 additional IV carboplatin cycles as well as a higher IP cisplatin dose in GOG 114; and an additional dose of paclitaxel on day 8 of every cycle in GOG 172, resembling a dose-dense IV regimen. Additionally, 44% of patients in the IP treatment arm of GOG 172 received IV carboplatin and paclitaxel after discontinuing the IP protocol. This IV regimen may have been less toxic and more effective than the IV regimen used in the control arm (paclitaxel on day 1 and cisplatin day 2), which itself does not resemble today’s standard-of-care treatment. Because of these issues and toxicity concerns, as well as an only marginally significant OS benefit in the GOG 172 trial, an opposing statement was published in the Journal of Clinical Oncology in October 2006 advising against IP therapy outside of clinical trials.[27]

Recently, Tewari et al[28] presented an updated long-term survival analysis of GOG 114 and GOG 172, with a median follow-up of 10.7 years. Median OS with IP therapy was 61.8 months, compared with 51.4 months in the IV group, with a reduction in the risk of death of 23%. Additionally, the number of IP cycles revealed itself as an independent prognostic factor: completing all 6 cycles had a statistically significant association with improved OS, whereas completion of fewer than 6 cycles of IP therapy did not. IP therapy also improved the survival of patients with gross residual disease (≤ 1 cm); for this reason, patients with suboptimal debulking have been included in the ongoing GOG 252 trial. GOG 252 compares the following three treatment groups: conventional dose-dense IV chemotherapy, dose-dense IV chemotherapy with IP (instead of IV) carboplatin delivery, and a modified GOG 172 IP protocol. In all treatment arms, patients have received 22 cycles of every-3-weeks bevacizumab, 15 mg/kg. The first results of GOG 252 are anticipated either this year or next.

Challenges Regarding Establishment of IP Chemotherapy as Standard of Care
The major disadvantages of IP chemotherapy are the increased toxicity and the highly complex management of patients and their side effects. In GOG 172, 58% of patients discontinued therapy due to increased hematologic and gastrointestinal toxicity; inadequate hydration or inadequate antiemetic therapy; or port complications, including obstruction, leakage, and infection.[29,30] Additionally, Havrilesky et al, using a Markov state transition model, showed that IP treatment was not cost-effective compared with IV therapy, mainly because of the need for inpatient treatment for the 24-hour delivery of paclitaxel.[31] Both the 24-hour paclitaxel infusion in the GOG 172 protocol and the increased adverse effects of IP chemotherapy have been addressed by a modified GOG 172 outpatient regimen that was developed at Memorial Sloan Kettering Cancer Center (MSKCC) in recent years: IV paclitaxel, 135 mg/m2, infused on day 1 within 3 hours, followed by reduced IP cisplatin (75 mg/m2) and IP paclitaxel (60 mg/m2) on day 8, along with implementation of new potent antiemetic drugs (eg, aprepitant). This approach has been validated in a single-arm phase II study that showed low discontinuation rates[32]: 30 patients (73%) received all 6 cycles of IP chemotherapy and 35 patients (85%) received at least 4 cycles. The greatly reduced toxicity of this regimen is reassuring, given that it is one of the treatment arms of the ongoing GOG 252 trial.

Independent of whether the outpatient protocol will have a comparable efficacy to that of the GOG 172 regimen, IP treatment will still be challenging for healthcare providers due to higher complication rates, the need for additional homecare to ensure adequate IV hydration, longer treatment times, and intensified nurse involvement. These factors remain the major limitations impeding the establishment of IP chemotherapy as the standard of care.

HIPEC: Rationale
In recent years, a new form of IP therapy has emerged for patients with ovarian carcinoma: intraoperative hyperthermic IP chemotherapy (HIPEC). Many investigators are now evaluating and conducting critical discussions of the role and the rationale for this delivery technique, which requires intraoperative perfusion machines, elaborate logistics, and a high degree of organizational effort. It is still unknown whether HIPEC is associated with an improved survival that would justify the effort involved, but there are several potential advantages that make it a promising therapeutic option as part of a multimodality treatment:

• A high volume of chemotherapy can be delivered, and a homogenous distribution can be achieved. This is often not practical in conventional IP therapy, because of abdominal distension and pain, but it is feasible in HIPEC, since the patient is under anesthesia.

• There is no interval between cytoreduction and chemotherapy. The cytotoxic therapy is applied at the time of minimal disease manifestation, and there are no adhesions that might alter the distribution of the drug.

• Hyperthermia has a pharmacokinetic benefit. Several studies have convincingly shown that hyperthermia can increase both the tumor penetration of cisplatin[33] as well as the DNA crosslinking.[34]

• High concentrations of chemotherapy can be achieved in the intraperitoneal compartment with low systemic exposure—in a single intraoperative treatment.

HIPEC: Clinical Significance
HIPEC is already an established treatment alternative in three tumor types, based on some prospective evidence and a large number of retrospective studies: peritoneal carcinomatosis of colorectal cancer, appendiceal cancer (pseudomyxoma peritonei), and malignant peritoneal mesothelioma. Two randomized trials from France and the Netherlands[35,36] have shown a significant improvement in OS with HIPEC in peritoneal dissemination of colorectal cancer—albeit with a major limitation: the control arms in these studies did not resemble the current gold standard of oxaliplatin-based[37,38] or irinotecan-based therapy[39] (FOLFOX [folinic acid, fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, fluorouracil, and irinotecan], respectively). Nevertheless, compared with fluorouracil (5-FU) and folinic acid (leucovorin), HIPEC improved median OS from 10 months to 29 months, especially favoring patients with complete cytoreduction (in whom OS improved from 28 months to 60 months).[40] In pseudomyxoma peritonei, there is evidence of a substantial benefit from HIPEC[41,42]; however, there have been no randomized trials of HIPEC in this entity, and it is unclear whether the improved outcome is attributable to the successful cytoreduction at the highly specialized centers at which studies have been performed or whether it is actually due to the addition of the IP chemotherapy. In malignant peritoneal mesothelioma, HIPEC has been accepted as the first-line treatment, despite the lack of randomized trials. Large retrospective studies have shown improved OS compared with historical controls.[43,44] In all the above studies in various malignancies, a compelling benefit was shown for patients with a complete cytoreduction. Attention must now be focused on the issue of patient selection for this very involved procedure, through the use of objectified tumor volume scores, such as the peritoneal cancer index (PCI).[45]
In recent years, HIPEC has been studied in ovarian cancer; however, due to the lack of randomized trials there are no substantive efficacy data. The largest retrospective study in persistent and recurrent ovarian cancer, by Bakrin et al, described survival and morbidity in 246 patients over a period of 17 years,[46] and showed both acceptable morbidity (12%) and a median OS of 48.9 months. Still, this study has substantial limitations that cannot be ignored: the use of different postoperative treatment regimens over the 17-year time period (1991 to 2008), high complete resection rates of 92% (which are usually not achieved even by leading institutions), and the inclusion of platinum-resistant and platinum-sensitive disease.[47] Despite its weaknesses, the study proves the feasibility of the procedure and encourages prospective randomized trials. At the same time, however, this study demonstrates an unfortunate development in the treatment of ovarian cancer patients: more than 500 patients in this and other smaller retrospective evaluations have been treated with HIPEC outside a prospective study protocol, without control arms and consequently without proof of efficacy, indicating a wide application of a yet immature and not validated treatment modality.

TO PUT THAT INTO CONTEXT

David L. Bartlett, MD
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

The concept of intraperitoneal (IP) chemotherapy for peritoneal metastases makes intuitive sense: it maximizes the concentration of chemotherapy delivered to the tumor cells while minimizing systemic toxicity. Randomized trials have demonstrated a significant and meaningful benefit to IP dwell therapy, but this approach also has significant limitations: technical complexity, pain for the patient, increased toxicity, and limited distribution of the drug due to adhesions after surgery.

WHY HIPEC?
In an attempt to address these limitations, gastrointestinal (GI) surgical oncologists began to use hyperthermic IP chemotherapy (HIPEC) in the early 1990s. This approach has theoretical advantages over IP dwell therapy: it is delivered under general anesthesia at the time of cytoreduction; it utilizes hyperthermia, which has direct cytotoxic effects and which potentiates chemotherapy; and it virtually assures complete distribution of drug throughout the abdominal cavity. What makes sense for GI tumors makes even more sense for ovarian cancer, since the latter is more chemosensitive. This means that a brief exposure to cisplatin and hyperthermia can have dramatic effects.

WHY IS HIPEC STILL CONTROVERSIAL?
After almost 25 years of data, however, the utility of HIPEC is not uniformly accepted, techniques vary, drugs and dosages differ, and we have no idea which aspect of the treatment (cytoreduction, hyperthermia, or chemotherapy) makes it effective.

WHAT DOES THE FUTURE HOLD?
It is exciting to see the results of one randomized trial demonstrating a greater than doubling of median survival in patients with recurrent ovarian cancer. It is even more encouraging to see that seven randomized trials examining HIPEC are ongoing in ovarian cancer. The results of these ongoing trials will help answer important questions regarding the efficacy of HIPEC and the most appropriate indications for its use. The implications for clinical practice will likely be significant.

For this reason, many groups are advising against the use of HIPEC in ovarian cancer patients outside of clinical trials.[48] Two main criticisms are dominating the discussion: OS data are missing, and complication rates are higher than with conventional surgical treatment. Although there is no question that the lack of OS data is a problem, there are convincing studies that refute safety and feasibility concerns regarding this treatment modality. A number of phase I trials were conducted in both primary[49,50] and recurrent disease.[50,51] Severe complications ranged between 15% and 25% and morbidity between 0% and 4.2%. In one of these trials, even heavily pretreated patients with recurrent disease who had already undergone extensive surgery and adjuvant chemotherapy tolerated secondary cytoreductive surgery and HIPEC with low complication rates, no deaths, no delay in the initiation of standard postoperative carboplatin and gemcitabine chemotherapy, and no increased chemotherapy-associated adverse effects.[51] This dose-finding study showed that high IP cisplatin concentrations (100 mg/m2) are feasible in pretreated patients.

Much as with postoperative IP chemotherapy, paclitaxel has only recently been investigated in the setting of HIPEC. With the peritoneal uptake of paclitaxel significantly slower than that of cisplatin,[52] an increased antitumor effect has been shown in vitro.[53] In a single-arm phase I study, the delivery of paclitaxel, 175 mg/m2, in the setting of HIPEC showed acceptable morbidity (38%; minor and major complications), with no postoperative deaths.[54] Ansaloni et al conducted a multi-regimen phase II trial, including 11 patients who received cisplatin and paclitaxel in the setting of HIPEC; however, the authors did not provide complication rates for this specific regimen.[55] A pharmacokinetic evaluation of concurrent cisplatin and paclitaxel in HIPEC indicated that the serum concentration of paclitaxel would be below that associated with the regimen’s dose-limiting toxicity yet would constitute an effective IP concentration.[56]

HIPEC: Randomized Trials
A single-institution randomized phase III trial by Spiliotis et al was recently published that compared conventional cytoreduction in a first recurrence with cytoreduction and HIPEC (with cisplatin, 100 mg/m2, and paclitaxel, 175 mg/m2, in platinum-sensitive disease; and doxorubicin, 35 mg/m2, and paclitaxel, 175 mg/m2, or mitomycin, 15 mg/m2, in platinum-resistant disease).[57] The authors demonstrated a significant improvement in the mean OS: 29.7 months in the HIPEC arm vs 13.4 months in the surgery-only arm (P = .006). Interestingly, patients with platinum-resistant disease showed a stronger improvement in median OS, while still having a significantly impaired OS compared with the OS seen in patients with platinum-sensitive disease. As anticipated, the highest OS was observed in patients with complete cytoreduction who received HIPEC; in addition, the preoperative tumor burden as reflected in the PCI score was described as an independent prognostic factor, with PCI score > 15 associated with a significantly impaired survival. Unfortunately, there are several weaknesses in the presentation of the data that decrease the validity of this first randomized HIPEC trial: There is no information on PFS, the authors do not provide median follow-up data, and the Kaplan-Meier survival curve shows a high number of censored cases. There is no information regarding the postoperative first-line treatment, nor are the complication rates addressed. Also, different regimens were used in patients with platinum-sensitive and platinum-resistant disease.

Currently, there are six open randomized trials (Table) recruiting patients with both primary and recurrent disease, as well as women who have already received 3 cycles of neoadjuvant chemotherapy. The CARCINOHIPEC study has completed recruitment, and the first results are anticipated soon. These studies will certainly provide more useful information about this treatment modality.

HIPEC: Future Outlook
As unclear as the patient outcome benefit may be, HIPEC is highly important as a platform for studying the effect of IP chemotherapy and hyperthermia on cancer cells in vivo. It offers the unique possibility of evaluating macroscopic lesions within the peritoneal cavity during chemoperfusion and then harvesting them after the procedure. The application of gene expression and proteomics to biopsy specimens could shed new light on the escape mechanisms of cancer cells and mechanisms of drug resistance. Pre- and post-perfusion biopsies could facilitate human in vivo studies of either new agents for IP therapy or methods for the improvement of chemotherapy uptake, thereby accelerating the process by which new therapeutics become available for clinical use. Two of the most promising emerging approaches are nanoparticle delivery systems and immunotherapy.

Nanoparticle delivery of paclitaxel and cisplatin has been the subject of recent clinical studies. The chief rationale for nanoparticle-facilitated IP chemotherapy is reduced clearance of the nanoparticle-bound drug from the peritoneal cavity compared with the clearance of a conventional drug in solution, and because of that, a higher peritoneum-to-plasma ratio as well as reduced systemic effects and longer tumor exposure. Especially for the small-molecule and water-soluble drugs cisplatin and carboplatin, reduced peritoneal clearance would result in a higher diffusion gradient and thus enhanced tumor penetration. In a murine model, paclitaxel has been successfully incorporated into nanoparticles,[58] in order to achieve higher tumor selectivity after IP injection and longer retention times. It was combined with yttrium-90 as part of a multimodal treatment.[58] Instead of incorporating paclitaxel into a nanoparticle, a new synthesis technique called precipitation with compressed antisolvent (PCA) allows the production of 800 nm–sized paclitaxel crystals that do not require use of the toxic solvent Cremophor EL; this technique has shown promising results after IP injection in a murine model.[59] A phase I trial was completed and the results are anticipated. Clinical trials of nanoparticle delivery systems for cytotoxic drugs have until now involved predominantly IV injection, with two agents that use this mode of delivery approved by the US Food and Drug Administration: nanoparticle albumin-bound paclitaxel and pegylated liposomal doxorubicin.[60,61] Other nanoparticles incorporating paclitaxel[62] or platinum polymers[63] for IV injection are under clinical investigation. A phase III noninferiority trial of a novel water-soluble formulation of paclitaxel and XR-17 (paclical) has been completed and was presented at the 2015 American Society of Clinical Oncology Annual Meeting.[64] The trial showed comparable rates of adverse effects and PFS; however, contrary to expectations, Cremophor EL–related adverse effects, such as neuropathy and allergic reactions, were not significantly reduced. Paclical has been approved for use in the Russian Federation, but approvals in the United States and the European Union are still pending.

In addition to their use for the delivery of cytotoxic agents, nanoparticles can be utilized to encapsulate other substances that are unstable in serum or ascites, releasing agents such as small interfering RNAs (siRNAs) into the cell cytoplasm of cancer cells.[65] siRNAs can silence overexpressed genes and reduce tumor growth and invasion, with low toxicity. The use of nanoparticles to deliver siRNAs has recently been shown to be applicable to humans.[66] Major targets for siRNAs in ovarian cancer are the genes encoding folate receptor, follicle-stimulating hormone receptor, luteinizing hormone–releasing hormone receptor, mucin 1, and epidermal growth factor receptor.[67]

Another new approach is IP immunotherapy, which involves the delivery of programmed T cells. Since Zhang et al showed that tumor infiltration with CD8-positive lymphocytes is associated with improved 5-year survival in epithelial ovarian cancer,[68] several attempts have been made to modify the T-cell response.[69] This can be achieved either by harvesting cells, reprogramming them in vitro, and then reintroducing the cells via autologous injection,[70,71] or by stimulating T-cell activation in vivo.[72] There are several ongoing phase I trials, but the efficacy as well as the relevance of IP applications are unclear.

Conclusion
The rationale for HIPEC as part of a multimodal treatment in patients with advanced ovarian cancer is strong. Given that hyperthermia enhances tumor penetration and the cytotoxic effects of chemotherapy, recent improvements in drug distribution and in patient monitoring in the operating room, as well as encouraging results in nonrandomized trials, justify further investigation of HIPEC in randomized clinical trials. The possibility of easily acquiring pre- and post-treatment biopsies in the course of the procedure also makes HIPEC an excellent setting for human in vivo studies of antitumor effects and pharmacodynamics.

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.

2. Kaatsch P, Spix C, Hentschel S, et al. Krebs in Deutschland 2009/2010 – 9. Ausgabe, 2013. http://www.rki.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2013/krebs_in_deutschland_2013.pdf?__blob=publicationFile. Accessed August 19, 2015.

3. National Cancer Institute. Howlader N, Noone A, Krapcho M, et al, editors. SEER cancer statistics review, 1975-2012. http://seer.cancer.gov/CSR/1975_2012. Accessed August 26, 2015.

4. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248-59.

5. Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol. 2006;103:559-64.

6. Winter WE 3rd, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:3621-7.

7. Eisenkop S, Friedman R, Wang H. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol. 1998;69:103-8.

8. Winter WE 3rd, Maxwell GL, Tian C, et al. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2008;26:83-9.

9. Giede KC, Kieser K, Dodge J, Rosen B. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol. 2005;99:447-61.

10. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:3194-200.

11. Lengyel E. Ovarian cancer development and metastasis. Am J Pathol. 2010;177:1053-64.

12. Bamberger ES, Perrett CW. Angiogenesis in epithelian ovarian cancer. Mol Pathol. 2002;55:348-59.

13. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82:4-6.

14. Dedrick RL. Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol. 1985;12:1-6.

15. Fujiwara K, Armstrong D, Morgan M, Markman M. Principles and practice of intraperitoneal chemotherapy for ovarian cancer. Int J Gynecol Cancer. 2007;17:1-20.

16. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7:573-84.

17. Speyer JL, Sorich J. Intraperitoneal carboplatin: rationale and experience. Semin Oncol. 1992;19:107-13.

18. Gould N, Sill MW, Mannel RS, et al. A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol. 2012;125:54-8.

19. Markman M, Rowinsky E, Hakes T, et al. Phase I trial of intraperitoneal Taxol: a Gynecoloic Oncology Group study. J Clin Oncol. 1992;10:1485-91.

20. Francis P, Rowinsky E, Schneider J, et al. Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: a Gynecologic Oncology Group pilot study. J Clin Oncol. 1995;13:2961-7.

21. Markman M, Brady MF, Spirtos NM, et al. Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group study. J Clin Oncol. 1998;16:2620-4.

22. Rothenberg ML, Liu PY, Braly PS, et al. Combined intraperitoneal and intravenous chemotherapy for women with optimally debulked ovarian cancer: results from an intergroup phase II trial. J Clin Oncol. 2003;21:1313-9.

23. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590-8.

24. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-5.

25. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-7.

http://www.cancernetwork.com/ovarian-cancer/intraoperative-hyperthermic-intraperitoneal-chemotherapy-patients-advanced-ovarian-cancer/page/0/2#sthash.BXrIb0IV.dpuf

http://www.cancernetwork.com/ovarian-cancer/intraoperative-hyperthermic-intraperitoneal-chemotherapy-patients-advanced-ovarian-cancer#sthash.X82WGYEZ.dpuf

SJ Williams

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Larry H Bernstein, MD, Reporter

Leaders in Pharmaceutical Intelligence

Lasker~Koshland
Special Achievement Award in Medical Science

Award Description

Mary-Claire King
For bold, imaginative, and diverse contributions to medical science and human rights — she discovered the BRCA1 gene locus that causes hereditary breast cancer and deployed DNA strategies that reunite missing persons or their remains with their families.

The 2014 Lasker~Koshland Award for Special Achievement in Medical Science honors a scientist who has made bold, imaginative, and diverse contributions to medical science and human rights. Mary-Claire King(University of Washington, Seattle) discovered the BRCA1 gene locus that causes hereditary breast cancer and deployed DNA strategies that reunite missing persons or their remains with their families. Her work has touched families around the world.

As a statistics graduate student in the late 1960s, King took the late Curt Stern’s genetics course just for fun. The puzzles she encountered there—problems posed by Stern—enchanted her. She was delighted to learn that people could be paid to solve such problems, and that mathematics holds their key. She decided to study genetics and never looked back.

During her Ph.D. work with the late Allan Wilson (University of California, Berkeley), King discovered that the sequences of human and chimpanzee proteins are, on average, more than 99 percent identical; DNA sequences that do not code for proteins differ only a little more. The two primates therefore are much closer cousins than suggested by fossil studies of the time. The genetic resemblance seemed to contradict obvious distinctions: Human brains outsize those of chimps; their limbs dwarf ours; and modes of communication, food gathering, and other lifestyle features diverge dramatically. King and Wilson proposed that these contrasts arise not from disparities in DNA sequences that encode proteins, but from a small number of differences in DNA sequences that turn the protein-coding genes on and off.

Just as genetic changes drive species in new directions, they also can propel cells toward malignancy. From an evolutionary perspective, the topic of breast cancer began to intrigue King. The illness runs in families and is clearly inherited, yet many affected women have no close relatives with the disease. It is especially deadly for women whose mothers succumbed to it—and risk increases for those who have a mother or sister with breast cancer, particularly if the cancer struck bilaterally or before menopause. Unlike the situation with lung cancer, no environmental exposure distinguishes sisters who get breast cancer from those who remain disease free.

By studying a rare familial cancer, Alfred Knudsen (Lasker Clinical Medical Research Award, 1998) had shown in the early 1970’s how an inherited genetic defect could increase vulnerability to cancer. In the model he advanced, some families harbor a damaged version of a gene that normally encourages proper cellular behavior. Genetic mishaps occur during a person’s lifetime, and a second “hit” in a cell with the first physiological liability nudges the injured cell toward malignancy. A similar story might play out in families with a high incidence of breast cancer, King reasoned. She began to hunt for the theoretical pernicious gene in 1974.

2014_illustration_special
The hunt
Many geneticists doubted that susceptibility to breast cancer would map to a single gene; even if it did, finding the culprit seemed unlikely for numerous reasons. First, most cases are not familial and the disease is common—so common that inherited and non-inherited cases could occur in the same families. Furthermore, the malady might not strike all women who carry a high-risk gene, and different families might carry different high-risk genes. Prevailing views held that the ailment arises from the additive effects of multiple undefined genetic and environmental insults and from complicated interactions among them. No one had previously tacked such complexities, and an attempt to unearth a breast cancer gene seemed woefully naïve.

To test whether she could find evidence that particular genes increase the odds of getting breast cancer, King applied mathematical methods to data from more than 1500 families of women younger than 55 years old with newly diagnosed breast cancer. The analysis, published in 1988, suggested that four percent of the families carry a single gene that predisposes individuals to the illness.

The most convincing way to validate this idea was to track down the gene. Toward this end, King analyzed DNA from 329 participating relatives with 146 cases of invasive breast cancer. In many of the 23 families to which the participants belonged, the scourge struck young women, often in both breasts, and in some families, even men.

In late 1990, King (by then a professor at the University of California, Berkeley) hit her quarry. She had zeroed in on a suspicious section of chromosome 17 that carried particular genetic markers in women with breast cancer in the most severely affected families. Somewhere in that stretch of DNA lay the gene, which she named BRCA1.

This discovery spurred an international race to find the gene. Four years later, scientists at Myriad Genetics, Inc. isolated it. Alterations in either BRCA1 or a second breast-cancer susceptibility gene, BRCA2, found by Michael Stratton and colleagues (Institute of Cancer Research, UK) increase risk of ovarian as well as breast cancer. The proteins encoded by these genes help maintain cellular health by repairing marred DNA. When theBRCA1 or BRCA2 proteins fail to perform their jobs, genetic integrity is compromised, thus setting the stage for cancer.

About 12 percent of women in the general population get breast cancer at some point in their lives. In contrast, 65 percent of women who inherit an abnormal version of BRCA1 and about 45 percent of women who inherit an abnormal version of BRCA2 develop breast cancer by the time they are 70 years old. Individuals with troublesome forms of BRCA1 and BRCA2 can now be identified, monitored, counseled, and treated appropriately.

Harmful versions of other genes also predispose women to breast cancer, ovarian cancer, or both. Several years ago, King devised a scheme to screen for all of these genetic miscreants. This strategy allows genetic testing and risk determination for breast and ovarian cancer; it is already in clinical practice.

Genetic tools, human rights
King has applied her expertise to aid people who suffer from ills perpetrated by humans as well as genes. She helped find the “lost children” of Argentina—those who had been kidnapped as infants or born while their mothers were in prison during the military regime of the late 1970s and early 1980s. Some of these youngsters had been illegally adopted, many by military families. In 1983, King began identifying individuals, first with a technique that was originally designed to match potential organ transplant donors and recipients. She then developed an approach that relies on analysis of DNA from mitochondria—a cellular component that passes specifically from mother to child, and is powerful for connecting people to their female forebears. King helped prove genetic relationships and thus facilitated the reunion of more than 100 of the children with their families.

Later, the Argentinian government asked if she could help identify dead bodies of individuals thought to have been murdered. King harnessed the same method to figure out who had been buried in mass graves. She established that teeth, whose enamel coating protects DNA in the dental pulp from degradation, offer a valuable resource when attempting to trace remains in situations where long periods have elapsed since the time of death.

This and related approaches have been used to identify soldiers who went missing in action, including the remains of an American serviceman who was buried beneath the Tomb of the Unknowns in Arlington National Cemetery for 14 years, as well as victims of natural disasters and man-made tragedies such as 9/11.

Mary-Claire King has employed her intellect, dedication, and ethical sensibilities to generate knowledge that has catalyzed profound changes in health care, and she has applied her expertise to promote justice where nefarious governments have terrorized their citizens.

by Evelyn Strauss

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Good and Bad News Reported for Ovarian Cancer Therapy

Reporter, Curator: Stephen J. Williams, Ph.D.

 

In a recent Fierce Biotech report

FDA review red-flags AstraZeneca’s case for ovarian cancer drug olaparib”,

John Carroll reports on a disappointing ruling by the FDA on AstraZeneca’s PARP1 inhibitor olaparib for maintenance therapy in women with cisplatin refractory ovarian cancer with BRCA mutation.   Early clinical investigations had pointed to efficacy of PARP inhibitors in ovarian tumors carrying the BRCA mutation. The scientific rationale for using PARP1 inhibitors in BRCA1/2 deficiency was quite clear:

  1. DNA damage can result in

1. double strand breaks (DSB)

  1.  DSB can be repaired by efficient homologous recombination (HR) or less efficient non-homologous end joining (NHEJ)

b. BRCA1 involved in RAD51 dependent HR at DSB sites

  1. In BRCA1 deficiency DSB repaired by less efficient NHEJ

 

 

2. single strand breaks, damage (SSB)

  1. PARP1 is activated by DNA damage and poly-ADP ribosylates histones and other proteins marking DNA for SSB repair
  2. SSB repair usually base excision (BER) or sometimes nucleotide excision repair (NER)

B. if PARP inhibited then SSB gets converted to DSB

C. in BRCA1/2 deficient background repair is forced to less efficient NHEJ thereby perpetuating some DNA damage pon exposure to DNA damaging agent

 

A good review explaining the pharmacology behind the rationale of PARP inhibitors in BRCA deficient breast and ovarian cancer is given by Drs. Christina Annunziata and Susan E. Bates in PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

(http://f1000.com/prime/reports/b/2/10/) and below a nice figure from their paper:

 

parpbrcadnadamage

 

 

 

 

 

 

 

(from Christina M Annunziata and Susan E Bates. PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer.  F1000 Biol Reports, 2010; 2:10.)  Creative Commons

Dr. Sudipta Saha’s post BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair discusses how BRCA1 affects the double strand DNA repair process, augments histone modification, as well as affecting expression of DNA repair genes.

Dana Farber’s Dr. Ralph Scully, Ph.D., in Exploiting DNA Repair Targets in Breast Cancer (http://www.dfhcc.harvard.edu/news/news/article/5402/), explains his research investigating why multiple DNA repair pathways may have to be targeted with PARP therapy concurrent with BRCA1 deficiency.

 

However FDA investigators voiced their skepticism of AstraZeneca’s clinical results, namely

  • Small number of patients enrolled
  • BRCA1/2 cohort were identified retrospectively
  • results skewed by false benefit from “underperforming” control arm
  • possible inadvertent selection bias
  • hazard ratio suggesting improvement in progression free survival but higher risk/benefit

The FDA investigators released their report two days before an expert panel would be releasing their own report (reported in the link below from FierceBiotech)

UPDATED: FDA experts spurn AstraZeneca’s pitch for ovarian cancer drug olaparib

in which the expert panel reiterated the findings of the FDA investigators.   The expert panel’s job was to find if there was any clinical benefit for continuing consideration of olaparib, basically stating

“This trial has problems,” noted FDA cancer chief Richard Pazdur during the panel discussion. If investigators had “pristine evidence of a 7-month advantage in PFS, we wouldn’t be here.”

The expert panel was concerned for the above reasons as well as the reported handful of lethal cases of myelodysplastic syndrome and acute myeloid leukemia in the study, although the panel noted these patients had advanced disease before entering the trial, raising the possibility that prior drugs may have triggered their deaths.

 

This was certainly a disappointment as ….

it was at last year’s ASCO (2013) that investigators at Perelman School of Medicine at the University of Pennsylvania and Sheba Medical Center in Tel Hashomer, Israel presented data showing that in 193 cisplatin-refractory ovarian cancer patients carrying a BRCA1/2 mutation, 31% had a partial or complete tumor regression. In addition the study also showed good response in pancreatic and prostate cancer with tolerable side effects.

 

See here for study details: http://www.uphs.upenn.edu/news/News_Releases/2013/05/domchek/

 

As John Carrol from FierceBiotech notes, the decision may spark renewed interest by Pfizer of a bid for AstraZeneca as the potential FDA rejection would certainly dampen AstraZeneca’s future growth and profit plans. Last month AstraZeneca’s CEO made the case to shareholders to reject the Pfizer offer by pointing to AstraZeneca’s potential beefed-up pipeline. AstraZeneca had projected olaparib as a potential $2 billion-a-year seller, although some industry analysts see sales at less than half that amount.

A company spokeswoman said the monotherapy use of olaparib for ovarian cancer assessed by the U.S. expert panel this week was only one element of a broad development program.

 

 

Please see a table of current oncology clinical trials with PARP1 inhibitors

at end of this post

 

However, on the same day, FierceBiotechreports some great news (at least in Europe) on the ovarian cancer front:

 

EU backs Roche’s Avastin for hard-to-treat ovarian cancer

As Arlene Weintraub   of FierceBiotech reports:

EU Committee for Medicinal Products for Human Use (CHMP) handed down a positive ruling on Avastin, recommending that the European Commission approve the drug for use in women with ovarian cancer that’s resistant to platinum-based chemotherapy. It’s the first biologic to receive a positive opinion from the CHMP for this hard-to-treat form of the disease.

Please see here for official press release: CHMP recommends EU approval of Roche’s Avastin for platinum-resistant recurrent ovarian cancer

 

EU had been getting pressure from British doctors to approve Avastin based on clinical trial results although it may be important to note that the EU zone seems to have an ability to recruit more numbers for clinical trials than in US. For instance an EU women’s breast cancer prevention trial had heavy recruitment in what would be considered a short time frame compared to recruitment times for the US.

 

Below is a table on PARP1 inhibitors in current clinical trials (obtained from NewMedicine’s Oncology KnowledgeBase™). nm|OK is a relational knowledgeBASE covering all major aspects of product development in oncolology. The database comprises 6 modules each dedicated in a specific sector within the oncology field.

 

PARP1 Inhibitors Currently in Clinical Trials for Ovarian Cancer

 

Developer and

Drug Name

Development Status & Location
– Indications
AbbVie

Current as of: March 27, 2014

PARP inhibitor: ABT-767

Phase I (begin 5/11, ongoing 2/14) Europe (Netherlands) – solid tumors with BRCA1 or BRCA2 mutations, locally advanced or metastatic • ovarian cancer, advanced or metastatic • fallopian tube cancer, advanced or metastatic • peritoneal cancer, advanced or metastatic
AstraZeneca
Affiliate(s):
· Myriad GeneticsCurrent as of: June 26, 2014Generic Name: Olaparib
Brand Name: Lynparza
Other Designation: AZD2281, KU59436, KU-0059436, NSC 747856
Phase I (begin 7/05, closed 9/08) Europe (Netherlands, UK, Poland); phase II (begin 6/07, closed 2/08, completed 5/09) USA, Australia, Europe (Germany, Spain, Sweden, UK), phase II (begin 7/08, closed 2/09) USA, Australia, Europe (Belgium, Germany, Poland, Spain, UK), Israel, phase II (begin 8/08, closed 12/09, completed 3/13) USA, Australia, Canada, Europe (Belgium, France, Germany, Poland, Romania, Spain, Ukraine, UK), Israel, Russia; phase II (begin 2/10, closed 7/10) USA, Australia, Canada, Europe (Belgium, Czech Republic, Germany, Italy, Netherlands, Spain, UK), Japan, Panama, Peru (combination); MAA (accepted 9/13) EU, NDA (filed 2/14) USA – ovarian cancer, advanced or metastatic, BRCA positive • ovarian cancer, recurrent, platinum sensitive • ovarian cancer, advanced, refractory, BRCA1 or BRCA2-associatedPhase I (begin 5/08, ongoing 5/12) USA; phase II (begin 7/08, closed 10/09) Canada – breast cancer, locally advanced, BRCA1/BRCA2-associated or hereditary metastatic or inoperable • ovarian cancer, locally advanced, BRCA1/BRCA2-associated or hereditary metastatic or inoperable • breast cancer, triple-negative, BRCA-positive • ovarian cancer, high-grade serous and/or undifferentiated, BRCA-positive

Phase I (begin 10/10, ongoing 1/13) USA (combination) – ovarian cancer, inoperable or metastatic, refractory • breast cancer, inoperable or metastatic, refractory

Phase III (begin 8/13) USA, Australia, Brazil, Canada, Europe (France, Italy, Netherlands, Poland, Russia, Spain, UK), Israel, South Korea, phase III (begin 9/13) USA, Australia, Brazil, Canada, Europe (France, Germany, Italy, Netherlands, Poland, Russia, Spain, UK), Israel – ovarian cancer, serous, high grade, BRCA mutated, platinum-sensitive, relapsed, third line, maintenance • ovarian cancer, serous or endometrioid, high grade, BRCA mutated, platinum responsive (PR or CR), maintenance, first line • primary peritoneal cancer, high grade, BRCA mutated, platinum responsive (PR or CR), maintenance • fallopian tube cancer, high grade, BRCA mutated, platinum responsive (PR or

BioMarin Pharmaceutical

Current as of: June 14, 2014

PARP inhibitor:

BMN-673, BMN673, LT-673

Phase I/II (begin 1/11, ongoing 3/14) USA – solid tumors, advanced, recurrent

Phase I (begin 2/13, closed 4/13, completed 5/14) USA – healthy volunteers

Phase I/II (begin 11/13) USA – solid tumors, relapsed or refractory, BRCA mutated, second line

BiPar Sciences

Current as of: April 16, 2009

Parp inhibitor:

BSI-401

Preclin (ongoing 4/09) – solid tumors
Clovis Oncology
Affiliate(s):
· University of Newcastle Upon Tyne
· Cancer Research Campaign Technology
· PfizerCurrent as of: June 21, 2014Generic Name: Rucaparib
Brand Name: Rucapanc
Other Designation: AG140699, AG014699, AG-14,699, AG-14669, AG14699, AG140361, AG-14361, AG-014699, CO-338, PF-01367338
Phase I (begin 03, completed 05) Europe (UK) (combination), phase I (begin 2/10, closed 11/13) Europe (France, UK) (combination) – solid tumors, advanced

Phase II (begin 12/07, closed 10/13) Europe (UK) – breast cancer, advanced or metastatic, in patients carrying BRCA1 or BRCA2 mutations • ovarian cancer, advanced or metastatic, in patients carrying BRCA1 or BRCA2 mutations

Phase I/II (begin 11/11, ongoing 6/14) USA, Europe (UK) – solid tumors, metastatic, with mutated BRCA • breast cancer, metastatic, HEr2 negative, with mutated BRCA

Sanofi

Current as of: June 03, 2013

Generic Name: Iniparib
Brand Name: Tivolza
Other Designation: BSI-201, NSC 746045, SAR240550

Phase I/Ib (begin 3/06, closed 3/10) USA (combination), phase I (begin 7/10, closed 11/10) USA, phase I (begin 9/10, ongoing 2/11) Japan (combination); phase Ib (begin 1/07, ongoing 1/11) USA (combination) – solid tumors, advanced, refractory
Phase II (begin 5/08, closed 1/09) USA – ovarian cancer, advanced, refractory, BRCA-1 or BRCA-2 associated • fallopian tube cancer, advanced, refractory, BRCA-1 or BRCA-2 associated • peritoneal cancer, advanced, refractory, BRCA-1 or BRCA-2 associated
Tesaro
Affiliate(s):
· MerckCurrent as of: May 18, 2014Generic Name: Niraparib
Other Designation: MK-4827, MK4827
Phase I (begin 9/08, closed 2/11) USA, Europe (UK) – solid tumors, locally advanced or metastatic • ovarian cancer, locally advanced or metastatic, BRCA mutant • chronic lymphocytic leukemia (CLL), relapsed or refractory • prolymphocytic leukemia, T cell, relapsed or refractory
Phase Ib (begin 11/10, closed 3/11, terminated 10/12) USA (combination) – solid tumors, locally advanced or metastatic • ovarian cancer, serous, high grade, platinum resistant or refractoryPhase III (begin 5/13, ongoing 5/14) USA – ovarian cancer, platinum-sensitive, high grade serous or BRCA mutant, chemotherapy responsive • fallopian tube cancer • primary peritoneal cancer
Teva Pharmaceutical Industries

Current as of: May 04, 2013

Designation:

CEP-9722

Phase I (begin 5/11, closed 11/12, terminated 10/13) USA, phase I (begin 6/09, closed 7/12, completed 1/12) Europe (France and UK) (combination) – solid tumors, advanced, third line
Phase I (begin 5/11, completed 1/13) Europe (France) (combination) – solid tumors, advanced • mantle cell lymphoma (MCL), advanced

 

 

Summary of Combination Ovarian Cancer Trials with Avastin (current and closed)

 

Indication in Development ovarian cancer, advanced, recurrent, persistent • ovarian cancer, progressive, platinum resistant, second line • fallopian tube cancer, progressive, platinum resistant, second line • primary peritoneal cancer, progressive, platinum resistant, second line
Latest Status Phase II (begin 4/02, closed 8/04) USA, phase II (begin 11/04, closed 10/05) USA; phase III (begin 10/09) Europe (Belgium, Bosnia and Herzegovina, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, Sweden), Turkey
Clinical History Refer to the Combination Trial Module for trials of Avastin in combination with various chemotherapeutic regimens.According to results from the AURELIA clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911), the median PFS in women with progressive platinum resistant ovarian, fallopian tube or primary peritoneal cancer treated with Avastin in combination with chemotherapy, was 6.7 months compared to 3.4 months in those treated with chemotherapy alone for an HR of 0.48 (range =0.38–0.60).. In addition, the objective response rate was 30.9% in women treated with Avastin compared to 12.6% in those on chemotherapy (p=0.001). Certain AE (Grade 2 to 5) that occurred more often in the Avastin arm compared to the chemotherapy alone arm were high blood pressure (20% versus 7%) and an excess of protein in the urine (11% versus 1%). Gastrointestinal perforations and fistulas occurred in 2% of women in the Avastin arm compared to no events in the chemotherapy arm (Pujade-Lauraine E, etal, ASCO12, Abs. LBA5002).A multicenter (n=124), randomized, open label, 2-arm, phase III clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911; http://clinicaltrials.gov/ct2/results?term=NCT00976911 ), dubbed AURELIA, was initiated in October 2009, in Europe (Belgium, Bosnia and Herzegovina, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, and Sweden), and Turkey, to evaluate the efficacy and safety of Avastin added to chemotherapy versus chemotherapy alone in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer with disease progression within 6 months of platinum therapy in the first line setting. The trials primary outcome measure is PFS. Secondary outcome measures include objective response rate, biological PFS interval, OS, QoL, and safety and tolerability. According to the protocol, all patients are treated with standard chemotherapy with IV paclitaxel (80 mg/m²) on days 1, 8, 15 and 22 of each 4-week cycle; or IV topotecan at a dose of 4 mg/m² on days 1, 8 and 15 of each 4-week cycle, or 1.25 mg/kg on days 1-5 of each 3-week cycle; or IV liposomal doxorubicin (40 mg/m²) every 4 weeks. Patients (n=179) randomized to arm 2 of the trial are treated with IV Avastin at a dose of 10 mg/kg twice weekly or 15 mg/kg thrice weekly concomitantly with the chemotherapy choice. Treatment continues until disease progression. Subsequently, patients are treated with the standard of care. Patients in arm 1 (n=182), on chemotherapy only may opt to be treated with IV Avastin (15 mg/kg) three times weekly. The trial was set up in cooperation with the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) and was conducted by the international network of the Gynecologic Cancer Intergroup (GCIG) and the pan-European Network of Gynaecological Oncological Trial Groups (ENGOT), under PI Eric Pujade-Lauraine, MD, Hopitaux Universitaires, Paris Centre, Hôpital Hôtel-Dieu (Paris, France). The trial enrolled 361 patients and was closed as of May 2012..Results were presented from a phase II clinical trial (protocol ID: CDR0000068839; GOG-0170D; NCT00022659) of bevacizumab in patients with persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer that was performed by the Gynecologic Oncology Group to determine the ORR, PFS, and toxicity for this treatment. Patients must have been administered 1-2 prior cytotoxic regimens. Treatment consisted of bevacizumab (15 mg/kg) IV every 3 weeks until disease progression or prohibitive toxicity. Between April 2002 and August 2004, 64 patients were enrolled, of which 2 were excluded for wrong primary and borderline histology and 62 were evaluable (1 previous regimen=23, 2 previous regimens=39). The median disease free interval from completion of primary cytotoxic chemotherapy to first recurrence was 6.5 months. Early results demonstrated that some patients had confirmed objective responses and PFS in some was at least 6 months. Observed Grade 3 or 4 toxicities included allergy (Grade 3=1), cardiovascular (Grade 3=4; Grade 4=1), gastrointestinal (Grade 3=3), hepatic (Grade 3=1), pain (Grade 3=2), and pulmonary (Grade 4=1). As of 11/04, 36 patients were removed from the trial, including 29 for disease progression and 1 for toxicity in 33 cases reported. Preliminary evidence exists for objective responses to bevacizumab (Burger R, et al, ASCO05, Abs. 5009).An open label, single arm, 2-stage, phase II clinical trial (protocol ID: AVF2949g, NCT00097019) of bevacizumab in patients with platinum resistant, advanced (Stage III or IV), ovarian cancer or primary peritoneal cancer for whom subsequent doxorubicin or topotecan therapy also has failed was initiated in November 2004 at multiple locations in the USA to determine the safety and efficacy for this treatment.A multicenter phase II clinical trial was initiated in April 2002 to determine the 6-month PFS of patients with persistent or recurrent ovarian epithelial or primary peritoneal cancer treated with bevacizumab (protocol ID: GOG-0170D, CDR0000068839, NCT00022659). IV bevacizumab is administered over 30-90 minutes on day 1. Treatment is repeated every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. A total of 22-60 patients will be accrued within 12-30 months. Robert A. Burger, MD, of Chao Family Comprehensive Cancer Center is Trial Chair.This trial was closed in August 2004.

 

 

Sources

http://www.fiercebiotech.com/story/fda-review-red-flags-astrazenecas-case-ovarian-cancer-drug-olaparib/2014-06-23

 

http://www.fiercebiotech.com/story/fda-experts-spurn-astrazenecas-pitch-ovarian-cancer-drug-olaparib/2014-06-25

 

http://www.fiercepharma.com/story/eu-backs-roches-avastin-hard-treat-ovarian-cancer/2014-06-27

 

In a followup to this original posting A Report From the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine entitled

Evolving Approaches in Research and Care for Ovarian Cancers

was generated in a ViewPoint piece in JAMA which discussed their Congressional mandated report on the State of the Science in Ovarian Cancer Research, titled

Ovarian Cancers: Evolving Paradigms in Research and Care 

highlights some of the research gaps felt by the committee in the current state of ovarian cancer research including:

  • consideration in research protocols of the multitude of histologic and morphologic subtypes of ovarian cancer, including the feeling of the committee that high grade serous OVCA originates from the distal end of the fallopian tube (espoused by Dr. Doubeau and Dr. Christopher Crum) versus originating from the ovarian surface epithelium
  • a call for expanded screening and prevention research with mutimodal screening including CA125 with secondary transvaginal screen
  • better patient education of the risk/benefit of genetic testing including BRCA1/2 as well as in consideration for PARP inhibitor therapy
  • treatments should be standardized and disseminated including more research in health outcomes and decision support for personalized therapy

This Perspective article can be found here: jvp160038

Some other posts relating to OVARIAN CANCER on this site include

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Ultrasound-based Screening for Ovarian Cancer

Dasatinib in Combination With Other Drugs for Advanced, Recurrent Ovarian Cancer

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

 

Read Full Post »


Good and Bad News Reported for Ovarian Cancer Therapy

Reporter, Curator: Stephen J. Williams, Ph.D.

 

In a recent Fierce Biotech report

FDA review red-flags AstraZeneca’s case for ovarian cancer drug olaparib”,

John Carroll reports on a disappointing ruling by the FDA on AstraZeneca’s PARP inhibitor olaparib for maintenance therapy in women with cisplatin refractory ovarian cancer with BRCA mutation.   Early clinical investigations had pointed to efficacy of PARP inhibitors in ovarian tumors carrying the BRCA mutation. The scientific rationale was quite clear:

A good review explaining the pharmacology behind the rationale of PARP inhibitors in BRCA deficient breast and ovarian cancer is given by Drs. Christina Annunziata and Susan E, Bates in PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

(http://f1000.com/prime/reports/b/2/10/)

 

Dr. Sudipta Saha’s postBRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair discusses how BRCA1 affects the double strand DNA repair process, augments histone modification, as well as affecting expression of DNA repair genes.

Dana Farber’s Dr. Ralph Scully, Ph.D., in Exploiting DNA Repair Targets in Breast Cancer (http://www.dfhcc.harvard.edu/news/news/article/5402/), explains his research investigating why multiple DNA repair pathways may have to be targeted with PARP therapy concurrent with BRCA1 deficiency.

 

 

However FDA investigators voiced their skepticism of AstraZeneca’s clinical results, namely

  • Small number of patients enrolled
  • BRCA1/2 cohort were identified retrospectively
  • results skewed by false benefit from “underperforming” control arm
  • possible inadvertent selection bias
  • hazard ratio suggesting improvement in progression free survival but higher risk/benefit

The FDA investigators released their report two days before an expert panel would be releasing their own report (reported in the link below from FierceBiotech)

UPDATED: FDA experts spurn AstraZeneca’s pitch for ovarian cancer drug olaparib

in which the expert panel reiterated the findings of the FDA investigators.   The expert panel’s job was to find if there was any clinical benefit for continuing consideration of olaparib, basically stating

“This trial has problems,” noted FDA cancer chief Richard Pazdur during the panel discussion. If investigators had “pristine evidence of a 7-month advantage in PFS, we wouldn’t be here.”

The expert panel was concerned for the above reasons as well as the reported handful of lethal cases of myelodysplastic syndrome and acute myeloid leukemia in the study, although the panel noted these patients had advanced disease before entering the trial, raising the possibility that prior drugs may have triggered their deaths.

 

As John Carrol from FierceBiotech notes, the decision may spark renewed interest by Pfizer of a bid for AstraZeneca as the potential FDA rejection would certainly dampen AstraZeneca’s future growth and profit plans. Last month AstraZeneca’s CEO made the case to shareholders to reject the Pfizer offer by pointing to AstraZeneca’s potential beefed-up pipeline.

 

However, on the same day, FierceBiotechreports some great news (at least in Europe) on the ovarian cancer front:

 

EU backs Roche’s Avastin for hard-to-treat ovarian cancer

As Arlene Weintraub   of FierceBiotechreports:

EU Committee for Medicinal Products for Human Use (CHMP) handed down a positive ruling on Avastin, recommending that the European Commission approve the drug for use in women with ovarian cancer that’s resistant to platinum-based chemotherapy. It’s the first biologic to receive a positive opinion from the CHMP for this hard-to-treat form of the disease.

Please see here for official press release: CHMP recommends EU approval of Roche’s Avastin for platinum-resistant recurrent ovarian cancer

 

EU had been getting pressure from British doctors to approve Avastin based on clinical trial results although it may be important to note that the EU zone seems to have an ability to recruit more numbers for clinical trials than in US. For instance a wonen’s breast cancer prevention trial had heavy recruitment in what would be considered a short time frame compared to the US.

 

 

 

Sources

http://www.fiercebiotech.com/story/fda-review-red-flags-astrazenecas-case-ovarian-cancer-drug-olaparib/2014-06-23

 

http://www.fiercebiotech.com/story/fda-experts-spurn-astrazenecas-pitch-ovarian-cancer-drug-olaparib/2014-06-25

 

http://www.fiercepharma.com/story/eu-backs-roches-avastin-hard-treat-ovarian-cancer/2014-06-27

 

 

Some other posts relating to OVARIAN CANCER on this site include

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Ultrasound-based Screening for Ovarian Cancer

Dasatinib in Combination With Other Drugs for Advanced, Recurrent Ovarian Cancer

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

 

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Reporter: Aviva Lev-Ari, PhD, RN

 

Marisa Weiss, M.D.

Director of Breast Health Outreach & Breast Radiation Oncology, Lankenau Medical Center; President and Founder of Breastcancer.org

Unlocking the Code

Posted: 06/26/2013 5:31 pm

 

I was building my medical practice when the breast cancer gene mutations were discovered. My family, Ashkenazi Jews with a history of breast and ovarian cancer, was one of the first to take advantage of genetic testing years ago. We felt indebted to all of the scientists who contributed incrementally to the discovery of the mutations to the BRCA1 and BRCA2 genes, as well as to the scientists at Myriad Genetics who were the first to nail the “secret code” — thereby securing the patent and developing the gene test that has allowed so many women to decide on a course of action to help protect their lives.

With the answers provided by these tests, members of my family with a BRCA2 mutation were able to take immediate steps to lower their risk of breast and ovarian cancer. My relatives without the gene mutation were able to avoid drastic measures. Genetic test results have also helped my patients make the smartest treatment choices and utilize the best follow-up surveillance options. And knowledge of my own personal genetic make-up guided my treatment decisions after my own breast cancer diagnosis.

Unlocking this genetic code brought new hope to a field of sluggish discovery for which many patients, myself included, feel tremendous gratitude. But we are also deeply grateful for the recent Supreme Court decision declaring that human genes cannot be patented. This ruling is a major victory for science and patients since these genes will now be available to researchers who can learn more about them and to companies that can develop additional diagnostic products. By removing this huge hurdle to progress, it will fuel new advances in breast cancer risk assessment, diagnosis, and personalized prevention and treatment — discoveries that are desperately needed.

Breast cancer genetic testing has been greatly underutilized, for a number of reasons, including cost. Access to BRCA tests will increase as competition reduces their costs and makes them more affordable to more women who, until now, were unable to pay for the critical information needed to make choices that could save their lives. But, as essential as it is to make these tests more accessible, cheaper tests should not mean indiscriminate testing. And, it would be a terrible thing if removal of the patent limits Myriad’s incentive and slows their fierce quest for new discoveries.

Angelina Jolie’s decision to have a double mastectomy based on the results of BRCA testing has already increased interest and spurred many women to consider if they too should be tested. Lower-cost tests could further that momentum.

The reality is that only a small portion of women and men should be tested. Less than 1 percent of the general population and 2.5 percent of Ashkenazi Jews have the BRCA1 or BRCA2 gene mutation that considerably raises the odds of developing breast and ovarian cancers. The determining factor for whether or not testing is warranted is family history of cancer. If there are multiple cases of breast and ovarian cancers in a family, especially if diagnosed at a young age, it’s important to consider testing. A family history of male breast cancer also is an indication for testing. The results of these tests allow individuals to make choices that can dramatically reduce their risks and in many cases prevent these cancers from occurring.

But it’s important to keep in mind that only 5-10 percent of breast cancers are due to single gene mutations like BRCA1 or BRCA2. The other 90 percent are primarily caused by lifestyle and environmental factors that we ultimately have more control over, but currently we have far less understanding of many of these risks.

To make prevention a possibility for the millions of women who are at risk for breast cancer, we need the same level of passion for discovery and research dollars directed at efforts to decipher the lifestyle and environmental causes of the disease.

While so much more research is needed on prevention, we currently do have clear evidence on a number of steps women can take to reduce their risks of breast cancer which include maintaining a healthy weight, eating healthy foods, exercising regularly, restricting alcohol consumption to 2-3 drinks per week, breastfeeding (especially important for African American women and BRCA1 mutation carriers), not smoking, not using postmenopausal combination hormonal therapy, and avoiding extended use of hormone-based birth control.

The Supreme Court decision will no doubt lead to new understandings and advances that will benefit many. However, it’s essential that we also look beyond inherited genes and start focusing on what we’re doing with and to our bodies to find the real answers to preventing breast cancer for most women.

SOURCE

http://www.huffingtonpost.com/marisa-weiss-md/breast-cancer-gene-mutation_b_3492233.html?utm_hp_ref=science

 

 

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ethicspersonalizedmedicine-page1

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Reporter/Curator: Stephen J. Williams, Ph.D.

Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing[1]

Direct-to-consumer (DTC) genetic testing and genetic health information in 2007 with the advent of personalized testing services by companies who offered microarray-based genotyping of single-nucleotide-polymorphisms (SNP) which had strong correlations to disease risk.  Three companies started to offer such services directly to the consumer:

A common test which is offered analyzes the consumers BRCA1/2 mutation status.  Three mutations in the BRCA gene are known to predispose women to hereditary breast and ovarian cancer: BRCA1 185delAG, BRCA1 538insC, and BRCA2 617delT.  These BRCA1 mutation confer a 60% breast cancer risk and a 40% risk of ovarian cancer while the BRCA2 mutation confers a breast cancer risk of 50% and 20% risk of ovarian cancer.

However, the commercial availability of this genetic disease-risk associated testing has led to certain ethical issues concerning communication and responses of risk information by:

  1. Consumers who request BRCA1/2 testing (focus of the Francke article
  2. BRCA1/1 testing and communication of results to minors and relatives (Bradbury: see below)

There has been much opinion, either as commentary in literature, meeting proceedings, or communiques from professional societies warning that this type of “high-impact” genetic information should not be given directly to the consumer as consumers will not fully understand the information presented to them, be unable to make proper risk-based decisions, results could cause panic and inappropriate action such as prophylactic oophorectomy or unwarranted risk-reduction mastectomy, or false reassurance in case of negative result and reduced future cancer screening measures taken by the consumer.  However, there have been few studies to investigate these concerns.

A report by Dr. Uta Francke in the open access journal PeerJ, assesses and quantifies the emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service® report of the three BRCA mutations known to be associated with high risk for breast/ovarian cancer.  One hundred thirty six (136) individuals, who tested positive for BRCA1 and/or BRCA2 mutations as well as 160 users of the service, who tested mutation-free were invited to participate in phone interviews addressing personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of results, emotional responses, perception of personal cancer risk, information sharing, and actions taken.  Thirty two (32) mutation carriers (16 female and 16 male) and 31 non-carriers responded to the phone questionnaire.

Questions were based on the following themes:

  1. When you purchased the 23andME Personal Genome Service® were you aware that it included testing for mutations that predispose to breast and ovarian cancer?
  2. Were you aware that having Ashkenazi Jewish ancestry influences your risk of carrying one of the three mutations?
  3. Have you or a first or second degree relative been diagnosed with breast, ovarian or any other cancer?
  4. What did you learn from your results?
  5. Were you surprised by the result?
  6. How did you feel about this information (extremely, moderately, somewhat upset or extremely relieved)?

Results:  Eleven women and 14 men had received an unexpected result that they are carriers of one of the three mutations however none of them reported extreme anxiety and only four reported moderate anxiety which did not last long.  Participants were at least 8 years of age. Five women and six men described their reaction as neutral.  Most carrier women sought medical advice and four underwent risk-reducing procedures. Some to the male carriers felt burdened to share their test results with their female relatives, which led to additional screenings of relatives.  Almost all of the mutation-positive customers appreciated learning their BRCA mutational status.

Other highlights of the results include:

  • More women got tested if they had a first or second degree relative previously diagnosed with breast/ovarian cancer
  • Ten mutation-positive individuals who were surprised at the test results cited the lack of family history of breast/ovarian cancer as the reason for their surprise.  The rest who were surprised at their positive test results believed that the frequency of these mutations were low in the general population so they shouldn’t have been affected.
  • For the mutation-positive group, none of the 32 reported as being “extremely upset”.
  • Interestingly, on male who learned, for the first time, he was a positive carrier for BRCA mutation, reported feeling “relieved” because his daughter who was also tested by 23andMe had not acquired his mutation.

A brief interview with Dr. Francke follows:

Q:     In your results you had noted that none of the mutation carriers showed extreme anxiety about their reports however there were many of Ashkenazi descent who was well aware of the increased risk to breast cancer.  In another study by Dr. Angela Bradbury, anxieties and communication to their children depended on mutation status and education status.  Do you feel that most women in your study were initially aware they could be in a high risk category for cancer, whether breast, ovarian, or other?

Dr. Francke:   As we show in Table 1, 6 of 16 women and 6 of 16 men who found out that they were BRCA mutation carriers had not been aware that being of Ashkenazi descent confers an increased risk of breast/ovarian cancer.  In Table S1, we show that 6 of these 32 people did not self-identify as Ashkenazi.
Q:     The reporting and communication of test results to offspring and genetic testing of offspring as a result of positive tests has been under much debate.  I had noticed that there was a high proportion of relatives who went for screening after learning of a family members BRCA testing, whether it showed a mutation or not.  Some studies have shown that offspring of carriers may misinterpret genetic testing results and take inappropriate action, such as considering having early testing  before age 25.  It appears some anxiety may be due to misinformation and lack of genetic counseling.  Should these test results be considered in guidelines for oncologist such as NCCN guidelines with respect to informing family members using genetic counselors as an intermediary?

Dr. Francke:    The “high proportion of relatives who went for screening after learning of a family member’s BRCA testing”, were only those related to a BRCA-positive person. Most of the BRCA testing of relatives was done through health care providers at Myriad as these people were eligible for insurance coverage of the test. In our interviews we found no evidence for inappropriate action of carriers or non-carriers. With one exception, we found no evidence for misinterpretation or “anxiety due to lack of genetic counseling”.  In our online reports we recommend genetic counseling for all customers who have questions about their results.

Q:     I was also particularly interested the male carrier felt a heightened burden to tell their offspring.  This has been suggested in other studies.  I would assume the mothers and not the fathers would feet more pressure to tell their children.  Is there a reason for this?
Dr. Francke:     The heightened burden reported by the male carriers was mostly about the realization of the risk for their daughters, not so much about to telling their offspring.  Female carriers were primarily concerned about their own health risk and management, and decision-making about preventive measures – therefore, the risk for offspring appeared to be of secondary concern for them.

However, the availability of this type of predictive genetic testing for hereditary cancer has raised some ethical issues regarding the communication of risk and genetic results to family members and especially offspring, specifically whether informing minors would incur unnecessary testing, anxiety among minors of parents who tested positive for genetic risk-factors, or even premature risk-reduction surgeries or medical interventions.

The aforementioned ethical issues concerning communicating results of BRCA mutational testing to offspring was addressed by two large studies conducted by Dr. Angela Bradbury M.D. and colleagues at Fox Chase Cancer Center Family Risk Assessment Program (now she is at University of Pennsylvania) and University of Chicago Cancer Risk Clinic.  These studies evaluated the parental opinions regarding BRCA1/2 testing of minors, and how parents communicate BRCA1/2 genetic testing with their children.

In the JCO article (Parent Opinions Regarding the Genetic Testing of Minors for BRCA1/2)[2], Bradbury and colleagues used semistructured interviews (yes/no questions and open-ended questions) of 246 parents at Fox Chase and University of Chicago, who underwent BRCA1/2 whether they supported testing of minors in general and testing of their own offspring.  Parents were asked, “If you were deciding, do you think children under 18 years old should be given the opportunity to be tested” and followed by the open-ended question: “Why do (don’t) you support the genetic testing of minors for BRCA1/2?”.

Results:  In response to the first question (Would you support testing in minors) 37% of parents supported testing of minors in the general population.  The follow-up open-ended question revealed that 4% support testing minors in some or all circumstances.  This decision was independent of parent sex or race.  44% of parents would test their own offspring.  Parents who opposed testing in minors thought testing would cause fear and anxiety for their children but those who supported unconditional testing (regardless of whether they were positive for the BRCA mutation or not) mentioned that the medical information would foster better health behaviors in their offspring.  21% of parents who opposed testing minors, in general, actually supported testing of their own children.  Interestingly parents who tested positive for the BRCA1 overwhelmingly (64%) opposed testing of minors, in general.  In addition, statistical analysis of the open-ended questions revealed that parents who did not have a college degree, had a negative test result, and were non white favored testing of their own children.  The authors had suggested larger studies before any guidelines were given as to whether testing in minors of BRCA mutation carriers should be standard.

In a recent publication by Dr. Bradbury and colleagues (Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls)[3],  studied how adolescent girls understood and responded to breast cancer risk by interviewing 11-19 year-old girls at high-risk and population-risk for breast cancer. Although most girls said they were aware of increased risk because either a family member had or was predisposed to breast cancer (66 %) only 17 % of girls were aware of BRCA1/2 genes. Mother was the most frequently reported source of information for breast cancer among both high-risk (97 %) and population-risk (89 %) girls.  The study also showed that most girls who believe they are at high-risk could alter their lifestyles or change dietary habits to lower their risk.

In an adjacent study in the journal Cancer[4], Bradbury and colleagues at Fox Chase Cancer Center had gauged the frequency with which parents had told their children of their BRCA1/2 teat results and how their children felt about the results.

When parents disclose BRCA1/2 test results: Their communication and perceptions of offspring response[4]

Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least 1 child <25 YO.  A total of 253 parents completed interviews (61% response rate), reporting on 505 offspring. Twenty-nine percent of parents were BRCA1/2 mutation carriers. Three hundred thirty-four (66%) offspring learned of their parent’s test result. Older offspring age (P ≤ .01), offspring gender (female, P = .05), parents’ negative test result (P = .03), and parents’ education (high school only, P = .02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). Thirteen percent of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent’s BRCA1/2 positive or variant of uncertain significance result.

CONCLUSIONS:

Many parents communicate their BRCA1/2 test results to young offspring. Parents’ perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk life span.

Below is an excellent article by Steven Reinberg from HealthDay interviewing Dr. Angela Bradbury concerning their JCO study: (reported for ABC News at http://abcnews.go.com/Health/Healthday/story?id=4508346&page=1#.UVNJUVef2RM)

Many Parents Share Genetic Test Findings With Kids

By Steven Reinberg
HealthDay Reporter

Mar. 23

FRIDAY, Aug. 17 (HealthDay News) — As genetic testing for diseases becomes more commonplace, the impact of those findings on family members may be underestimated, researchers say.

For instance, some women who discover they have the BRCA gene mutation, which puts them at higher risk for breast cancer, choose to tell their children about it before the children are old enough to understand the significance or deal with it, a new study found.

“Parents with the BRCA mutation are discussing their genetic test results with their offspring often many years before the offspring would need to do anything,” said study author Dr. Angela Bradbury, director of the Fox Chase Cancer Center’s Family Risk Assessment Program, in Philadelphia.

According to Bradbury, more than half of parents she surveyed told their children about genetic test results. Some parents reported that their children didn’t seem to understand the significance of the information, and some had initial negative reactions to the news.

“A lot of genetic information is being shared within families and there hasn’t been a lot of guidance from health-care professionals,” Bradbury said. “While this genetic risk may be shared accurately, there is risk of inaccurate sharing.”

In the study, Bradbury’s team interviewed 42 women who had the BRCA mutation. The researchers found that 55 percent of parents discussed the finding and the risk of breast cancer with at least one of their children who was under 25.

Also, most of the women didn’t avail themselves of the services of a doctor or genetic counselor in helping to tell their children, Bradbury’s group found.

Bradbury is concerned that sharing genetic information with young children can create anxiety. “The children could be overly concerned about their own risk at a time when there is nothing that they need to do,” she said.

But, she added, “it may be possible that sharing may be good for children in adapting to this information.”

The findings are published in the Aug. 20 issue of the Journal of Clinical Oncology.

The lack of definitive data on when — or if — to discuss genetic test results with children is a real problem, Bradbury said.

“As we move genetic testing forward for cancer or other illnesses, we have to consider the context of the whole family and focus our counseling to the whole family, and not just the person who comes in for testing,” Bradbury said. “We should learn more about how and when we should talk to children about this, so that we can promote healthy behaviors without causing too much anxiety for the offspring.”

Barbara Brenner, executive director of Breast Cancer Action, agreed that the psychological component of genetic testing needs more attention.

“This is the tip of a very scary iceberg,” Brenner said. “We don’t know the psychological consequences [of BRCA testing], not only to the person who has the test, but to her family members.”

Brenner thinks guidelines to help parents deal with this information are needed. So is help from doctors and genetic counselors in counseling family members, especially children, she added.

LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth), supported by the National Institutes of Health. This study will follow the girls prospectively in order to evaluate epidemiologic and epigenetic pathways of childhood exposures in relation to pubertal development, age at menarche, breast tissue characteristics, biomarkers of exposure, genomic DNA methylation, and the psychosocial impact of increased breast cancer susceptibility in 6-13 YO girls. http://legacygirlsstudy.org/

1.         Francke U, Difamco C, Kiefer AK, Eriksson N, Moiseff B, Tung JY, Mountain JL: Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. PeerJ 2013:1-21.

2.         Bradbury AR, Patrick-Miller L, Egleston B, Sands CB, Li T, Schmidheiser H, Feigon M, Ibe CN, Hlubocky FJ, Hope K et al: Parent opinions regarding the genetic testing of minors for BRCA1/2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010, 28(21):3498-3505.

3.         Bradbury AR, Patrick-Miller L, Egleston BL, Schwartz LA, Sands CB, Shorter R, Moore CW, Tuchman L, Rauch P, Malhotra S et al: Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls. Breast cancer research and treatment 2012, 136(3):749-757.

4.         Bradbury AR, Patrick-Miller L, Egleston BL, Olopade OI, Daly MB, Moore CW, Sands CB, Schmidheiser H, Kondamudi PK, Feigon M et al: When parents disclose BRCA1/2 test results: their communication and perceptions of offspring response. Cancer 2012, 118(13):3417-3425.

Sources:

http://abcnews.go.com/Health/Healthday/story?id=4508346&page=1#.UVNJUVef2RM

Other article on Ethics and Personalized Medicine on the site include:

Genomics in Medicine- Tomorrow’s Promise

Attitudes of Patients about Personalized Medicine

Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

Volume One: Genomics Orientations for Individualized Medicine

Directions for Genomics in Personalized Medicine

The Way With Personalized Medicine: Reporters’ Voice at the 8th Annual Personalized Medicine Conference,11/28-29, 2012, Harvard Medical School, Boston, MA

Highlights from 8th Annual Personalized Medicine Conference, November 28-29, 2012, Harvard Medical School, Boston, MA

Clinical Genetics, Personalized Medicine, Molecular Diagnostics, Consumer-targeted DNA – Consumer Genetics Conference (CGC) – October 3-5, 2012, Seaport Hotel, Boston, MA

Genetic basis of Complex Human Diseases: Dan Koboldt’s Advice to Next-Generation Sequencing Neophytes

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Improving Mammography-based imaging for better treatment planning

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BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Interest in BRCA1 stems from its role as a tumour suppressor in breast and ovarian cancer. Intensive research in BRCA1 has revealed little about its specific role in cancer; rather, this protein has been implicated in a multitude of important cellular processes.

The diverse biochemical activities of BRCA1 combine to protect the genome from damage.

New data reveal that BRCA1

BRCA1 functions in several processes, but it is unclear how these relate to the BRCA1 requirement in all cell types. Similar to the p53 tumour suppressor, BRCA1 activates genes encoding the DNA-repair response. Unlike p53, BRCA1 also has a direct role in the repair process.

According to the earlier suggested model, BRCA1–BARD1 functions in genome surveillance by scanning active genes in association with the holo-pol, and when the elongating transcription complex encounters DNA lesions, BRCA1 initiates a repair response. It is interesting to note that a BRCA1-binding cofactor, COBRA1, which regulates BRCA1 function in a chromatin decompression assay, has been found to be a required subunit of a complex that regulates transcription elongation.

When damage is encountered on the DNA template, the lesion could be corrected by transcription-coupled repair (step 1), a known BRCA1 function. Alternatively, some types of damage might require that the polymerase be removed to effect repair. Since the polymerase synthesizing mRNA on a DNA template is quite stably bound, it has been hypothesized that BRCA1 would then ubiquitinate the polymerase signaling its degradation (step 2).

Although current evidence does not implicate BRCA1 in this process, the polymerase is ubiquitinated and degraded following DNA damage. The residual BRCA1 complex might remain bound to the DNA lesion.

BRCA1 has been found to bind DNA cruciforms and three-way junctions, such as might occur at damage sites (step 3). This bound BRCA1 would then recruit repair factors, such as the RAD50-containing complex, which would then mend the lesion (steps 4 and 5).

One might infer from the recruitment of the H2AX kinase to sites in which BRCA1 is bound to DNA that this surveillance of the template by transcription results in BRCA1-dependent degradation of the transcription apparatus and recruitment of the H2AX kinase to nucleate the assembly of a repair focus.

Although there is no yeast homolog for BRCA1, perhaps a analogous pathway is conserved in this organism, mediated by a transcription elongation factor that is genetically linked in this pathway to holo-pol components.

The key cellular functions assigned to BRCA1 are numerous. BRCA1 can interact with many cellular proteins and pathways, but how these many interactions address the key questions of required ubiquitous function and tumour suppressing breast and ovarian cell function are unclear. These diverse activities of BRCA1 may be linked in a single pathway, or BRCA1 might function in multiple nuclear processes.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed?term=The%20multiple%20nuclear%20functions%20of%20BRCA1%3A%20transcription%2C%20ubiquitination%20and%20DNA%20repair

 

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