BRCA 1 and 2 and Early Detection of Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

BRCA1 and BRCA2: Cancer Risk and Genetic Testing

• What are BRCA1 and BRCA2?

• How much does having a BRCA1or BRCA2 gene mutation increase a woman’s risk of breast and ovarian cancer?
• What other cancers have been linked to mutations in BRCA1and BRCA2?
• Are mutations in BRCA1and BRCA2 more common in certain racial/ethnic populations than others?

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. Edwards^1, *, Zsofia Kote-Jarai^1, *, Julia Meitz¹, Rifat Hamoudi², Questa 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).

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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.

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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

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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