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Posts Tagged ‘American Society of Clinical Oncology’


Business Intelligence Application for Pharmaceutical and Biotech Professionals

Submitted by

Dr Stephen Breslin

Chief Executive | Glasgow Science Centre

50 Pacific Quay | Glasgow | G51 1EA

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The Sophie Pharma & Biotech App is a powerful personal business and technology intelligence tool to increase your productivity.  Sophie will work on your Ipad, Iphone, Android tablet or smartphone.

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Personalized Medicine in NSCLC

Reviewer: Larry H Bernstein, MD, FCAP

Introduction

Early in the 21st century, gefitinib, an epi­dermal growth factor receptor (EGFRtyrosine kinase inhibitor became available  for the treatment of non-small cell lung can­cer (NSCLC). Over 80% of selected patients

  • EGFR mutation-positive patients, respond to gefitinib treatment;
  • most patients develop acquired resistance to gefitinib within a few years.
Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects.
Lung cancers are classified according to their his­tological type. Because each variant has different bio­logical and clinical properties, including response to treatment, a precise classification is essential to pro­vide appropriate therapy for individual patients. Lung cancer consists of two broad categories—non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

NSCLC  – 20%–40% RR to chemotherapy

  • ade­nocarcinoma (AC),  40%–50% ( most common form)
    • higher sensitivity to chemotherapy than SCC or LC
  • squamous cell carcinoma (SCC),  ∼30%
  •  large cell carcinoma (LCC). 10%
The majority of patients with SCLC are diagnosed with
  • advanced cancer with distant metastasis
  • high sensitivity to chemotherapy.
  • response rate (RR) for SCLC is reportedly 60%–80%
  • complete remission is observed in only 15%–20% of patients
The Potential of Personalized Medicine in Advanced NSCLC
Personalized medicine—
  • matching a patient’s unique molecular profile with an appropriate targeted therapy—
  • is transforming the diagnosis and treatment of non–small-cell lung cancer (NSCLC).

Through molecular diagnostics, tumor cells may be differentiated based on the presence or absence of

  • receptor proteins,
  • driver mutations, or
  • oncogenic fusion/rearrangements.

The convergence of advancing research in drug development and genetic sequencing has permitted the development of therapies specifically targeted to certain biomarkers, which may offer a differential clinical benefit.

Putting personalized medicine in NSCLC into practice
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC.1,2
Biomarker Testing in Advanced NSCLC: Evolution in Pathology Clinical Practice
http://www.medscape.com/infosite/letstest/article-3
Multidisciplinary Approaches in the Changing Landscape of Advanced NSCLC
http://www.medscape.com/infosite/letstest/article-4
Oncology Perspectives on Biomarker Testing
http://www.medscape.com/infosite/letstest/article-1

References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                   August 6, 2012.
2. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

Over the last decade, a growing number of biomarkers have been identified in NSCLC.3,4 To date, 2 of these molecular markers have been shown to have both prognostic and predictive value in patients with advanced NSCLC: epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.5-8 Testing for these biomarkers may provide physicians with more information on which to base treatment decisions, and reflex testing may permit consideration of appropriate therapy from the outset of treatment.2,9,10

References:
Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
Quest Diagnostics. Lung Cancer Mutation Panel (EGFR, KRAS, ALK).                       Sept 17, 2012
http://questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=Lung/TS_LungCancerMutation_Panel.htm.

Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Presented at: 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, J Clin Oncol. 2011;29(suppl). Abstract 7503.                        Aug 6, 2012.                    http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78285.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                        Aug 6, 2012
College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) expert panel. Lung cancer biomarkers guideline draft recommendations. http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf.      Aug 6, 2012.
Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

 Background Studies
In 2002, gefitinib (ZD1839; AstraZeneca) , the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, became available as an innovative molecular-targeted drug for the treatment of unresectable NSCLC. Initially, many NSCLC patients were expected to respond to gefitinib because many solid tumors, including NSCLC, are known to overexpress EGFR, which has a role in tumor pro­liferation and is used as a biomarker to predict poor prognosis. Gefitinib was shown to have a dra­matic effect on a limited number of patients; but  it was ineffective in 70%–80% of patients with NSCLC. There have been reports of death caused by interstitial pneumonia (IP), one of the critical adverse drug reactions (ADRs) associated with gefitinib use. Therefore, there is a need for  predicting the effects of gefitinib, and criteria for select­ing patients who could be treated with gefitinib.
 In 2004, Lynch et al. and Paez et al. each pub­lished, on the same day, sensational reports in the New England Journal of Medicine and Science, identifying somatic mutations in the tyrosine kinase domain of the EGFR gene in patients with gefitinib-sensitive lung cancer, as compared with none of the patients who had no response. Therefore, screening for EGFR mutations in lung cancer showed potential for identifying patients who would respond to gefi­tinib therapy. It then was found that patients with EGFR mutations in the area of the gene cod­ing for the ATP-binding pocket of the tyrosine kinase domain responded to gefitinib. Consequently, the EGFR genotyping has been used to select patients who will respond to gefitinib. Other genetic mutations have also been reported as indicators of the response or resistance to gefitinib; for example, mutations of the KRAS gene are associated with primary resistance to gefitinib. Thus, screening of EGFR and KRAS is used to
  • predict the effects of gefi­tinib and
  • to select patients who will respond to gefitinib in the clinical setting.
Until now, the effects of gefitinib have been predicted only by genotyping factors, such as EGFR and KRAS mutations. However, Nakamura et al showed a relationship between the blood concentration of gefitinib and its clinical effects. In their study of 23 NSCLC patients with EGFR mutations, the ratio of the gefitinib concentration on day 8 to that on day 3 after the first administration of gefitinib (C8/C3) correlated with the progression-free survival (PFS) period. Patients with a higher C8/C3 ratio had a significantly lon­ger PFS (P = 0.0158, 95% confidence interval [CI]: 0.237–0.862), which  suggests the importance of the PK of gefitinib on its clinical outcome.   Chmielecki et al. concurrently reported that maintain­ing a high concentration of erlotinib, another EGFR tyrosine kinase inhibitor (EGFR-TKIs) with the same mechanism of action as gefitinib, could
  1. delay the establishment of drug-resistant tumor cells and
  2. decrease the proliferation rate of drug-resistant cells compared to
    • treatment using a lower concentration of erlotinib.
Pharmacogenetic profile
Initially, gefitinib was expected to induce a response in patients with tumors that overexpressed EGFR because it exerts its antineoplastic effects by com­petitively inhibiting the binding of ATP to the ATP-binding site of EGFR.  A number of studies contradict this hypothesis:
(1) while approxi­mately 40%–80% of NSCLC overexpress EGFR, only 10%–20% of NSCLC patients respond to gefi­tinib;5,6 and
(2) while EGFR overexpression is known to be more common in SCC than AC, gefitinib shows a higher antineoplastic effect on AC than on SCC, while other reports indicated no correlation between the expression levels of EGFR and clinical outcomes.
In 2004, somatic mutations were identified in the EGFR tyrosine kinase domain of patients with gefitinib-responsive lung cancer, as compared with no mutations in patients exhibiting no response, and the presence of an EGFR mutation was highly correlated with a good response to gefitinib.The conformational change of the EGFR ATP-binding site caused by genetic mutations constitutively acti­vates the EGFR downstream signaling pathway and increases the malignancy of cancer. Conversely, the conformational change of the ATP-binding site can also increase its affinity for gefitinib; therefore, gefi­tinib can inhibit the downstream signaling pathway more easily, strongly induces apoptosis, and reduces the proliferation of cancer cells.
Mutations in exons 18–21 of EGFR are predictive factors for the clinical efficacy of gefitinib;
  • deletions in exon 19 and missense mutations in exon 21 account for ∼90% of these mutations.

The detection of EGFR muta­tions in exons 19 and 21 is considered to be essential to predict the clinical efficacy of gefitinib.
Acquired resistance
All responders eventually develop resistance to gefitinib but in 2005, an EGFR mutation in exon 20, which substitutes methionine for threonine at amino acid position 790 (T790M), was reported to be one of the main causes of acquired resistance to gefitinib. The EGFR T790M vari­ant

  1. changes the structural conformation of the ATP-binding site, thereby
  2. increasing the affinity of ATP to EGFR, while
  3. the affinity of gefitinib to ATP is unchanged.

Screening methods for EGFR and KRAS mutations
The detection of EGFR and KRAS mutations has been usually achieved by sequencing DNA amplified from tumor tissues; however, sequencing techniques are too complex, time-consuming, and expensive.  The selection of an appropri­ate method to detect EGFR and KRAS mutations is essential to make an exact prediction of the efficacy of gefitinib in individual patients. Advances in diagnostics and treatments for NSCLC have led to better outcomes and higher standards of what outcomes are expected. These new understandings and treatments have raised multiple new questions and issues with regard to the decisions on the appropriate treatment of NSCLC patients.

  • Biomarkers are increasingly recognized and applied for guidance in diagnosis, prognosis and treatment decisions and evaluation.
  • Biologics and newer cancer treatments are enabling the possibility for new combined treatment modalities in earlier stage disease
  • Maintenance therapy has been shown to be useful, but optimal therapy choices before and after maintenance therapy need clarification
  • The importance of performance status on treatment decisions
  • Comparative effectiveness is becoming an expectation across all treatments and diseases, and will prove difficult to accomplish within the complexity of cancer diseases
NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement
PF Engstrom, MG Bloom,GD Demetri, PG Febbo, et al.
Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decisionmaking is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility. The NCCN Molecular Testing Work Group identified
challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence. (JNCCN 2011;9[Suppl 6]:S1–S16)
Executive Summary
The FDA recently announced plans for oversight of laboratory-developed tests (LDTs) and released draft guidance regarding the development of companion diagnostics concurrently with therapeutics, both areas over which the FDA has regulatory authority. As recognized by the FDA, these types of diagnostic tests are used increasingly to directly inform treatment decisions, and this especially impacts patients with cancer and their oncologists. However, because of the increasing complexity of some LDTs and increasing commercial interest in oncology-related LDTs in general, the FDA is considering whether its policy of exercising “enforcement discretion”

for LDTs is still appropriate. To provide guidance regarding challenges of molecular testing to health care providers and other stakeholders, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations external to NCCN.  The NCCN Molecular Testing Work Group agreed to define molecular testing in oncology as

  • procedures designed to detect somatic or germline mutations in DNA and
  • changes in gene or protein expression that could impact the
    • diagnosis,
    • prognosis,
    • prediction, and
    • evaluation of therapy of patients with cancer.
Therefore, the discussion focused on molecular tests that predict outcomes for therapy.
Realizing the importance of personalized medicine in advanced NSCLC
E Topol, B Buehler, GS Ginsburg.       Medscape Molec Medicine
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/
Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna

Lung cancer in the never smoker population is a distinct disease entity with specific molecular changes, offering the potential for targeted therapy.
Experts And Viewpoint, Medscape Hematology-Oncology, December 2007

An Update on New and Emerging Therapies for NSCLC
Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD
On completion of these readings participants will be thoroughly familiar with these issues:
  1. The influence of histologic types and genetic and molecular markers on choosing and personalizing therapy in patients with advanced NSCLC
  2. The role of the pathologist in properly classifying subtypes of NSCLC and reporting the presence of molecular markers in tumor samples
  3. Familiarize themselves with effective methods of obtaining adequate tissue samples from patients and recognize the importance of accurate pathologic assessment of NSCLC
The rapid developments in molecular biology have opened up new possibilities for individualized treatment of non-small cell lung cancer (NSCLC), and, in recent years, has mainly focused on the epidermal growth factor receptor (EGFR). A greater understanding of the molecular mechanisms behind
  • tumorigenesis and
  • the identification of new therapeutic targets
    • have sparked the development of novel agents
    • intended to improve the standard chemotherapy regimens for NSCLC.
Along with the advent of targeted therapy, identifying biomarkers to predict the subset of patients more likely to benefit from a specific targeted intervention has become increasingly important.
EGFR TYROSINE KINASE INHIBITORS 
tumor-associated mutations in the tyrosine kinase domain of EGFR have been associated with response to EGFR TKIs
The most common EGFR-sensitizing mutations encompass deletions in exon 19 and a point mutation at L858R in exon 21; together,
  • they account for approximately 85% of EGFR mutations in NSCLC.
  • Other EGFR mutations have been detected, particularly in exon 20.
    •  mutations identified in exon 20 have been linked to resistance to EGFR TKIsNon-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
      Taofeek K. Owonikoko, MD, PhD
What is the role and application of molecular profiling in the management of NSCLC?
It is essential to:
  1. Identify advances in the understanding of molecular biology and histologic profiling in the treatment of NSCLC
  2. Summarize clinical data supporting the use of tumor biomarkers as predictors of therapeutic efficacy of targeted agents in NSCLC
  3. Devise an individualized treatment plan for patients with advanced NSCLC based on a tumor’s molecular profile
  4. Identify methods for overcoming barriers to effective incorporation of molecular profiling for the management of NSCLC into clinical practice
Non-small cell lung cancer (NSCLC),the most common type of lung cancer, usually grows and spreads more slowly than small cell lung cancer.
The three common forms of NSCLC are:
  1. Adenocarcinomas are often found in an outer area of the lung.
  2. Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  3. Large cell carcinomas occur in any part of the lung and tend to grow and spread faster than the other two types
Smoking causes most cases of lung cancer. The risk depends on the number of cigarettes you smoke every day and for how long you have smoked. Some people who do not smoke and have never smoked develop lung cancer.
Working with or near the following cancer-causing chemicals or materials can also increase your risk:
  • Asbestos
  • Chemicals such as uranium, beryllium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, and diesel exhaust
  • Certain alloys, paints, pigments, and preservatives
  • Products using chloride and formaldehyde
Non-small cell lung c

ancer
(NSCLC) accounts for
  • approximately 85% of all lung cancers.
Lung cancer  may produce no symptoms until the disease is well advanced, so early recognition of symptoms may be beneficial to outcome.
At initial diagnosis,
  • 20% of patients have localized disease,
  • 25% of patients have regional metastasis, and
  • 55% of patients have distant spread of disease.
Revisiting Doublet Maintenance Chemo in Advanced NSCLC 
H. Jack West, MD
  • Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
Ardizzoni A, Tiseo M, Boni L, et al
J Clin Oncol. 2102;30:4501-4507
Historically, our second-line therapy has evolved into a strategy of pursuing single-agent therapies for patients with advanced non-small cell lung cancer (NSCLC) who have received prior chemotherapy. This approach was developed on the basis of benefits conferred by such established treatments as docetaxel, pemetrexed, and erlotinib — each well-tested as single agents — and evidence indicating a survival benefit in previously treated patients.
A study out of Italy by Ardizzoni and colleagues published in the Journal of Clinical Oncology directly compares carboplatin/pemetrexed with pemetrexed alone, and
  • it provides more evidence that our current approach of sequential singlet therapy remains appropriate.
This randomized phase 2 trial enrolled 239 patients with advanced NSCLC, initially of any histology, then later amended (September 2008) to enroll
  • only patients with non-squamous NSCLC because of mounting evidence that pemetrexed is not active in patients with the squamous subtype of advanced NSCLC.
Patients must have received prior chemotherapy (without restriction on regimen except that it could not include pemetrexed). Participants were randomly assigned 1:1 to receive pemetrexed at the standard dose of 500 mg/m2 IV every 21 days or the same chemotherapy with carboplatin at an area under the curve of 5, also IV every 21 days.
The primary endpoint for the trial was progression-free survival (PFS), and the trial was intended to have results pooled with a nearly identically designed trial that was done in The Netherlands. The Dutch trial compared pemetrexed with carboplatin/pemetrexed at the same dose and schedule. The vast majority of patients (97.5%) had a performance status of 0 or 1, and the median age was 64 years.
The Italian study found no evidence to support a benefit in efficacy from the more aggressive doublet regimen. Specifically,
  • median PFS was 3.6 months with pemetrexed alone vs 3.5 months with carboplatin/pemetrexed.
  • Response rate (RR) and median overall survival (OS) were also no better with the doublet regimen
      • RR 12.6% vs 12.5%, median OS 9.2 vs 8.8 months, for pemetrexed and carboplatin/pemetrexed.

Moreover, pooling the data from the Italian trial with the Dutch trial demonstrated no significant differences between the 2 strategies. Subgroup analysis showed that

  • the patients with squamous NSCLC had a superior median PFS of 3.2 months with the carboplatin doublet vs 2.0 months with pemetrexed alone.

Unfortunately, this only confirms that adding a second agent is beneficial for patients receiving an agent previously shown to be ineffective in that population.

Viewpoint
Putting it in the context of previous data, these results only provide further confirmation that more is not better.
  • combinations are associated with more toxicity than single-agent therapy, and
  • this is likely to be especially relevant in previously treated patients whose ability to tolerate ongoing therapy over time may be reduced.

It is critical to balance efficacy with tolerability to enable us to deliver the treatment over a prolonged period. We need to recognize the importance of pacing ourselves if our goal is to administer treatments in a palliative setting for an increasingly longer duration.

Epidermal growth factor receptor (EGFR) signal...

Epidermal growth factor receptor (EGFR) signaling pathway. (Photo credit: Wikipedia)

EGFR structure

EGFR structure (Photo credit: Wikipedia)

ATP synthase

ATP synthase (Photo credit: Ethan Hein)

Non-small cell carcinoma - FNA

Non-small cell carcinoma – FNA (Photo credit: Pulmonary Pathology)

Articles on NSCLC in Pharmaceutical Intelligence:
Key Sources:
  1. Realizing the importance of personalized medicine in advanced NSCLC
    E Topol, B Buehler, GS Ginsburg. 

    Medscape Molec Medicine The Potential of Personalized Medicine in Advanced NSCLC

    With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
  2. Revisiting Doublet Maintenance Chemo in Advanced NSCLC
    H. Jack West, MD     http://www.medscape.com/viewarticle/777367
    Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
    Ardizzoni A, Tiseo M, Boni L, et al
    J Clin Oncol. 2102;30:4501-4507
  3. Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna
    Experts And Viewpoint, Medscape Hematology-Oncology, December 2007
  4. Non-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
    Taofeek K. Owonikoko, MD, PhD   August 24, 2011.   Medscape
  5. An Update on New and Emerging Therapies for NSCLC
    Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD     Medscape
  6. Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
  7. Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.

  8. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
  9. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy.

    Cancer Metastasis Rev. 2010;29:37-48.

  10. NCCN Oncology Insights Report on Non-Small Cell Lung Cancer 1.2010
  11.   Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib
    T Araki, H Yashima, K Shimizu, T Aomori
    Clinical Medicine Insights: Oncology 2012:6 407–421  http://dx.doi.org/10.4137/CMO.S7340

 

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Larry H Bernstein, MD
Leaders in Pharmaceutical Intelligence
https://pharmaceuticalintelligence.com/2013/03/02/9530/recurrence risk for breast cancer

Testing recurrence risk for breast cancer
Karen Titus
June 2011 CAP Today

http://www.cap.org/apps/cap.portal_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=cap_today%2F0611%2F0611a_testing_recurrence.html&_state=maximized&_pageLabel=cntvwr

{EXTRACT}

Gene panels for breast cancer recurrence risk have arrived. In fact, they’ve been around since the mid-2000s. And now, like guests at a wedding reception, it’s a matter of figuring out where to seat them.
Like it or not, tests such as Oncotype DX (Genomic Health Inc.), MammaPrint (Agendia), and Mammostrat (Clarient)—to name just a few—are making their presence felt.
Clinicians favor these tests for a simple reason: the results help them decide if patients with breast cancer need chemotherapy. More broadly, the tests reflect a shift in thinking among physicians, one that emphasizes molecular profiling of tumors. They’ve arrived on the scene when physicians are also starting to question the value of lymph node status to help determine treatment.George W. Sledge, MD, finds these changes remarkable. Not all that long ago, he might have pink-slipped a test that would help parse treatment decisions. When the NIH held its consensus development conference on adjuvant therapy with breast cancer in 2000, he recalls, the agreement was, basically, that everyone with a tumor greater than one centimeter ought to be treated with chemotherapy. “There’s no question that resulted in us hugely overtreating patients,” he says. “So I think a test that reduces the quantity of human suffering by half in that group is a useful test,” says Dr. Sledge, professor of medicine and pathology, Indiana University, Indianapolis, and immediate past president of the American Society of Clinical Oncology.
In clinical practice, these tests are functioning like traffic managers. “We now see fewer patients getting chemotherapy who would have gotten it before,” says Thomas Julian, MD, professor of surgery, Drexel University College of Medicine, Philadelphia, and director of breast surgical oncology for the West Penn Allegheny Health Care System, Pittsburgh. “We’re also seeing a few who are getting chemo who might not have gotten it before. So it’s changed in both directions,” says Dr. Julian, who is also senior surgical director for medical affairs for the National Surgical Adjuvant Breast and Bowel Project.
Oncotype DX is a real-time RT-PCR assay measuring RNA expression in 16 cancer-related genes and five reference genes, using paraffin-embedded tissue. Results are given as a recurrence score between zero and 100, which are translated as low risk (a score of 18 or lower), medium risk (19 to 30), or high risk (31 or above). The MammaPrint microarray assay measures expression of 70 genes in fresh tissue; it categorizes patients as either high risk, with a so-called poor signature, or low risk (a so-called good signature) for recurrence. There is no intermediate category. Mammostrat is an immunohistochemistry test measuring five markers: p53, HTF9C, CEACAM5, NDRG1, and SLC7A5. The results are combined into a quantitative risk index: low, moderate, and high. For now, only MammaPrint has FDA clearance.
The test is not useful in patients whose tumors are HER2 positive. The test nearly always will show such patients to be at high risk; moreover, the paradigm for treating such patients is with chemotherapy and trastuzumab (Herceptin). It is used for patients who are lymph node negative, ER positive, and HER2 negative, with “moderate-size tumors—say, tumors that are over a centimeter but less than four or five centimeters. Another consideration is tumor size. The test is most useful for tumors of around five millimeters or greater in size.For patients with very, very small tumors—one, two, three millimeters—there’s no need for the test. Elizabeth Hammond, MD, agrees these tests are useful, although she suspects they may best prove their mettle in second- or third-generation assays. It’s simple biology: phenotypic expression of a genetic alteration of ER or HER2 status is the result of cell-signaling pathway changes. “Looking at multiple expressions of that problem with a gene panel, either by RT-PCR or some other method, will in the long run give us better information.

Comment:  In 1982, labs were running RIA assays for Estrogen Receptor.  It was known for some time that breast cancer is estrogen-dependent.  This was a major discovery by a surgeon at University of Chicago, that led to oophorectomy with resection of the lesion.  The assay was quite elaborate and required a “scatchard plot”.  The assay was no longer used when a good histochemical stain became widely used with a progesterone receptor a few years later.  We went into the 1990’s knowing that if the patient is pre-menopausal, positive ER+/PR+ is likely, and the cancer is aggressive.  If the patient was postmenopausal, the test is more likely ER/PR negative.  This gives us a perspective on how far we have come.

Image representing Genomic Health as depicted ...

Image via CrunchBase

English: Validation chart for Agendia's MammaP...

English: Validation chart for Agendia’s MammaPrint Assay, part of the Symphony Breast Cancer Suite (Photo credit: Wikipedia)

Ovarian and breast cancer patients in a pedigr...

Ovarian and breast cancer patients in a pedigree chart of a family (Photo credit: Wikipedia)

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State of the art in oncologic imaging of breast.

Author-Writer: Dror Nir, PhD

In the coming posts I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on breast cancer imaging.

Breast Cancer Imaging

As a start the authors describes the evolution in the ACS imaging guidelines for breast cancer screening. Most interesting to learn is how age limits are changing. The most recent: “In 2010, the Society of Breast Imaging and the Breast Imaging Commission of the ACS issued recommendations for breast cancer screening to provide guidance in light of the controversies and emerging technologies.5 These recommendations were based on multiple prospective randomized trials as well as population-based experience.

Recommendations for screening with non-mammographic imaging are based not on evidence showing mortality reduction but largely on surrogate indicators, i.e., tumor size and nodal status, suggesting improved survival compared with women who are not screened.” I have referred to these guidelines in my recent post: Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

As long as imaging interpretation is based mainly on observations related to lesion morphology:

“The imaging characteristics of malignant lesions are nonspecific and usually do not allow a definitive diagnosis. When a biopsy is recommended based on mammography, it has a 25% to 45% likelihood of resulting in a diagnosis of carcinoma.11 Similar positive predictive values are reported for biopsies recommended based on MRI.”

It is worthwhile noting that these results do not reflect purely the specificity of the imaging device but rather the specificity of the whole workflow; i.e imaging, biopsy and histopathology. All imaging techniques have false negatives: Mammography screening of general population misses approximately 20% of the cancers. This rate increases as breast density increases. MRI is not applied to general population. When applied to highly suspicious cases MRI misses ~10% of the invasive cancers. Although ultrasound has proven to be useful in detecting cancer especially in women with dense breasts: Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need! Based on the literature reviewed by the authors of this paper they do not recommend routine sonography for these women.

For women with locally advanced breast cancer (Fig. 2) who undergo neoadjuvant therapy before breast surgery, the authors recommends post-treatment staging using MRI, which has been found to predict complete response with sensitivity above 60% and specificity as high as 90%.26

A 27-year-old female with locally advanced poorly differentiated invasive ductal carcinoma underwent evaluation of extent of disease before starting neoadjuvant chemotherapy. Sagittal fat-suppressed T1-weighted postcontrast MR images demonstrate an almost 6-cm heterogeneously enhancing mass (A) involving the skin of the lower breast (arrow) with (B) right axillary (arrow) and (C) right internal mammary adenopathy (arrow).

A 27-year-old female with locally advanced poorly differentiated invasive ductal carcinoma underwent evaluation of extent of disease before starting neoadjuvant chemotherapy. Sagittal fat-suppressed T1-weighted postcontrast MR images demonstrate an almost 6-cm heterogeneously enhancing mass (A) involving the skin of the lower breast (arrow) with (B) right axillary (arrow) and (C) right internal mammary adenopathy (arrow).

Same is recommended for women who have undergone lumpectomy if the surgical margins are positive. As post therapy follow-up, a new baseline mammogram of the treated breast is recommended followed by annual mammography.

In regards to emerging technology the following are discussed: Mammographic tomosynthesis – see also Improving Mammography-based imaging for better treatment planning

Contrast-enhanced digital mammography – “involves the injection of iodinated contrast material, as is done for computed tomography (CT); this enables hypervascular lesions to be seen with modified mammography technology, potentially providing the same information obtained through MRI. Little has been published on the clinical application of this technology, but diagnostic accuracy better than that of mammography and approaching that of MRI has been reported.3132

MR choline spectroscopy – has been shown to improve the positive predictive value of breast MRI and may be useful in reducing the number of lesions that require biopsy (Fig. 4).33 Studies of spectroscopy have reported sensitivities of 70% to 100% and specificities of 67% to 100% in the detection of breast cancer. Decreasing choline concentrations may also be a useful indication of tumor response to treatment before any change in tumor volume can be detected.3435 Technical factors have limited the use of spectroscopy to lesions 1 cm in size or larger.”

Sagittal fat-suppressed T1-weighted postcontrast MR image is shown (A) of the right breast of a 48-year-old female who was status post–contralateral mastectomy for DCIS with the spectroscopy voxel placed over an enhancing mass (arrow). The magnified spectrum (B) demonstrated no choline peak. Biopsy yielded fibroadenoma.

Sagittal fat-suppressed T1-weighted postcontrast MR image is shown (A) of the right breast of a 48-year-old female who was status post–contralateral mastectomy for DCIS with the spectroscopy voxel placed over an enhancing mass (arrow). The magnified spectrum (B) demonstrated no choline peak. Biopsy yielded fibroadenoma.

Diffusion-weighted MRI (DW-MRI) – “adding DW-MRI data to other imaging characteristics of lesions on breast MRI may increase the positive predictive value of the examination, in turn decreasing the number of benign lesions requiring biopsy for diagnosis.” See also Imaging: seeing or imagining? (Part 2).

Axial T1-weighted fat-suppressed postcontrast MR image is shown (A) of the left breast of a 42-year-old female with biopsy-proven contralateral cancer undergoing evaluation of disease extent. An enhancing mass (arrow) was seen in the left breast. This mass (arrow) was also demonstrated on the axial diffusion-weighted MR image (B). Biopsy yielded fibroadenoma with atypical ductal hyperplasia and lobular carcinoma in situ.

Axial T1-weighted fat-suppressed postcontrast MR image is shown (A) of the left breast of a 42-year-old female with biopsy-proven contralateral cancer undergoing evaluation of disease extent. An enhancing mass (arrow) was seen in the left breast. This mass (arrow) was also demonstrated on the axial diffusion-weighted MR image (B). Biopsy yielded fibroadenoma with atypical ductal hyperplasia and lobular carcinoma in situ.

Ultrasound-elastography – “Ultrasound elastography has been reported to differentiate benign from malignant breast lesions with sensitivities of 78% to 100% and specificities of 21% to 98%.39 When added to other US techniques, it may improve radiologists’ performance in distinguishing malignant breast lesions.”

Positron emission tomography (PET) – “alone or combined with CT, allows noninvasive, quantitative assessment of biochemical and functional processes at the molecular level in the body. It is most often performed with the radiolabeled glucose analogue [18F] fluorodeoxyglucose ([18F]FDG) to detect the elevated glucose metabolism that is a hallmark of cancer. In breast cancer, its utility depends on the pretest probability for advanced disease, and thus the clinical stage.” The authors found that the use of [18F] FDG PET to patients with stage I and II disease is “limited”. Specifically, they claim that it is not sufficiently accurate for axillary nodal staging in this subset of patients.40 The did find enough evidence to recommend the use of FDG PET in patients with advanced disease: “where it accurately defines disease extent,41 and frequently eliminates the need for other imaging tests, and provides an early readout of treatment response as well as prognostic information.”

Combined PET/MRI is mentioned as a promising technology for predicting response to therapy “but this remains to be proven”.

Positron emission mammography (PEM) – “adapts full-body PET imaging to the breast. In a multicenter study, the interpretation of PEM in conjunction with mammographic and clinical findings yielded a sensitivity of 91% and a specificity of 93% for breast cancer.47 “. However, the authors mention that its use for screening (applying to healthy women) has been criticized because of the need to administer a radioactive tracer.

Lung Cancer Imaging

To be followed…

Other research papers related to the management of breast cancer were published on this Scientific Web site:

The unfortunate ending of the Tower of Babel construction project and its effect on modern imaging-based cancer patients’ management

 Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Introducing smart-imaging into radiologists’ daily practice.

Will Bio-Tech make Medical Imaging redundant?

Improving Mammography-based imaging for better treatment planning

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

Predicting Tumor Response, Progression, and Time to Recurrence

“The Molecular pathology of Breast Cancer Progression”

Personalized medicine gearing up to tackle cancer

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

What could transform an underdog into a winner?

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Nanotech Therapy for Breast Cancer

A Strategy to Handle the Most Aggressive Breast Cancer: Triple-negative Tumors

Optical Coherent Tomography – emerging technology in cancer patient management

Breakthrough Technique Images Breast Tumors in 3-D With Great Clarity, Reduced Radiation

Closing the Mammography gap

Imaging: seeing or imagining? (Part 1)

Imaging: seeing or imagining? (Part 2)

 

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Reported by: Dr. Venkat S. Karra, Ph.D

An interesting Interview by Dr. Miller with renowned OncoMeds on ASCO 2012 annual meeting:

American Society of Clinical Oncology

Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis. I would like to welcome you to Medscape Oncology Insights, our annual wrap-up of the 2012 meeting of the American Society of Clinical Oncology (ASCO®). I am joined today by several of my colleagues: Dr. David Kerr, Professor of Cancer Medicine from the University of Oxford and former President of the European Society of Medical Oncology; Dr. Bruce Cheson, Deputy Chief of Hematology and Oncology, and Head of Hematology at the Georgetown University Hospital and Lombardi Comprehensive Cancer Center in Washington, DC; and last but not least, Dr. Maurie Markman, Vice President, Patient Oncology Services, and National Director for Medical Oncology, Cancer Treatment Centers of America, based in Philadelphia. Thank you all for joining us today.

Maurie, let’s start with you. When you think about highlights of this year’s ASCO® meeting for genitourinary (GU) and ovarian cancers, what are you taking home?

Ovarian Cancer: Clear Benefit With Bevacizumab

Maurie Markman, MD: There was a very interesting session, because of what was seen and what was not seen. The surprise for me was the randomized phase 3 trial[1] that looked at the question of bevacizumab plus chemotherapy vs chemotherapy alone in platinum-resistant ovarian cancer. Everyone would have predicted, on the basis of 30-plus years of research in this area, that it would be a negative trial, as all past trials have been. In fact, I was convinced it would be a negative trial because there were no press releases ahead of time. That usually tells you the story.

It turns out that the combination of bevacizumab and chemotherapy substantially improved progression-free survival in this setting — the first time this has ever been seen. I would suspect, however, that what most people take away from it is the fact that there was a tripling of the objective response rate, and clear evidence of patient benefit. This was very much a surprise; I don’t think anyone expected this.

The next question is going to be, what happens next? Is this drug going to receive regulatory approval on this basis? This is clearly an unmet need. That was a real positive.

On the other hand, one could argue that in contrast to other things that we will hear about, there is still no target of therapy in any of the gynecologic cancers. We haven’t found anything that would suggest an epidermal growth factor receptor (EGFR) mutation, or anything to suggest a KRAS mutation or anything that could point to where we need to go in this area. On the one hand, that is a very interesting finding, from the perspective of biology. But it is quite discouraging from the perspective of drug development.

Dr. Miller: The Cancer Genome Atlas (TCGA) data had to be discouraging. Essentially, every ovarian tumor is a different ovarian tumor.

Dr. Markman: Absolutely.

Dr. Miller: You have 10,000 rare diseases.

Dr. Markman: Other than p53, and we have known of that mutation for decades. It is universal, certainly in the high-grade cancers. But we don’t know how to deal with it. Other than that, the number of mutations found per tumor is enormous, and there are no patterns. So we have to do a lot of thinking. That is, the smart biologists have to do a lot of thinking.

Lymphoma: Chemotherapy? Enough Is Enough

Dr. Miller: Bruce, you spend a lot of your time focusing on the hematology side of malignancies. With the American Society of Hematology (ASH) and a whole separate meeting, sometimes it seems as though hematology doesn’t get as much attention at ASCO®. Was there any big news in the hematologic malignancies that people need to know about?

Bruce D. Cheson, MD: There were not. However, this has the potential to be an historic meeting, because we are going to finally learn that “enough is enough” with chemotherapy, and we are at that point.

We saw some very historic presentations. We saw rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), vs rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), vs rituximab, fludarabine, and mitoxantrone (RFM) — where basically the only difference is in toxicity.[2]

Dr. Miller: “Pick your poison” — toxicity, but you will get to the same place.

Dr. Cheson: Yes. We also saw that R-bendamustine was better than R-CHOP,[3] but there are questions about the R-CHOP arm looking kind of lame. We were thinking, where are we going in follicular lymphoma?

Where we are going is what John Leonard and colleagues[4] presented in the relapse setting, and that’s biological agents. We have lots of those. We have lots of targeted agents. I predict that in the next year, instead of hearing more about R-CHOP and R-bendamustine, we are going to be hearing more about the GS-1101s; the PI3-kinase inhibitors; ibrutinib, the Bruton tyrosine kinase (BTK) inhibitor; and those drugs which we in the Cancer and Leukemia Group B (CLGB) (now Alliance) have been planning on combining with biological strategies. We are going to be trying to get rid of chemotherapy. This may be, hopefully, the last meeting we hear about regimen A vs regimen B. It’s kind of sickening.

We have the same situation in Hodgkin lymphoma — where we cure, depending on the stage, up to 90% of people, and at this meeting we see adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) vs bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) again for about the fourth iteration. Lo and behold, there is no survival difference.

We saw lots of that, but now we have other drugs. We have brentuximab vedotin, which is an antibody/drug conjugate. It is anti-CD30, linked to auristatin, a tubulin poison, which in transplant-refractory patients had a 75% response rate. There weren’t any data at this meeting. The data on that drug were presented at ASH. But there are now trials incorporating brentuximab/vedotin, not only in second-line treatment, but we are now moving it up into front-line.

So, we have the tools; it’s just a question of being smart enough, and figuring out how to put them together in a coherent fashion, on the basis of scientific rationale. The most important thing I took away from this meeting is, enough is enough. You can pick your poison, as you put it. But don’t hold on to it for dear life, because there are new, very exciting drugs coming along that are being combined in a biological fashion.

Breast Cancer: Targeted Therapies Are Clear Winners

Dr. Miller: You might have snuck into a breast cancer session, because that is how I would summarize the breast cancer world this year as well. We saw adjuvant trials, metastatic trials, comparing one chemotherapy regimen with another. To summarize a lot of data, pick your third-generation adjuvant chemotherapy regimen and the toxicity will differ, depending on the drugs, but the efficacy doesn’t differ at all. In the metastatic setting, newer wasn’t better. It brought more toxicity, which then led to more dose reductions, which hampered efficacy.

So when we thought we were getting newer and better drugs, they didn’t actually do better for our patients. It sounded a little bit like ABVD vs BEACOPP in Hodgkin disease.

Dr. Cheson: We have to get rid of chemotherapy.

Dr. Miller: Targeted therapies, either with direct molecular targets or antibody/ drug conjugates, were the clear winners, with major improvements in efficacy and substantially less toxicity. I would be quite happy if I didn’t have to look at another basic chemotherapy study in breast cancer again. Was that the case in the gastrointestinal (GI) studies as well, David?

GI Phenotypes and 5 Daughters of Eve

David J. Kerr, MD: It was. We are seeing mildly disappointing and moderately good results. The big, well-designed study, REAL 3,[5] looking at the role of panitumumab with combination chemotherapy, had negative findings. Panitumumab seemed to do a bit worse, which was somewhat disappointing.

Some positives are coming out in colorectal cancer. The antiangiogenic therapies look as if they are here to stay. A nice randomized trial[6] looking at discontinuation or continuation of bevacizumab following progression in first-line chemotherapy shows that the bevacizumab follow-through has significant advantages, in terms of progression-free survival.

An interesting, clever, genetically designed drug, aflibercept, which is a vascular endothelial growth factor (VGEF) trap, showed very promising activity in second- line therapy.[7] So something is holding true there. We have a new drug, regorafenib, which is one of these oral multitargeted kinase inhibitors, that seems to have an important clinically useful role to play in third-line chemotherapy.

For me, the take-home message, in contradistinction to Maurie, is that we are starting to get a feel for the different molecular phenotypes for colorectal cancer. It looks as though there may be 5 daughters of Eve, and it needs to be confirmed. We need to internationalize what we are doing. It looks as though some patterns are starting to emerge that will allow us to make prognostic inferences, possibly treatment-wise, and so on. Things are starting to stack up for us, in terms of driver mutations, therapeutics, and providing the patient with better information, so this is somewhat luckier than the situation with ovarian just now.

How Do We Eliminate Chemotherapy?

Dr. Miller: When we look ahead, we would all love to get rid of chemotherapy. How do we do that? By understanding the biology, which is the easy answer. Bruce, you mentioned that we do tend to cling to our chemotherapy regimens. We have been having discussions about how to do this in breast cancer, and there is a great reluctance to give up the regimens that have gotten us to where we are.

Dr. Cheson: Reluctance from the doctor, but not from the patient.

Dr. Miller: So how do we move forward?

Dr. Cheson: There are a couple of ways. First is a better understanding of tumor biology. We have been sitting around doing what we do for so long. Now we have some tools, but we need to know how to apply them. At every clinical trial in CLGB (now Alliance), we have correlative science. We are doing natural killer (NK) cell numbers and functions. We are doing microarrays so that we can understand which regimen works in which patient. It may not be like your field (gynecologic cancer), where every patient has their own disease, which is what I get accused of saying in lymphoma all the time. I am glad someone else has that problem.

We have the drugs. We need to know how to put them together, but which patients should we target? Then, we need to figure out how to move them up front — such drugs as brentuximab, the Hodgkin drug, and anti-CD30, which in anaplastic large cell lymphoma has an 86% response rate in relapsed patients. In a good clinical trial, we need to take a risk and just do it. If a drug is 86% effective in the refractory setting, it is not going to be worse up front.

There are those who will say, “Well, the response may not last as long.” But there are several ways you can introduce these drugs in an up-front setting, such as window-of-opportunity studies, Or, you can first tack them on to some chemotherapy and then try and wean off the chemotherapy.

There are a number of ways to do it. You just have to do it. You have to take a risk and view it as a challenge. You have to say, “We have had enough of this; let’s move on.” We have the tools; let’s do it.

I-SPY: New Paradigm for Clinical Trials?

Dr. Miller: Maurie, you know I can’t resist, because this issue of clinical trials came up last year when we were talking about melanoma data, with striking activity reported by the BRAF investigators. Are you going to do those trials? Are you willing to take that risk?

Dr. Markman: Obviously, you have to look at the individual cancers. Consider the report that said breast cancer had 10 different cancers, maybe more. It is going to be harder and harder to do randomized trials in 10 subsets, even in a disease that is as common as breast cancer.

Dr. Miller: We are actually closer to your problem, where each patient is an individual disease, than to Bruce’s situation.

Dr. Markman: We do have to come up with a different clinical trial paradigm as we get to smaller subsets. Of course, the tsunami that many have predicted is here. It wasn’t part of the meeting directly, but a half-dozen or dozen companies are now offering whole-genome sequencing. We have to figure out how to use all these things. It may not be as simple as a particular molecular abnormality, but it may be, as many people are saying, particular systems.

For example, in the ovarian cancer area, there are BRCA1 and BRCA2, and there are some drugs that affect those mutations. But a very important study from last year looked at maintenance therapy in the second-line setting with olaparib[8] in tumors that were said to have a BRCA-ness profile. In other words, there is a molecular profile that is similar to that of BRCA1 and BRCA2, and in fact, it was a very positive trial, at least from the perspective of progression-free survival. You may not be able to find a particular molecular abnormality, but there may be patterns. And that may be (in our area, where you can’t find an abnormality) much more complicated than just finding a mutation. That may be the way forward in such diseases as ovarian cancer.

Dr. Cheson: Maybe I did wander into the breast meeting, but we need to reconsider how many phase 3 trials we want to do. The I-SPY concept is where we need to be going. You take a regimen that should work in a subset of patients, and you test that and see if it does. Then you can figure out who responded and who didn’t, doing various molecular techniques, and then you take the patients who responded and put them in one pile, and enrich that pile. You take the patients who didn’t respond, figure out why they didn’t respond, and retarget them. After a while, you have high response rates in this one, and you start to improve the outcome in the other one. We need to do this. There is no way around it. It’s coming.

I hate to say this, but I think maintenance is for losers, because if you are going to do right, you have to do it up front. Progression-free survival doesn’t necessarily correlate with overall survival. It is nice. You don’t see the doctor as often. But we need to do this right the first time. I thoroughly agree with you, Maurie — it is going to be a conglomerate of things, and that is why we have new, exciting drugs coming down the pipeline, such as these PI3-kinase mammalian target of rapamycin (mTOR) hybrid inhibitors. We need to block multiple pathways, because the tumors are damn smart. If you block one, it has all these other ways of getting around you.

More Fun With Something vs Nothing Trials

Dr. Kerr: Indeed, and that comes back to Maurie’s point about thinking in systems and programmatically. The answer to Kathy’s question — can we get rid of chemotherapy? — is no. But can we do better? Think about the huge focus that we have in trying to map biomarkers to the new drugs, often mechanistic. We are not doing enough with the conventional cytotoxic drugs that we have.

We could do a lot more. Genome-wide association studies, looking at patterns of toxicity, so that we can use polymorphisms to say “you get full dose of the drug, you get the reduced dose.” We could be using the tools of trade that we have much better. With the new platform technologies, we should be able select patients who do better with 5-fluorouracil (5-FU), with taxane, and so on.

Dr. Cheson: So, how do you study that in randomized trials?

Dr. Kerr: We are lucky in that we have been collecting material from the old days. Makes us something like Dickensian characters. We have hoarded a lot of material from something vs nothing-type trials, and that gives us the opportunity, in that large randomized setting, to develop some of these predictive markers for “yes or no 5-FU, yes or no taxane.” So, it is going back to our youths, when we did all that stuff.

Dr. Miller: That is how we made advances in breast cancer. The predecessors in my field collected tumors long before the technology that we now use to interrogate them was even a glint in someone’s eye. That may actually have a bigger global impact.

Dr. Kerr: I think so.

Dr. Miller: Although this is the American Society of Clinical Oncology, one third of our members are from outside the United States, one half of the attendees are from outside the United States, and most of the fabulous molecular things we have been talking about are not within reach of most patients globally. But some of our old things are cheap. Perhaps using them in a more intelligent way may actually have more benefit on a global scale.

A Question of Value

Dr. Kerr: Exactly. So you have segued into the concept of value. I was delighted to see the brief stance that ASCO® has taken toward value, and saying that there are some things that we do that don’t add value to the care of the patients that we look after. I am a huge fan of US medicine at its the very best, but there’s a lot of waste in what we do. The fact that ASCO® is trying to identify this — 17.5% of the gross domestic product (GDP) is being spent in health now — I thought that was fantastic. Yes, there is value out there, and we should seek it. We should mine old databases, fiddle with new drugs and old drugs, teach old drugs new tricks, and so on.

Dr. Cheson: Five years from now, you are going to look at this video, and you had a whole list of “mabs and mibs” that you are going to figure out and put together, and all of a sudden, FOLFOX, FOLFIRI will be “pffft.” You are going to be combining those biologic agents intelligently, and you are going to get rid of those chemotherapy drugs, I predict.

Dr. Miller: We are out of time for this year, but I am going to book you both for 5 years from now to see whose prediction of the future comes true, where the value lies, and where we can make improvements, because I’m not so sure that they are mutually exclusive. But that’s all from this year’s Medscape Oncology wrap-up of the Annual Oncology Society Meeting. Thank you again for joining me.

References

  1. Pujade-Lauraine E, Hilpert F, Weber B, et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract LBA5002.
  2. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 8006.
  3. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 3.
  4. Leonard J, Jung SH, Johnson JL, et al. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 8000.
  5. Waddell TS, Chau I, Barbachano Y, et al. A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract LBA4000.
  6. Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract CRA3503.
  7. Allegra CJ, Lakomy R, Tabernero J, et al. Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: a phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen. Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 3505.
  8. Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). Program and abstracts of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, Illinois. Abstract 5003.

Source

Article(s) of Relevance:

I-SPY 2 Clinical Trial Design Promises to Accelerate FDA Approvals

Reported by: Dr. Venkat S. Karra, Ph.D

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