Report from the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO), June 1-5
As the world's largest meeting of clinicians and scientists, the American Society of Clinical Oncology's 2012 Annual Meeting gathered over 31,400 cancer professionals from around the globe in Chicago. The meeting opened with a moving tribute to Evelyn H. Lauder
, founder of The Breast Cancer Research Foundation (BCRF). "Let us remember Evelyn, her vision, her verve, and her vibrancy," said Martin J. Murphy, Jr., PhD, Chairman of ASCO's Conquer Cancer Foundation. "Let us also pledge to redouble our commitment in her memory -- a commitment to help create a future free of the fear of cancer."
Inherent in that commitment is ASCO's promise to constantly advance patient care. In addition to providing a forum for cancer investigators to share data and engage in productive interactions, this conference serves an important educational function, updating practitioners about the latest advances in cancer screening, diagnosis, treatment and prevention. BCRF grantees played a major role in the meeting and contributed to 292 of the accepted 2,487 oral and poster presentations, which included studies on ovarian, skin, lung, and gastrointestinal cancers in addition to breast cancer.
The highlights of BCRF-funded investigators who were prominent in meeting presentations included studies on improving clinical care, targeting cancer metastasis (the spread of cancer), developing interventions to address post-cancer therapy issues, and focusing on cancer prevention strategies.
Preceding the opening session of the Annual Meeting, BCRF, in collaboration with Plato Foundation and the European School of Oncology, hosted a satellite meeting for breast cancer fellows, which was co-chaired by BCRF Scientific Director Larry Norton, MD and grantee Fatima Cardoso, MD. Watch the Fellows Forum...
ADVANCES IN CLINICAL CARE
One of this year's highly anticipated reports came from the international EMILIA trial for women with HER2-positive (HER2+) breast cancer that has spread, or metastasized. The study examined the effectiveness of T-DM1, which delivers toxins directly into cancer cells thereby causing their demise. In the trial, the disease progression of women on T-DM1 was delayed longer than those who received the conventional therapy of capecitabine plus lapatinib, while causing far fewer serious side effects. Based on the optimistic results, T-DM1 is expected to be submitted for FDA approval this year and could reach the market as early as next year. A number of BCRF grantees' research institutions are participating in studies of this agent, which include Dana-Farber Cancer Institute, University of Miami, and Institut Curie.
On the heels of the EMILIA report, the FDA approved the use of pertuzumab, another investigational drug for metastatic HER2+ breast cancer, based on results from the CLEOPATRA trial reported at the San Antonio Breast Cancer Symposium in December 2011 by José Baselga, MD, PhD (Massachusetts General Hospital Cancer Center), who is also an investigator in the EMILIA trial. These studies are making a significant impact on the care of women with metastatic HER2+ breast cancer. Again, ongoing studies designed to improve and expand the use of pertuzumab are underway at many of BCRF grantees' clinical research sites.
Another focus of research efforts was on triple negative breast cancer, a disease subtype which currently lacks targeted treatments. Poly (ADP-ribose) polymerases, or PARP, pathways, have been known to play a critical role in DNA repair but have not yet lived up to expectation. Mark E. Robson, MD (Memorial Sloan-Kettering Cancer Center, MSKCC) reviewed the use of PARP inhibitors in hereditary and sporadic breast cancers and suggested that high-grade papillary serous ovarian cancer is a disease that may benefit most from PARP inhibitors. Much work remains to realize the full therapeutic potential of PARP inhibitors. In this same group of patients, Ayca Gucalp, MD, a research fellow at MSKCC presented on behalf of the BCRF-supported Translational Breast Cancer Research Consortium, that a small number of triple negative breast cancer have functional receptors for the male hormone, androgen, and can be successfully treated using bicalutamide, an established drug for prostate cancer. This work, spearheaded by Tiffany Traina, MD, under the supervision of Clifford Hudis, MD, Chairman of BCRF's Scientific Advisory Committee and ASCO President-Elect, has led to renewed interest in agents that target the androgen receptor in breast cancer.
Chemotherapy remains an important therapy option for all breast cancer subtypes, especially for the types that have a high percentage of dividing cells, such as triple negative and inflammatory breast cancers. Hope S. Rugo, MD (University of California, San Francisco) reported results from a study on women with either metastatic estrogen receptor positive (ER+) or triple negative breast cancer. The study was the collaboration of many BCRF grantees and included Dr. Clifford Hudis. This trial tested a new dosing schedule for two experimental drugs (nab-paclitaxel or ixabepilone) in comparison with that of paclitaxel, which is part of standard cancer therapy. Trial participants had not been previously treated with chemotherapy for their metastatic disease and could choose to take or not take the anti-angiogenesis drug, bevacizumab (Avastin®). Dr. Rugo noted that paclitaxel was as effective as the two newer drugs, which provide broader options for patients and their physicians.
Kathy Miller, MD (Indiana University School of Medicine) discussed the results of the NSABP B-38 trial, which compared the effectiveness of dose dense adjuvant chemotherapy versus simultaneous chemotherapy. The dose dense schedule was created by Larry Norton, MD (MSKCC), BCRF Scientific Director. As predicted by the Norton-Simon Model, results showed that the sequential schedule was superior to the simultaneous one, while also being less toxic. Dr. Miller also reviewed Dr. Rugo's presentation along with two others and challenged her colleagues to think about the design and conduct of future clinical trials. She stated that major improvements would result only if future clinical trials focus on tumor biology and use that information to identify the subset of patients who truly need chemotherapy and will benefit from it.
As scientists gain additional insights into the biology of tumors, the heterogeneity, or differences, within a single specimen is ever more apparent. For example, triple negative breast cancers - even though the name suggests the contrary - still express estrogen (ER) and progesterone (PgR) receptors. In an effort help researchers and clinicians better match patients to treatments so that patients can experience the maximum benefits, the North American Breast Cancer Group and Breast International Group are trying to establish a more precise definition of "triple negative patients."
Gabriel Hortobagyi, MD (University of Texas MD Anderson Cancer Center, MDACC), a member of BCRF's Executive Board of Scientific Advisors, discussed posters derived from two large, multinational clinical trials. Researchers in the MA27 trial conducted a retrospective analysis to see if bone-strengthening drugs called bisphosphonates affected patient outcomes, specifically in terms of bone metastasis. Investigators of the AZURE trial preliminarily explored the outcomes of bisphosphonate use in women with breast cancer, according to their menopausal status. Dr. Hortobagyi reported that the data demonstrated that bisphosphonates were beneficial to patients with osteoporosis; however, definitive evidence is still lacking in the advantages of prescribing these drugs to those without bone loss. He encouraged more thorough and rigorous studies.
Lori Pierce, MD, FASTRO (University of Michigan), an authority in radiation oncology, participated on a multidisciplinary panel with a surgeon and a medical oncologist in an overview of breast cancer care and the role of radiation therapy. She noted that there has been an increased use of neoadjuvant (pre-surgical) therapy, for several reasons: shrinking tumor size before surgery may decrease the likelihood of complications and increase the chance of breast conservation procedures; and the neoadjuvant setting provides the opportunity to assess the patient's response before and after surgery.
In a later session, Richard Zellars, MD (Johns Hopkins University, JHU) reviewed data from three post-mastectomy radiation therapy trials by groups in Denmark and Canada, as well as two studies on partial-breast irradiation therapies, including brachytherapy. While Dr. Zellars believes that current data support partial breast irradiation as a promising new treatment, he cautioned that until long-term randomized controlled data is available, it is probably safest to reserve this therapy for patients at lowest risk of recurrence.
In addition, researchers are harnessing the new gene sequencing technology to produce insights into clinical treatment decisions and forecasting patient prognosis. Matthew J. Ellis, MD, PhD (Washington University) reported on his team's efforts in whole genome sequencing of ER+ breast cancer tissues that have been treated with conventional aromatase inhibitors (AIs). They had the goal of identifying genetic mutations that may indicate resistance to AI therapy. They found that mutations were doubled in the tumors that were resistant to AI. They also observed commonalities in the genetic mutations of some breast cancer cases and other forms of cancer, such as leukemia. In her discussion of Dr. Ellis's study, Martine Piccart-Gebhart, MD, PhD (Institut Jules Bordet) noted the critical importance of establishing the "hub genes" in AI resistance, to help researchers in their search for markers that can predict response to therapy or indicate disease progression.
"Treatment of patients with metastatic disease always requires a delicate balance," said Dr. Kathy Miller. "Our goals are to prolong survival when we can, to palliate symptoms when they exist, and to improve and hopefully preserve the quality of life of our patients. That always requires recognition that both the disease and our treatment related toxicities can have a profound negative impact on our patients' lives."
This emphasis on strategies for metastatic breast cancer and targeting treatment resistance was prominent throughout the meeting. A panel, including BCRF grantees George W. Sledge, Jr., MD (Indiana University), immediate past president of ASCO; Fatima Cardoso, MD (Champalimaud Cancer Center); and Dr. Martine Piccart-Gebhart, addressed treatment strategies for advanced breast cancer. In his overview of the current standard of care, Dr. Sledge pointed out the great variations in the care provided to patients with metastatic disease, as well as the challenges in quality of life issues facing patients. Dr. Cardoso noted that the advances that have been made in metastatic breast cancer differed according to the breast cancer subtypes, while treatment resistance remains the greatest hurdle. She voiced the frustration of many patients and doctors that progress is still mostly measured in months, rather than years, but she expressed optimism in the pace of development of international treatment guidelines, which should produce greater benefits for all patients. Dr. Piccart-Gebhart gave a forecast of the future direction of research, which will emphasize developing drugs targeting "actionable mutations," as revealed by tumor biology, and breast cancer stem cells. She also expressed the opinion that scientists have not yet fully capitalized on the wealth of genetic discoveries into effective new therapies.
Many research efforts today center on the discovery or development of biomarkers, another tool to help predict either a patient's response or forecast disease progression and recurrence. These biomarkers can help prevent patients from undergoing therapies that yield very little benefit. In the sessions on estrogen receptor positive (ER+) and HER2+ breast cancers, several projects focused on the PI3K pathway, which was discovered by BCRF investigator Lewis Cantley, PhD (Beth Israel Deaconess Medical Center). PI3K is the most frequently mutated pathway in all types of cancer, and there are currently 20 drugs in development targeting this pathway. In his discussion of the FinHER study, Carlos Arteaga, MD (Vanderbilt University) provided constructive comparisons with earlier data on PI3K mutation and its correlation to resistance to anti-HER2 therapy such as trastuzumab.
Mitch Dowsett, PhD (The Royal Marsden Hospital) discussed a set of work on biomarker discovery to assess recurrence risk. W. Fraser Symmans, MD (MDACC) submitted a study with 605 specimens from patients that asked the question of whether genomic signatures from breast cancer samples differ according to disease stage. He also looked the changes in patients' tissues as they underwent either endocrine therapy or chemotherapy by using various markers, including one that he had developed called sensitivity to endocrine therapy (SET) index. The SET index was predictive of progression-free survival and overall survival following endocrine therapy.
Also, Dr. Dowsett discussed studies by John M.S. Bartlett, PhD (Ontario Institute for Cancer Research). "For many postmenopausal patients with hormone sensitive early breast cancer, the dilemma is whether or not to opt for adjuvant chemotherapy as well as endocrine therapy to reduce their risk of disease recurrence," said Dr. Bartlett in a later interview. His study suggests that Mammostrat, a five-gene signature assay, may provide additional information following endocrine treatment and can help patients and doctors decide future course of treatment following endocrine therapy.
In Dr. Bartlett's other study, investigators tested the validity of two forms of IHC4 in the prediction of residual risk. IHC4 is a measurement developed by Dr. Dowsett and fellow BCRF grantee, Jack Cuzick, PhD (Queen Mary, University of London), and uses the combination of hormone receptors, HER 2, and Ki67 markers to assess residual risk. Dr. Bartlett and colleagues found that this new tool should be considered in the clinical setting for prediction of residual risk in early breast cancer.
Furthermore, the collaboration between Vered Stearns, MD(JHU), a member of BCRF's Scientific Advisory Committee, fellow BCRF grantee, Seema Khan, MD (Northwestern University), and others to develop a non-invasive and cost-effective risk evaluation was discussed. Current methods to determine breast cancer risk are insufficiently sensitive and need improvement in the ability to identify women most likely to benefit from preventive strategies. Drs. Stearns and Khan are looking at various DNA methylation levels to see if they vary by menstrual phase or menopausal status. Results have been encouraging, and the investigators plan to continue their work in developing this tool.
One of the reports that made international news was a study of more than 1,200 childhood cancer survivors. Researchers from MSKCC found that women who received radiation to the chest, as part of cancer therapy, during childhood may be at higher risk of breast cancer than others. These findings further reiterate the importance of preventing exposure to unnecessary therapies and toxicities. This report further highlighted the importance of survivorship care and research, as the effects of cancer treatment often linger long after therapy has ended.
Two primary issues facing survivors are lingering effects from cancer treatments and adherence to prevention therapy. The number one reason why patients stop treatment prematurely is the toxicity and residual effects associated with certain cancer treatments. Therefore, the discovery of biomarkers to help predict which patient will respond to or experience toxicity from a given therapy is crucial. Bryan P. Schneider, MD (Indiana University), known for his work in nerve damage associated with taxane-based chemotherapies called "neuropathy," reviewed five studies that examined patient outcomes and biomarker discoveries. Noting the additional research needed to be done before accurate biomarkers can be used in clinical practice, Dr. Schneider said, "Biomarkers are conventionally good at predicting which patients should be receiving therapy but bad at whom should not get a standard form of therapy." It is crucial to biomarkers that can prevent exposing patients to unnecessary toxicities.
Also, Debra L. Barton, PhD (Mayo Clinic, Rochester) reported that the plant ginseng appears to help relieve treatment-related fatigue in 90% of the 360 patients studied more than half of whom had breast cancer. Dr. Barton also explored the biological basis of why ginseng may have therapeutic benefits, namely in its inhibition of MAP kinase pathway and decreases HPA activation and pro-inflammatory cytokines. While the study results are promising, Dr. Barton cautioned that patients should use pure ground root of ginseng, as opposed to an extraction, which is sometimes processed with ethanol and can give the mixture estrogen-like properties that can actually stimulate the growth of ER+ breast cancer cells.
Dr. Barton in discussed several additional survivorship studies, including one led by Carol Fabian, MD (University of Kansas Medical Center) exploring the use of vitamin D to alleviate musculoskeletal pain. Many women undergoing aromatase inhibitor therapy report musculoskeletal pain, which causes them to stop taking the drugs prematurely. Study participants were randomized to receive different dosages of vitamin D or placebo along with letrozole, a form of AI. A significantly higher proportion of women on placebo experienced worsening of pain, disability, or fatigue than those on vitamin D. Therefore, researchers believe that there is merit in continuing to study vitamin D as a possible prevention agent against musculoskeletal pain for women on AIs.
Dr. Fabian also reviewed two studies on the controversial use of hormone replacement therapy (HRT) and its correlation to breast cancer incidence and mortality, as HRT has been associated with increased risk of developing breast cancer. Italian scientists looked at the concurrent use of HRT and tamoxifen as breast cancer prevention. Study results suggest that combining low-dose tamoxifen and HRT is safe and provides a promising way to retain the benefits while reducing the risks of either agent, even though additional studies are needed. On the other hand, further analyses based on the Women's Health Initiative data on over 41,000 post-menopausal women suggested that the use of estrogen plus progestin as HRT is associated with increased breast cancer incidence and mortality. Therefore, Dr. Fabian cautioned against the use of HRT including both estrogen and progestin in clinical practice.
A group of researchers including several BCRF grantees used the PAM50 assay, developed by Charles M. Perou, PhD (University of North Caroline, Chapel Hill), to evaluate breast cancer subtypes among a group of older patients and found that although more favorable subtypes increase with age, older breast cancer patients still have a substantial percentage of high-risk subtypes. Therefore, age alone was not a significant factor in outcome.
The issue of race and breast cancer subtypes was also examined. In one project, scientists looked whether people of different races have more of one breast cancer subtype than another. Based on results, it appeared that African American women tend to have fewer cases of luminal breast cancer, as reported in earlier studies.
Another issue in breast cancer treatment is the correlation with aging. Hyman Muss, MD (University of North Carolina, Chapel Hill, a pioneer in this field, reviewed data suggesting that elderly patients assessed to be in good general health can be given the same treatment as younger patients; however, older and frail patients may need adapted treatment or palliative therapy. Dr. Muss highlighted the need to consider life expectancy, potential for toxicity, co-morbidity, effects on function and quality of life, and patient preferences when working with older patients and recommended several widely available resources for assessing risk factors.
As diabetes and breast cancer are both common conditions in women and share common risk factors, a special emphasis on obesity as risk factor for cancer incidence and mortality was evident throughout the meeting presentations. Pamela Goodwin, MD (Mount Sinai Hospital, University of Toronto) co-chaired a satellite symposium on diabetes and cancer and incorporated data from her own clinical trial evaluating metformin, a diabetes drug, as breast cancer prevention.
"One of the main reasons why the relationship between cancer and diabetes is of interest is we are in the midst of an obesity epidemic in the developed world," said Dr. Goodwin. "Evolution has not been able to keep up with changes in our lifestyle." Researchers looking at potential associations between diabetes, related factors, and breast cancer risk conducted a comprehensive literature review. They found that key risk factors for breast cancer appear to be body mass index and physical activity -- both of which are related to the risk of developing diabetes and can be modified through lifestyle changes.
While evidence is mounting that certain lifestyle factors can modify risk of developing breast cancer, there are also pharmacologic agents currently available. On a panel "Breast Cancer Chemoprevention: If Not Now, When?" Nancy Davidson, MD (University of Pittsburgh), a member of BCRF's Executive Board of Scientific Advisors, listed much evidence for the validity and benefits of chemoprevention. She highlighted barriers that discourage women from taking tamoxifen and raloxifene, the two FDA-approved drugs for breast cancer prevention, in spite of an abundance of data demonstrating their effectiveness and limited negative side effects. Dr. Davidson noted that the breast cancer field is far behind cardiovascular diseases in prevention and rallied her colleagues to strive towards the latter model to improve patient care.
In addition, Kala Visvanathan, MD, MHS (JHU) collaborated with colleagues in Ireland to explore the potential correlation between aspirin use and breast cancer mortality in women with stage I-III breast cancer. Recent studies have associated aspirin use with large reductions in breast cancer mortality, but why that may be the case is largely unknown. Also, the information on dose and duration of aspirin use are limited. Dr. Visvanathan and colleagues observed no mortality reduction in women who were exposed to low doses of aspirin. The benefits of aspirin exposure were associated with high doses and were greater in early stage, node negative disease. These findings may explain inconsistent results from previous studies and can inform future clinical trials.
FELLOWS FORUM CO-HOSTED BY BCRF
Preceding the opening session of the Annual Meeting, BCRF, in collaboration with Plato Foundation and the European School of Oncology, hosted a satellite meeting for breast cancer fellows, which was co-chaired by Dr. Larry Norton and Dr. Fatima Cardoso. A dynamic panel of BCRF grantees presented five cases from clinical practice that challenged the fellows' knowledge of current therapies and their clinical utility. They examined treatment strategies in the rare but aggressive inflammatory breast cancer, assessed therapeutic opportunities in HER2+ patients with brain metastases, and metastatic ER+ and triple negative breast cancers. Over 57 fellows from the US and abroad attended this educational forum and contributed to a lively question-and-answer session.