Report from the 35th Annual San Antonio Breast Cancer Symposium, December 4-8, 2012

The San Antonio Breast Cancer Symposium (SABCS), co-chaired by Carlos Arteaga, MD (Vanderbilt-Ingram Cancer Center) and Kent Osborne, MD (Baylor College of Medicine), is the largest annual breast cancer meeting. Marking its 35th anniversary in 2012, SABCS is a global forum for clinical trial updates, advances in translational science, the creation of new clinical tools, and initiatives to improve survivorship care. Unique features of the meeting included a review of 2012 research highlights and special awards to individual scientists. Heavy emphasis was placed on metastatic and advanced breast cancer. Fatima Cardoso, MD (Champalimaud Cancer Center, Portugal) led a special session sharing the first consensus guidelines on treatment for advanced breast cancer. These guidelines were developed through an international collaboration stewarded by Dr. Cardoso and BCRF Scientific Director, Larry Norton, MD (Memorial Sloan-Kettering Cancer Center, MSKCC), among others.

Contributing over 170 of the 1,000+ posters and presentations, BCRF-funded investigators were prominent at SABCS. Notably, with 2012 described as "the year of breast cancer genomics," ten of the eleven papers cited as exemplary contributions to basic science research were co-authored by BCRF grantees.

Selected highlights are as follows:

UPDATES FROM CLINICAL TRIALS
As clinical trials are conduits transferring research advances to the clinic, SABCS featured updates from international trials and conducted a special session focused on trial design. Among the panelists was Chairman of BCRF's Scientific Advisory Board, Clifford Hudis, MD (MSKCC), who provided useful guidelines for establishing endpoints, or outcome measures, throughout the three phases of a clinical trial. This session highlighted the need for more efficient trial designs to allow for rapid testing and approval of the many new agents now in development. This is part of a broad discussion throughout oncology about how to harness the power of digital records to lower the cost of bringing new drugs to patients.

Key clinical trials reported include:

Estrogen Receptor Positive (ER+) Breast Cancer
The highly anticipated follow-up results from the ATLAS (Adjuvant Tamoxifen - Longer Against Shorter) trial, enrolling 12,894 women, most of whom had estrogen receptor positive (ER+) breast cancer, and randomizing them to stop tamoxifen at the standard five years or continue an additional five, to ten in total. The results indicated that extending tamoxifen use from five to ten years significantly reduced disease recurrence and mortality especially in the later years. The authors' interpretation is that this suggests that tamoxifen has a carry-over effect that lasts long after women stop taking it. Also, although tamoxifen is associated with an increased risk for uterine cancer, the rate of uterine cancer mortality was low even with prolonged use.

Angelo Di Leo, MD, PhD (Hospital of Prato, Italy) reported final analysis from the CONFIRM trial comparing fulvestrant dose (500 mg vs. 250 mg) in recurrent and metastatic breast cancer. The higher dose was associated with 4.1-month increase in overall survival and with a 19% reduction in risk of death, without heightened toxicity, for postmenopausal women.

Researchers from the ongoing Breast International Group (BIG) I-98 trial, comparing the effectiveness of letrozole against tamoxifen, performed several additional analyses. One study focusing on patients with invasive lobular breast cancer indicated that letrozole as adjuvant therapy seemed to improve disease-free and overall survival in the subgroup of ER+ patients with luminal B tumors over other groups.

HER2-Positive Breast Cancer
Martine Piccart-Gebhart, MD, PhD (Breast International Group, Institut Jules Bordet) presented the median follow-up data from the HERA trial, comparing the effectiveness and safety between one vs. two years of therapy in 5,102 women with HER2-positive (HER2+) early-stage breast cancer. The longer regimen indicated improved overall survival rates among participants. Slightly more adverse cardiac events were reported in the two-year arm (7.2% vs. 4.1%), but Dr. Piccart noted that most cardiac events were reversible when the drug was stopped.

Further underscoring the importance of being able to identify patients who would benefit most from HER2-targeted therapies, José Baselga, MD, PhD (MSKCC) led a study using data from the CLEOPATRA trial, evaluating pertuzumab's effectiveness on metastatic HER2+ breast cancer, to assess biomarkers for patient selection. Focusing on the PI3K pathway--the most frequently mutated pathway in breast cancers--investigators observed that these mutations could help identify patients with poorer prognoses who might benefit from additional treatments now in development.

Triple Negative Breast Cancer
Triple negative breast cancer remains one of the biggest clinical challenges in cancer care. Although neoadjuvant, or pre-operative, chemotherapy can eliminate breast cancer in 30% of triple negative patients, researchers in the laboratory of Dr. Carlos Arteaga confirmed that 70% still have residual disease at the time of surgery. New genomic technologies are expected to produce additional insights that may guide therapy individualization and prognosis. Encouraging results were also reported from a novel targeted approach towards triple negative breast cancer that combines histone deacetylase (HDAC) inhibitors with a PARP inhibitor, and cisplatin.

CREATING NEW CLINICAL TOOLS

Molecular Profiling and Whole Genome Sequencing
Following the publication of Cancer Genome Atlas's first comprehensive genetic analysis of breast cancer in September, a number of presentations at SABCS emphasized how a better understanding breast cancer biology and the role of genomic (DNA) changes can improve clinical care. Two scientists instrumental in these efforts, Charles Perou, PhD (University of North Carolina, Chapel Hill) and Matthew Ellis, MD, PhD (Washington University School of Medicine), reviewed illustrations of how genomic technologies inform clinical decisions on therapy and prognostication. Dr. Ellis presented on the Z1031B trial, the most critical findings of which was that tumors that do not respond to aromatase inhibitors also do not respond to chemotherapy. This unsettling observation underscores the importance of molecular characterization of these tumors to lay the groundwork for new therapeutic strategies.

At an educational session, Antonio Wolff, MD (Johns Hopkins) and Lajos Pusztai, MD, DPhil (Yale University) led a review of "The Practical Use of Molecular Profiling" and tools that can help guide clinical decisions. Dr. Wolff focused on earlier stage breast cancer and Dr. Pusztai on more advanced disease. In addition to the need to collect and analyze data on metastatic disease, an initiative that BCRF will launch with the Evelyn Lauder Founder's Fund, they stressed the importance of developing biomarkers to guide therapy selection and find new and more effective combined therapies.

Other clinical tools highlighted in San Antonio were the use of the Oncotype DX, Ki67, and AQUA to assess disease recurrence and metastasis. BCRF-funded investigators were prominently featured in this group.

David Rimm, PhD (Yale University) presented a study using a mathematic model called AQUA which he developed to help determine response to therapy and predict metastasis. As part of the NCCTG N9831 trial testing the efficacy of trastuzumab on HER2+ breast cancer, Dr. Rimm and co-investigators applied AQUA to measure EGFR levels, which impact the effectiveness of trastuzumab. They observed a possible correlation between high EGFR level and decreased benefit from adjuvant concurrent trastuzumab, as well as shorter progression free survival in patients with metastatic breast cancer. EGFR, if validated, could help select patients for alternative or additive therapy.

Torsten Nielsen, PhD (University of British Columbia) on behalf of the North American Breast Cancer Group (NABCG) and Breast International Group (BIG) reported on an international effort to standardize the use and measurement of Ki67. High level of Ki67 is associated with high cell proliferation and, therefore, has potential for use in the prediction of breast cancer metastasis. However, based on previous studies funded by BCRF, inconsistencies in measuring Ki67 have limited its usage. To overcome this problem, Dr. Nielsen and colleagues implemented additional tools, such as visual images, to produce consistent results from different research centers. Early results are encouraging.

PI3K and mTOR Pathway
Following results from the BOLERO-2 trial reported last year, PI3K and mTOR pathways have attracted interest for drug development. BOLERO-2 demonstrated that combining exemestane (an aromatase inhibitor used to treat ER+ breast cancer) with an mTOR inhibitor called everolimus, more than doubled the length of time (from 3.2 months to 7.4 months) the patients' tumors responded to treatments. Dr. Carlos Arteaga moderated a session on the PI3K pathway that featured BCRF grantees, Lewis Cantley, PhD (Weill Cornell Medical College), Robert Schneider, PhD (NYU School of Medicine), and Fabrice André, MD, PhD (Institut Gustave Roussy).

Dr. Cantley, who is recognized for his discovery of the PI3K enzyme and its role in regulating cell growth, was featured in a plenary session in San Antonio. The PI3K signaling network is the most mutated in breast cancers and is commonly mutated in many other cancers. Currently, there are roughly 20 PI3K inhibitors in clinical trials. Dr. Cantley focused on his current explorations of inhibiting the PI3K pathway as a means of stopping tumor growth. In an earlier session, John Bartlett, PhD on behalf of investigators from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) study, demonstrated the potential clinical use of PI3K by analyzing mutations in trial participants to determine the impact of PIK3CA mutations on survival. Drs. Robert Schneider and Fabrice André led an informative session on the mTOR pathway, associated with PI3K. They reviewed the biological mechanisms at work and addressed issues faced by scientists trying to develop these new drugs.

SURVIVORSHIP CARE

Today, thanks to advances in research and treatment, there are nearly three million individuals in the US who have survived diagnosis with breast cancer. Patricia Ganz, MD (University of California, Los Angeles), who has pioneered research in cancer survivorship, reviewed studies on cognitive difficulties after cancer treatment. Sharing early results from the Mind Body Study, jointly funded by the National Cancer Institute and BCRF, Dr. Ganz reported that cognitive complaints are common after cancer treatments, especially when radiation is combined with chemotherapy. But they persist in a minority. Benefits of such interventions as cognitive training strategies to ameliorate effects were observed and point to the need for more development in this area.

Making international headlines this year was a study of over 1,200 childhood cancer survivors exposed to chest radiation during treatment, that indicated heightened risk of future breast cancer. Along similar lines, Dr. Antonio Wolff, reporting for the National Comprehensive Cancer Network on a study of over 21,000 early-stage breast cancer patients, assessed the risk of myelodysplatic syndrome and/or accute myelogenous leukemia after adjuvant chemotherapy. Radiation therapy and older age at cancer diagnosis seemed to increase risk in this series as has been previously reported. This finding does not suggest diminished overall effectiveness for these established interventions but points to the continuing need for new strategies to limit risk of subsequent cancers without compromising cure in patients with early-stage breast cancer.

In a separate session, Charlotte Kuperwasser, PhD (Tufts University) examined the link between inflammation and breast cancer in the context of obesity. The World Health Organization cites breast cancer as the most common co-morbidity cancer type associated with obesity. Dr. Kuperwasser reviewed the biological mechanisms linking breast cancer, inflammation, and obesity and explored the possibility of targeting inflammation to thwart tumor growth.

Another issue central in survivorship studies is the possible recurrence of cancer sometimes years or decades after initial treatment. George Sledge, Jr., MD (Indiana University) chaired an education session that centered on the phenomenon of tumor dormancy and was joined by Lewis Chodosh, MD, PhD (University of Pennsylvania) to review ways to develop drugs to target dormant tumor cells and micrometastases that seem to escape conventional therapy. Dr. Sledge also offered suggestions for the design of clinical trials to test dormancy therapy.

YEAR IN REVIEW

The 2012 SABCS concluded with a comprehensive Year in Review session, chaired by Dr. Kent Osborne. Kathy Miller, MD (Indiana University) summarized clinical advances. Addressing disease recurrence, she outlined the take-home messages from the ATLAS trial, where taking tamoxifen twice as long as the current recommendation significantly reduced risk of ER+ breast cancer recurrence and mortality. Dr. Miller also referred to the HERA and PHARE trial results where 12 months of trastuzumab remained the preferential course for HER2+ breast cancer and encouraged future studies to answer whether all, or even a subset of, patients with HER2+ disease could be spared chemotherapy. "Our future will come from trials focusing on the biology and targeting those therapies, even the cytotoxic therapies, to the patients who truly need them, sparing our patients who don't need them or won't benefit, based on toxicity or cost," concluded Dr. Miller.

SPECIAL AWARDS

Annually, the San Antonio Breast Cancer Symposium recognizes five individuals for their contributions to breast cancer research and care. This year, four out of the five honorees are BCRF investigators. BCRF Scientific Advisor, Gabriel Hortobagyi, MD, FACP (University of Texas MD Anderson Cancer Center) was honored with the William L. McGuire Memorial Lecture Award for his outstanding achievements in shaping cancer care.

Mina Bissell, PhD (Lawrence Berkeley National Laboratory) delivered the AACR Distinguished Lectureship in Breast Cancer Research. Hyman Muss, MD (University of North Carolina, Chapel Hill) received the Brinker Award for Scientific Distinction in Clinical Research for his critical contributions to treatment in older breast cancer patients.

Also, Kornelia Polyak, MD, PhD (Dana-Farber Cancer Institute), who is noted for her contributions to breast cancer biology, received the AACR Outstanding Investigator Award for Breast Cancer Research.