Report from the 2012 ASCO Breast Cancer Symposium, September 13-15

Over 900 cancer professionals and advocates gathered in San Francisco for the 2012 Breast Cancer Symposium hosted by the American Society of Clinical Oncology (ASCO) from September 13-15. A number of BCRF grantees presented data that addressed the meeting theme of Clinical Challenges and Opportunities to help enhance the daily practice and research of breast cancer.

In the opening session, "Controversial Topics in Medical Oncology Management," updates from two multinational clinical trials on metastatic breast cancer were presented. As follow-up to the data reported at the ASCO Annual Meeting in June, interim results from the EMILIA trial for women with HER2-positive (HER2+) breast cancer that has spread, or metastasized, suggested that there are significant differences seen in patient safety. Because T-DM1 is a new drug that delivers toxins directly into cancer cells thereby causing their demise, much emphasis is paid on patient safety. According to data to date, more toxicities are reported in the control arm, where the conventional therapy of capecitabine plus lapatinib was used, than in the TDM1 arm. The study has yet to cross the threshold for statistical significance in overall survival of patients in the T-DM1 arm.

Hope Rugo, MD (University of California, San Francisco) provided updates from BOLERO-2, a phase III randomized clinical trial of post-menopausal women with metastatic hormone receptor positive (HR+) breast cancer from 195 sites worldwide. This trial examines the effectiveness of combining exemestane (an aromatase inhibitor prescribed for HR+ breast cancer) with everolimus (Affinitor®), a new medicine inhibiting a cellular pathway component called "mTOR" thought to be important in most HR+ breast cancers. Consistent with earlier results presented last December at the San Antonio Breast Cancer Symposium by a member of BCRF's Scientific Advisory Board, Gabriel Hortobagyi, MD, FACP (University of Texas, MD Anderson Cancer Center), and published by José Baselga, MD (Memorial Sloan-Kettering Cancer Center), the updated findings showed that progression free survival of participants extended from 3.2 months with exemestane alone to 7.8 months with the addition of everolimus. This observation has opened up a new treatment option leading to the approval of this agent earlier in 2012.

William J. Gradishar, MD, FACP (Northwestern University) discussed both presentations and focused on the appropriate and optimal role of everolimus in treating patients with metastatic HR+ breast cancer. Based on current data, it appears that patients who have never been treated with endocrine therapy benefit less from everolimus than those who have. Dr. Gradishar offered the opinion that perhaps endocrine treatments may "activate" mTOR or make patients more sensitive to everolimus, and that it therefore would be even more important for practitioners to take into account previous therapies before prescribing the new drug. He also strongly encouraged further development of clinical tools measuring biomarkers to help physicians determine whether everolimus would benefit individual patients. Future data on the use of mTOR inhibitors as first-line therapy for breast cancer are expected and could further improve treatment results.

A longstanding goal in cancer care is the individualization of cancer therapies. Critical stepping stones have been made through advances in the understanding of tumor biology, much of which was greatly enhanced by new biotechnologies. In a sold-out "Meet the Professor" session, Dr. Gabriel Hortobagyi gave a talk on "Marker-Driven Personalized Therapy of Breast Cancer" and walked the audience through the evolution of biomarkers used in breast cancer. Biomarkers are features of tumors that aid physicians in determining the type and prognosis of specific cases of cancer. More recently, with advances in molecular science and technology, researchers have identified biomarkers to help physicians assess whether certain drugs would work for individual patients to spare them unnecessary treatments and toxicities, as well as biomarkers that can help predict how likely their cancer is to return. Through the use of genetic analysis of tumors, rather than their physical attributes such as size and location, clinicians are gaining clearer and more precise information to help with treatment decision making. There are several ongoing clinical trials testing the effectiveness of newly developed multi-gene assays, the results of which are highly anticipated.

Because the use of the genetic information of tumors in patient care is still a relatively new concept, the meeting organizers assembled a panel on "Genomics for the Clinician." Matthew J. Ellis, MD, PhD (Washington University School of Medicine) whose team sequenced the entire DNA of tumors from 50 patients provided insights on his work. Calling whole genome sequencing "pathology report for the 21st century," Dr. Ellis reviewed some of the most significantly mutated genes seen in his work, which has further revealed the multitude of cancer cells that exist within a single tumor. These genes include RUNX1 and its binding partner, CFBP, research on which may yield important clues about which mutations have the greatest impact on patient prognosis and outcome.

Ana Maria Gonzalez-Angulo, MD, MS (University of Texas MD Anderson Cancer Center) presented on using tumor gene information to help predict patient outcome. For instance, there are on-going trials in the US and Europe that seek to determine whether certain patients can be spared specific therapies yet receive the same amount of benefits. Biomarkers are imperative in the selection of these patients. Christos Sotiriou, MD, PhD (Institut Jules Bordet) and Fabrice Andre, MD, PhD (Institut Gustave Roussy) recently published results that provide key stepping stones towards these goals.

In a related study reported by Patrick Morris, MD (Memorial Sloan-Kettering Cancer Center), the inflammatory impact of obesity as it relates to breast cancer risk and progression was reviewed. These results are important as they provide a molecular link between obesity and the elevated risk of hormone-receptor positive cancers seen in post-menopausal women. His research is conducted under the direction of Andrew J. Dannenberg, MD (Weill Cornell Medical College) and Clifford Hudis, MD (Memorial Sloan-Kettering Cancer Center), Chairman of BCRF's Scientific Advisory Board. A clinical trial testing a dietary supplement that may reverse the specific low-grade inflammation often seen in obesity has now begun with additional support from the National Cancer Institute is being planned.

Several BCRF grantees presented at the session on "New Directions in Systemic Therapy for Advanced Disease," which centered on three major breast cancer subtypes: HR+, HER2+, and triple negative. Francisco Esteva, MD (University of Texas MD Anderson Cancer Center) focused on HR+ disease, the growth of which is mostly fueled by estrogen and accounts for as many as 80% of all breast cancers. Conventional treatment for HR+ disease is endocrine therapy, which lowers the estrogen level in the body or counteracts its effects. One of the main debates in the application of endocrine therapy revolves around sequential versus concurrent dosing schedule. Dr. Esteva reviewed results from the SWOG 0226 study, which showed that progression free and overall survival among the 694 patients studied were 1.5 and 6.4 months longer, respectively, for those randomly assigned to concurrent anastrozole (Arimidex®) plus fulvestrant (Faslodex®) than for those given anastrozole alone. However, these data contradicted those from a smaller trial called FACT, which tested the same combination and found no improvement in either outcome. The differing results may be attributed patient selection, underscoring the importance of understanding an individual's breast cancer and previous regimens in therapies for advanced disease. More information is needed before recommendations can be made for or against combining endocrine therapies.

Dr. Esteva also discussed potential new treatments for HR+ metastatic breast cancer. These include new classes of drugs (e.g. pI3K inhibitors, IGF-1R inhibitors, and epigenetics drugs) and the addition of metformin, a diabetes drug which has shown in some but not all studies to reduce the risk of recurrence in some breast cancer patients. Overall, based on current data, Dr. Esteva believes that endocrine therapies remain the best options for most HR+ breast cancer patients and emphasizes the importance of taking prior therapies into account in the treatment of metastatic breast cancer.

Dr. Hope Rugo gave an overview of current therapies for HER2+ breast cancer, which is estimated to account as many as 20% of all breast cancers. The biggest challenge facing patients and practitioners alike is that in spite of improved therapies, most patients eventually develop progressive disease. Dr. Rugo reviewed current data on new types of drugs and the combining of therapies that target different weaknesses in cancer cells in order to prevent recurrence and metastasis. The encouraging news is that combinatorial therapies seem to work better than most single-agent treatments for HER2+ breast cancer. Also, the newer generation of drugs seems to cause fewer negative side effects than earlier ones. On the other hand, much research on the effectiveness of these approaches is still needed. Critical among these efforts are the development of prognostic and predictive factors for HER2+ disease, in addition to the translation of these new strategies to early-stage breast cancer to prevent, rather than treat, recurrences. Furthermore, refining the use of these newer approaches is necessary. It is also of utmost importance to determine whether everolimus has the ability to help overcome resistance to trastuzumab that some patients develop.

Triple negative breast cancer is a disease subtype that has been difficult to treat due to the lack of a clear molecular feature that drives its growth and progression towards which scientists can target therapies. Lisa A. Carey, MD (University of North Carolina, Chapel Hill) described the current landscape of triple negative breast cancer, in which chemotherapy remains the predominant form of therapy. She pointed out that the prognosis for triple negative breast cancer patients can still be fairly estimated by the variables used for the other disease subtypes. However, the ten-year mortality metric may be more helpful for decision making than the five-year one usually used for HR+ and HER2+ breast cancers. Dr. Carey also focused on the subpopulation of triple negative breast cancer called "basal-like," which accounts for the majority of breast cancers associated with BRCA1 gene mutation. The high correlation between BRCA1 mutation and this disease phenotype suggests that targeting this gene may be explored in drug development. Also, platinum drugs and PARP inhibitors have been shown to have effects on BRCA1-associated triple negative breast cancers and continued exploration of the use of these drugs on these specific cases could prove beneficial to patient care. Dr. Carey also shared results from the Translational Breast Cancer Research Consortium trial on the successful use of bicalutamide, drug commonly prescribed for prostate cancer, in androgen receptor positive triple negative breast cancer. These results, reported earlier this year, further emphasize how advances made in one form of cancer may help to advance others.

In a dynamic format reminiscent of past BCRF Grantee Retreats, the concluding session was moderated by Dr. Gabriel Gortobagyi and featured panelists debating opposing sides of an issue. Dr. Clifford Hudis presented the "pro" argument for the use of anthracyclines (e.g. doxorubicin) to treat both HER2+ and HER2- patients. This stance is considered provocative by some clinicians because recent clinical trial results heralded the use of targeted therapies, specifically trastuzumab, in HER2+ disease, making systemic therapies such as antracyclines appear passé or less important. One reason is the reduction of negative side effects associated with trastuzumab and another is the suggestion that the chemotherapy "partner" for trastuzumab might not matter. However, Dr. Hudis reminded the audience that the dosing schedule, amount, and sequence of anthracyclines matter a great deal and not only help minimize the amount of toxicities but also optimize their efficacy. In the adjuvant (post-operative) setting the dose dense regimen is generally superior and all carefully studied situations, anthracyclines confer benefits that clearly exceed risks. Overall, patients treated with anthracyclines have superior survival (notwithstanding their toxicities) compared to patients who do not receive them and no adjuvant regimen has ever been superior to the sequence of an anthracycline followed by a taxane. The practical views presented by Dr. Hudis and his "opponent," gave the practitioners in the audience much to consider as they return to their patients.

Another topic debated is on the role of bisphosphonates in early-stage breast cancer. Julie R. Gralow, MD (University of Washington) took the "con" stance on the use of bisphosphonates. Citing 2-FAST trial results published in Cancer 2012, Dr. Gralow pointed out that the use of clodronic acid in the adjuvant setting did not show improved results among patients on placebo. The AZURE trial demonstrated similar results, where using the highest dose of another form of bisphosphonate, called zoledronic acid, on women at highest risk of breast cancer recurrence produced limited effects on overall survival and disease recurrence. Dr. Gralow concluded that not all patients should be given bisphosphonates because not everyone is at risk for bone loss or bone disease as result/side effect of cancer therapies. She also cautioned against the routine prescription of bisphosphonates in early-stage breast cancer. However, more data is needed to make further determination on the use of bisphosphonates either pre vs. post-menopausal and adjuvant vs. neoadjuvant (pre-operative) setting.

Other key findings reported at the Symposium included advances in radiation therapy. Good outcomes were reported for accelerated partial-breast irradiation (APBI) among women deemed suitable for this therapy. A two-day version of APBI was shown to be similar to traditional five-day APBI. However, long term prospective randomized studies are needed to completely weigh the pros and cons of this approach. Also, the final overall survival analysis of RIBBON-2 confirmed a lack of survival benefit with bevacizumab added to second-line chemotherapy in patients with HER2-negative, bevacizumab-naive metastatic breast cancer. In addition, the controversial US Preventive Services Task Force (USPSTF) recommendation that women aged 40 to 49 not undergo routine mammography screening has already resulted in a 5% reduction in screening in this age group, which for a two-year period translates into 90,000 fewer screenings. The potential impact this may have on early detection and outcomes was not directly addressed.

In addition to sharing new information from laboratories and clinical settings, several BCRF grantees contributed to this year's proceedings as session chairs, poster discussants, and leaders of poster walks. With new information and insights coming out of the laboratory and clinical settings at a faster than ever pace, BCRF's strategic investments in research towards the prevention and cure of breast cancer are more critical than ever before.