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 for 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.