Over the past decade, the oncology community has made significant progress in the development of highly effective treatment modalities for breast cancer. Moreover, our increasing knowledge of the molecular biology of cancer has engendered the potential to use gene expression profiling, molecular fingerprinting, and biomarkers to add increased, patient-specific value to our clinical decision making. More than ever, today's clinician must keep up to date on the rapid scientific advances in breast cancer management.
To that end, this year's Miami Breast Cancer Conference convened a highly select group of surgical, medical and radiation oncologists in order to advance the awareness of state-of-the-art treatments in each therapeutic area and encourage a team-driven synergy back in the clinic—multidisciplinary treatment of breast cancer has become the standard of care.
|Harold J. Burstein, MD, PhD, Associate Professor of Medicine, Harvard Medical School|
Day one set the stage for the conference by focusing on prevention strategies in high-risk breast cancer patients. Debu Tripathy, MD, led off with an informative session, "Identifying the High-Risk Patient," in which he stressed the clinical importance of identifying patients at high-risk for developing breast cancer, whether through routine screening or, in certain cases, referring the patient to a genetic counselor—a stepwise process from identifying at-risk patients, to providing post-test counseling and follow-up.
Dr. Tripathy gave a detailed rundown of the major risk factors and risk calculators. He reviewed the role of genetic mutations and estrogen exposure in breast cancer development, noting that the relationship between body mass, estrogen, energy balance, insulin/insulin resistance and inflammation is extremely complex and that all of these factors may play various roles in predisposing to breast tumorigenesis.
Dr. Tripathy reviewed life-style approaches to lessoning the risk of developing breast cancer, as well as chemoprevention. For women with hereditary BRCA1/2 mutations, he discussed consideration of prophylactic surgery or MRI surveillance of the breast.
V. Craig Jordan, PhD, DSc, spoke on "Chemoprevention in the High-Risk Patient," and reviewed the important role of selective estrogen receptor modulators (SERMs) in the prevention of breast cancer. Dr. Jordan traced the scientific journey of tamoxifen, ending with a detailed analysis of the Study of Tamoxifen and Raloxifene (STAR; NSABP P-2). He recommended tamoxifen as chemoprevention for high risk pre-menopausal women, who are generally not at risk for the increase in blood clots or endometrial cancer observed among postmenopausal women taking tamoxifen. He recommended raloxifene for high-risk post-menopausal women, as this SERM does not appear to be associated with increase in endometrial cancer.
Transition from Borderline Lesions to DCIS
On conference day two, the presentations moved into management of DCIS and invasive breast cancer. Lance Liotta, MD, PhD, remarks centered on "Defining the Spectrum from Indolent to Aggressive DCIS: Markers of Tumor Invasion and Metastases." As noted in a recent NIH consensus conference, management of DCIS remains controversial, and patients might be better served by a "name change" of this disorder. The NIH expert panel concluded that "the diagnosis and management of DCIS is highly complex with many unanswered questions. Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to remove the anxiety-producing term 'carcinoma' from the description of DCIS." Given this difficult clinical quandary, Dr. Liotta posed three important questions:
- Are the hallmarks of invasiveness and aggressiveness predetermined early at the level of DCIS?
- How does the DCIS survive in the hypoxic and nutrient poor duct lumen?
- Can we use this knowledge as a new treatment strategy?
Dr. Liotta pointed to two studies that examined micro-dissected lesions (Ma, Xiao-Jun et al. (2003) Proc. Natl. Acad. Sci. USA 100, 5974-5979, and Castro et al Br Ca Res Tr 2008); which found that DCIS cells may already have the molecular capacity to invade, but are somehow held in check in the duct microenvironment. This prompted Liotta to comment: "If we determine that the DCIS cells are pre-programmed we could perhaps develop predictive markers to determine which of these cells will become aggressive and which will not." Dr. Liotta reviewed several promising markers, such as DCIS marker for recurrence, Stromal Caveolin-1 and the P16, COX-2 /Ki67 ratios which correlate with later recurrent disease. Dr. Liotta stressed that although we have knowledge that certain markers within a DCIS lesion predict for in situ and invasive recurrence, more study is needed in this challenging scientific area before incorporating these marker tests into the clinical treatment of all DCIS patients.
Metastatic Breast Cancer
Debu Tripathy, MD, opened the day's final discussion, "The Role of Maintenance Therapy for Metastatic Breast Cancer," with the cautionary note that in this very difficult setting, we may know what therapies to start with, but the end point of treatment is harder to define. Dr. Tripathy discussed maintenance therapy for advanced hormonally sensitive breast cancer and for advanced HER2+ breast cancer, pointing out that combination chemotherapy and hormonal therapies continue to be an important treatment modality for these patients.
He then discussed several trials examining continuous versus interrupted/fixed therapy, making the point that toxicities in chemotherapy-alone treatment remain a major issue in this patient group. Balancing the potential benefit against the side-effect profile is vital. Therefore, it is important for the clinician to understand when to stop chemotherapy. According to Dr. Tripathy, chemotherapy should be held or changed when: there is progression of disease; when there is symptomatic heart failure from therapy; or when clinically significant neuropathy or mucocutaneous toxicity (in excess of grade 2) arise.
Tripathy's "takeaway" points were:
|•||Targeted (hormonal, HER2 and angiogenic) can be approached with an induction phase, often paired with chemotherapy, followed by non-chemotherapy maintenance phase.|
|•||Chemotherapy interruption or "holidays" result in shorter time to progression, but generally no survival difference, and sometimes achieve better quality of life without treatment-related toxicities. Thus, many patients may wish to consider such chemo holidays.|
|•||Re-initiation of chemotherapy after a holiday may be associated with ongoing periods of tumor control and/or response.|
|•||It is reasonable to introduce a break to chemotherapy with close observation after optimal stabilization or response.|
|•||Patient preference, bulk/symptoms of disease and specific therapy side effects influence decision.|
Age as a predictor
Hyman, Muss, MD, discussed "Adjuvant Chemotherapy in Older Women," asking the question, "Who has breast cancer in the United States?" While many of the previous sessions focused on the major impact breast cancer has in younger women, Dr. Muss noted that the single greatest risk factor in the development of this disease is not BRCA 1/2, but age, with the average age of breast cancer patients in the US now at 63 years.
Historically, older breast cancer patients have been more likely to receive treatment with lower doses of chemotherapy than younger women, despite the lack of data that older patients tolerate chemotherapy significantly worse than younger women. Our lack of knowledge about how best to treat older patients is compounded by the fact that older women with breast cancer are often underrepresented in clinical trials, and, therefore, data on adjuvant chemotherapy in this group are limited.
For Muss, the challenge centers on how to assess the clinical benefits of treatment in older and physically frailer patients. He suggests using a fairly simple geriatric assessment scale to gauge your patient's ability to undergo treatment. If the patient is in good shape, Muss recommends delivering the same therapies as you would in your younger patients.
Debu Tripathy wondered "Are We Hitting the Right Combination for Hormonally Sensitive Breast Cancer?" when discussing the hormone receptor pathways that lead to signal transduction and estrogen-receptor interaction. There is considerable interest in the use of a variety of small molecule growth factor inhibitors to reverse resistance to endocrine therapy in breast cancer. Dr. Tripathy reviewed data from several interesting trials looking at the aromatase inhibitor, letrozole, given with or without the mTOR inhibitor Temsirolimus (CCI-779) and, in the neo-adjuvant setting, Letrozole with or without RAD001 (everolimus). To date, the data are inadequate to strongly recommend combining an mTOR inhibitor with an aromatase inhibitor or other endocrine therapy for advanced breast cancer, though ongoing and larger trials may yet define whether and how to use such combinations.
Dr. Tripathy's "take-away" messages on this topic were:
|•||Estrogen and progesterone are important mediators of breast cancer development and progression.|
|•||Determination of hormonal and HER2 receptors are critical in making therapeutic decisions —ER or PR positivity defines potential hormonal responsiveness.|
|•||Hormone responsive disease tends to be more indolent although can evolve into more aggressive disease.|
|•||Serial hormonal therapy (with aromatase inhibitors being a reasonable initial choice) are useful although not curative for advanced hormone sensitive breast cancer.|
|•||HER2+ disease appears be more resistant to hormonal therapy but some patients with ER+, HER2+ breast cancer may respond to endocrine treatment.|
|•||Hormonal therapy might be more effective with rationally designed biologically targeted drugs.|
Management of late stage breast cancer remains a clinical challenge. Dr. Eric P. Winer discussed "Strategies for Patients with Refractory HER2-Positive Breast Cancer." He defined HER2-positive disease as refractory HER2+ metastatic breast cancer that has progressed after an initial course of trastuzumab. Dr. Winer summed up the difficulty in managing these patients by stressing that at present the only treatment options are limited to two choices: introduction of lapatinib-based therapy and a continuation of trastuzumab-based therapy paired with a different chemotherapy agent. Dr. Winer noted that even after progression HER2 remains a valid target, remarking that are several lines of evidence that validates continuing trastuzumab after progression. But, more importantly, current evidence also suggests that further manipulation of HER2 with new therapies may provide additional benefit to these patients. He identified promising new agents in development for HER2-positive breast cancer including neratinib, a small-molecular tyrosine-kinase inhibitor; pertuzumab, a humanized monoclonal antibody targeting a different epitope on HER2 than does trastuzumab; and T-DM1, a conjugate of trastuzumab and the maytansanoid chemotherapy, DM-1. He added that adjuvant trastuzumab has decreased the problem by reducing the number of cases of recurrent, HER2+ breast cancer, but that patients may still develop recurrent disease or present with metastatic disease at diagnosis.
This brief selection of highlights from the 2010 MBCC did not allow coverage of many of the clinically relevant discussions that were delivered by many esteemed colleagues, including such surgical topics as surgical nipple-sparing mastectomy techniques and procedures to improve cosmetic results. Also missed were many good talks about technology breakthroughs in genetics and proteomics.
Moreover, this year's conference had several sessions on new assays that will enhance our ability to deliver tumor-patient-specific treatments. In the future, we hopefully will have genomic assays that identify candidates for specific chemotherapy regimens or endocrine treatments. It is easy to imagine that within the next 5 years, we will be checking a molecular diagnostic result on all newly diagnosed breast cancers. Such individualized therapy will have major consequences for how we think about and treat breast cancer.
From the editor: It is also worth noting that a team of experts examined this year's MBCC posters, singling out the three top-scoring poster abstracts. Please look for Oncology's coverage and analyses of the winning posters.
121;Phase III Randomized Trial of Sunitinib/Paclitaxel vs. Bevacizumab/Paclitaxel in First-line Treatment of Patients With Advanced Breast Cancer
143: Improving Balloon-Based Brachytherapy Using the Contura® Multi-Lumen Balloon Breast Brachytherapy Catheter to Deliver Accelerated Partial-Breast Irradiation: Preliminary Dosimetric Findings of a Phase IV Trial
133: Effect of Combined Preoperative Axillary Ultrasound and Intraoperative Imprint Cytology of the Sentinel Node on the Recall Rate for Axillary Lymph Node Dissection