Updates from the Miami Breast Cancer Symposium

The Miami Breast Cancer Conference kicked off last week with the customary pre-symposium that focused on a variety of subject, mostly surgical in nature, but also covered unusual topics that most clinicians only see rarely. The important aspect about rare cases is that we all have to be prepared to take care of them and know something about how to diagnose and treat them. The topic of male gynecomastia (enlargement of the breast), which can be seen in men with no underlying cause or, in some cases, can be due to genetic or hormonal abnormalities or to certain drugs, can be approached with techniques similar to liposuction. Removal of benign tumors in women, such as the rather common fibroadenoma, can sometimes result in large scars, so the route of approach is important. In many cases, the incision can be hidden in the lower fold of the breast where there is a natural crease that is hidden from view. In fact, even for breast cancer operations, more breast surgeons are using techniques borrowed from plastic surgeons to offer patients the cosmetic benefits that were once not felt to be warranted for such a situation.Unusual malignancies were also reviewed. Metaplastic breast cancer is a rare form of cancer that looks more like lung cancer under the microscope and appears to not respond to chemotherapy or radiation. Newer biological analyses suggest that these cancers follow a different developmental pathway, but this has not solved the dilemma of how to treat these cancers – so for now, we tend to follow the same treatments used for typical cancers. The same holds for breast cancers that arise due to genetic predisposition in carriers of BRCA 1 or 2 gene mutations. These clearly have a distinct biology and we are starting to learn more about how they behave, but to date we still use drugs like chemotherapeutic, hormonal and biological therapies based their stage and the proteins they make – just like other breast cancers. Newer drugs such as PARP inhibitors may in the future find a role specifically for hereditary cases. For now, the more important consideration is to establish a genetic predisposition in the first place by checking family history and performing genetic counseling and testing when appropriate. If there is a mutation, then the consideration of removal of the ovaries (oophorectomy) and careful surveillance of the breast or preventive mastectomy should be given – with oophorectomy appearing to actually lower the chances of dying from both breast and ovarian cancer.An update of practice-changing developments over the past year was presented. The major advances were the ability to possibly use less surgery – in particular, when a sentinel node is involved. Whereas this previously meant automatic lymph node dissection and the accompanying risk of permanent arm swelling (lymphedema), there may now be the opportunity to omit a full dissection in selected cases. Also, the use of intraoperative radiation therapy as opposed to six weeks of standard external beam radiation was found to be equivalent in terms of recurrence risk. However, both these approaches remain controversial because the follow-up time is short – just a few years, so there is still a possibility that patients might be exposed to more risk of recurrence. In the area of medical oncology, newer therapies for bone metastases (Xgeva or generic name denosumab) and a novel chemotherapy for refractory breast cancer (Halaven or generic name eribulin) were discussed – both recently approved by the FDA. These agents offer benefits over their predecessors, but we still have a long way to go in the area of advanced metastatic breast cancer.As we concluded the final day of the meeting, I was struck by the lively debate surrounding early data that are potentially practice changing. The most heated arguments involved the interpretation of the American College of Surgeons Z0011 study, where patients with 1 to 3 positive sentinel nodes who were to receive post-operative radiation were randomized to completion axillary dissection compared to no further surgery. The study authors posited that the likelihood that more recurrences would be seen in the no dissection group over time was very small. However, at this conference, it is clear that many feel that it is premature to abandon dissection in this setting because of the fact that patient accrual and the number of recurrence events were lower than projected as well as the limited follow-up time. Others felt that we were negating data that sufficiently rules out a significant increase in recurrence and therefore denying patients less invasive surgery and less chance of lymphedema.More debate was held regarding intraoperative radiotherapy, which was shown, again with rather short follow-up, to result in low and similar recurrence rates compared with external beam radiation. Defining factors that identify candidates for accelerated partial breast irradiation and hypofractionation raised some finer points of disagreement. A rousing and entertaining debate drew out both the powers and limitations of gene profiling in decision-making. As rapidly as these assays have been incorporated into decision-making for adding chemotherapy to hormonal therapy for node-negative, hormone receptor-positive cancer, is it possible that standard pathological indices that can yield the same discrimination? Can gene profiling be extended into node-positive cases? Controversy can be a good thing – and in fact, tends to accompany most new findings. We should not adopt new data abruptly for all applicable patients because ongoing peer review and longer term follow-up may change the risk/benefit ratio over time.Incremental adoption, starting with those most likely to benefit and least likely to harm, is a much more tenable pattern that can be adapted over time as the data matures. The feedback I received from attendees suggests that this type of discourse, even though not conclusive, provides the clinician with the tools to formulate their own adoption patterns and arms them to better discuss these nuances with their patients and colleagues.No consensus could be found for the size threshold below which adjuvant trastuzumab (Herceptin) would not be considered in HER2-positive, node-negative breast cancer. Also, the definition of HER2 positivity itself might need to be adjusted in early-stage breast cancer with the finding that NSABP trial cases that were centrally reviewed as being HER2-negative seemingly benefitted from trastuzumab – this has led to a randomized trial testing this agent in HER2-negative cases (expression values of 1+ and 2+, but negative by FISH analysis).Other "what will I do on Monday" moments arose over the use of adjuvant bisphosphonates. All the momentum from early positive trials dissipated when the large, well-powered AZURE trial reported negative results in San Antonio. Here, we don't appear to have any real positive data unless one invokes the unplanned subset analysis of this trial showing a benefit in the 5 years postmenopausal subset. This is consistent with the smaller ABCSG-12 randomized trial in patients who had medical ovarian ablation with hormonal therapy – this study did yield fewer recurrences with zoledronate. Still, most presenters felt that bisphosphonates should only be used in the setting of osteopenia/osteoporosis. Similarly, the use of bevacizumab (Avastin) in the first line for advanced breast cancer was questioned with the now solid finding that survival is not improved with this agent despite a clear advantage conferred in progression-free survival. But most feel that this agent should still be an available option even though there are no predictive factors to identify those who might derive a more substantial benefit. Less debate was held over the use of eribulin (Halaven), a new anti-microtubule-directed chemotherapy for very refractory advanced breast cancer after 2 to 5 prior chemotherapy regimens, which yielded a survival advantage over single agent therapy chosen by the treating investigator. Conversely, therapies for triple-negative as well as BRCA-associated remain undefined – defaulting to standard recommendations that are used for all subtypes. Whether or not PARP inhibitors will ultimately emerge as effective therapies in this area will have to await further study and longer follow-up from the recent phase 3 trial of carboplatin plus gemcitabine with or without iniparib. This trial recently reported that the primary endpoint was not met, dashing hopes of replicating the earlier and strongly positive Phase II trial of the same design. However, there is still a clear benefit apparent in the second- and third-line setting from the recent trial – whether or not the results will be enough for approval in this setting remains to be seen. Moreover, iniparib may not even exert its effects through PARP inhibition, since it is a weaker inhibitor and has a different toxicity profile compared to other such agents in clinical development.One of the hallmarks of this conference has been the emphasis on basic science developments that are on a trajectory impact on practice. The latest frontier of whole genome sequencing is demonstrating intratumoral heterogeneity and evolutionary patterns that belie metastases (even to specific sites) and drug resistance. These could hold the key to better classifications and therapies aimed at residual tumor cells. Cancer stem cell biology may also reveal avenues to address recalcitrant cancer cells, with the beginning of testing of inhibitors of stem cell maintenance pathways known as Notch, Hedgehog and Wnt. There was also discussion of down-to-earth established aspects of breast cancer that are now in need of re-evaluation. One of the more notable trends has been the idea that we might be overclassifying and subsequently overtreating very well-behaved cases of low grade ductal and lobular carcinoma in situ. These entities may represent a biological spectrum, with atypical hyperplasia on the lower risk end, and therefore several speakers issued a call to use the term ductal intra-epithelial neoplasia (DIN) of several grades along this continuum as a more appropriate classification system.This longwinded memo is just a cross section of the 2011 Miami Breast Cancer Conference. For those who have never attended, the 2012 conference next March promises to deliver more thoughtful and invigorating discussions of how breast cancer clinicians should take evolving scientific and clinical progress and apply these in their practices.