By Karuna Jaggar, Executive Director
Longtime BCAction members have read plenty about the annual San Antonio Breast Cancer Symposium (SABCS) over the years.
The most recent symposium in December was my first time at SABCS, and it lived up to the hype about the size of the conference and the scope of the science. SABCS is the largest international symposium on breast cancer, and the presenters and audience are an international mix of researchers and clinicians, from virtually every specialty.
The conference also lived up to its reputation for failing to place emphasis on women living with breast cancer. There was only one presentation I saw that included photographs of actual women; all the rest were full of diagrams of biological modeling and graphs of data. One scientist actually referred to women as “hosts” for the tumor. And in the conference newsletter on day one, not a word was said about why all these researchers and clinicians were presumably here—to save women’s lives.
But a strong and dedicated community of activists and advocates attend SABCS every year to ensure patient needs are represented, and to glean and translate relevant information for women living with the disease.
Breast cancer is a complex disease with complex causes. Over the dozen years I’ve been a patient advocate, I’ve seen dramatic changes in how a breast cancer diagnosis is described. Doctors used to emphasize staging that focused on the size and location of the tumor. Now, there is much more of a spotlight on receptor status and gene expression. In other words, when talking about breast cancer diagnosis and treatment, the emphasis has gone from how much cancer to include considerations of what type of cancer, reflecting fundamental shifts in how we think of the disease.
The findings presented at SABCS spans the full sequence of research, from the lab, where scientists are working with petri dishes, to clinical trials, where women are taking newly developed drugs or new combinations of therapies.
The “basic science” presentations are anything but basic. Their focus is on experiments designed to lay a theoretical foundation for future studies. Many of the studies presented at SABCS are about developing an understanding of tumor biology, various mechanisms of action and other processes that are most readily observed in vials and petri dishes (otherwise known as “in vitro” studies). Other experiments then further test these hypotheses by repeating aspects of the studies in animals (also known as “in vivo” studies). Depending on results, this may then become the basis for study in humans, i.e. clinical trials.
The conference presentations on basic science, because of the very preliminary nature of the research, are not the place for advocates to learn about research that actually influences treatment, diagnosis, or prevention of breast cancer. No matter how good the basic science, it is not, to use one doctor’s phrase, “ready for prime time.”
It is the Phase III clinical trials that have the potential to actually produce meaningful change for women being treated for breast cancer. This year the main “practice- changing” developments focused on oncology and chemotherapy combinations rather than radiation or surgery.
Despite the excitement about the data from some long-anticipated trials presented at this year’s SABCS, we are not seeing game-changing research. Instead, we have incremental benefits for particular subsets of women with specific tumor characteristics. This is just not enough. I am the first person to recognize that extending a woman’s life by days and weeks is enormously meaningful and important to individual women and their loved ones in some situations. But we cannot settle for such small gains. We need dramatically more effective and less toxic treatments and nothing at SABCS pointed to those kinds of changes. That said, there were several practice-changing developments at this year’s conference that I want to share with you.
Two studies for women with metastatic disease found improvements of a few months’ survival, in addition to what current treatments offer, through new drug combinations.
- For metastatic HER2+ tumors, the CLEOPATRA trial results showed that combining Herceptin (trastuzumab) with pertuzumab delayed progression of tumor growth by 6 additional months, with greatest benefit for ER- tumors. The study examined the effect of combining pertuzumab + trastuzumab in a double blind randomized study for HER2+ metastatic breast cancer in women who were previously untreated for the metastasis. In addition to the benefit to progression free survival, it was suggested there is corresponding benefits to overall survival, although the data is not yet conclusive. At BCAction we always demand that we keep sight of overall survival as the meaningful endpoint.
- For HER2-, ER+ metastatic breast cancer, the BOLERO-2 Phase III trial found a 4.1 month in progression free survival by adding Everolimus to Exemestane (Aromasin). This study was developed in order to address the issue of resistance to standard hormone therapies. The standard of care for metastatic hormone receptive breast cancer is to sequentially give single agent therapies, switching therapies when the disease progresses. Each subsequent therapy typically has a shorter window of efficacy and the goal of this study is to overcome resistance to endocrine therapy. The trial found that progression free survival improved by adding Everolimus, which was thought to inhibit other pathways when a tumor became resistant to endocrine therapies. There was a high rate of discontinuing treatment, the majority because of disease progression. The presenter suggested that the serious side effect profile of Everolimus be evaluated by patients in contrast to chemotherapy given that the alternative to hormone therapy is chemotherapy for metastatic disease. The presenter concluded Everolimus is the first agent to increase the efficacy of hormone therapy in patients with ER+, HER2- metastatic breast cancer. FDA approval of XX will likely be sought, as a way to overcome endocrine resistance and delay chemotherapy. It should be noted this is a very expensive drug.
Several trials looked at bisphosphonates, and the focus seemed to be on ER+ early stage diagnosis. Bisphosphonates prevent the loss of bone mass and strengthen the bone, and have been studied in metastatic breast cancer on the theory that they make the bone less hospitable for tumor growth. Bisphosphonates are being investigated for their role in (a) protecting bone health due to negative effects of endocrine therapy, (b) preventing bone metastasis and (c) improving disease free survival (and hopefully overall survival).
- Long term follow up of the Austrian Breast and Colorectal Cancer Study Group (ABSCG-12) found that the bisphosphonate, zoledronic acid (marketed by Novartis under Zomera or Zometa) may be a new standard of care for premenopausal breast cancer patients with early stage ER+ tumors who are receiving hormone therapy (tamoxifen or Arimidex). Regardless of which estrogen suppressor was used, the zoledronic acid group showed a 28% reduction in recurrence with the treatment of this bisphospohonate. In addition to reducing recurrence, there was also a reduction in death. Overall survival was high in both groups and the study found that zoledronic acid improves overall survival compared with endocrine therapy alone. In summary, this study looked at patients with fairly good prognosis and met the primary and secondary endpoints of both disease free survival and overall survival. All women receiving zolodronic acid in the study saw these benefits; however, the age of the patient matters. The efficacy of this bisphosphonate is best in women over 40 with complete ovarian suppression, suggesting the need to deprive tumors of estrogen and bone growth factors.
- The ZO-FAST study found that long-term survival outcomes for postmenopausal women with ER+ early breast cancer benefited from adding zoledronic acid to letrozole. Similar to the ABCSG-12 trial, the Zo-FAST data indicate that zoledronic acid is most effective as an anticancer agent in a low-estrogen environment.
HER2 testing can produce different results for the same tumor based on different labs using different standards. Because it’s a spectrum, there are questions of how to treat tumors that are HER2-equivocal, or HER2-borderline. Data presented at SABCS found that Herceptin works just as well in HER2-equivocal cases as it does in those that are strongly HER2-positive. Patients with borderline HER-2 status derive as much benefit from Herceptin after surgery as patients with strong HER-2 status.
For ER+ tumors, GeparTrio Trial from Germany looked at whether there is greater benefit if neoadjuvant (i.e., pre-operative) chemotherapy is adjusted based on tumor response. This is called response-guided therapy. The somewhat surprising results of this trial appear to have sparked interest in further exploring pre-operative/ neoadjuvant chemotherapy, especially in hormone positive cancers for women who will benefit from chemotherapy. The study looked at patients who had received two cycles of TAC and evaluated the tumor response after 6 weeks. [Note: the trial occurred before Herceptin was widely available for HER2+ tumors.] “Tumor response” in this study was considered a 50% reduction in tumor size. The trial found that after 62 months of follow up—despite prior data showing no benefit to pathological free response—that there is benefit to this response guided therapy when it comes to both recurrence and death. This modified chemo treatment, based on tumor response, resulted in 30% reduction in recurrence and 20% reduction in deaths. Subgroup analysis showed that almost all of this benefit was seen in hormone positive tumors, whereas HER2+ and triple negative tumors did not benefit from response guided treatment.
Unfortunately, there were no major practice changing results announced that were relevant for triple negative cancers, which lack estrogen, progesterone, and HER2 receptors. Since triple negative breast cancers lack the presence of all three of these receptors, this subtype of breast cancer is more difficult to treat and more likely to recur. We need more to offer women with triple negative breast cancer.
An International Breast Cancer Study Group reinforced earlier studies that found no benefit of full axillary dissection—that is removal of all lymph nodes —for women with minimal sentinel micrometastases. Since the early days of the radical mastectomy, the rule of thumb for surgery has been “more is better,” and many surgeons have considered axillary dissection the gold standard for patients with micrometastases in the sentinel node. There is growing consensus that axillary dissection of lymph nodes appears to be unnecessary and represents overtreatment for many women. There was a strong plea from the presenters and Dr. Laura Esserman of UCSF who was seated in the audience that given the serious side effects of axillary dissection—including lymphedema and neuropathy—the standard of care should be to not do axillary dissection when there is minimal sentinel node involvement.
Partial radiation for breast cancer—a week of radiation to part of the breast instead of longer treatment to all of it—though brachytherapy appears to result in higher recurrent with 4% of brachytherapy patients needing surgery to remove the breast compared to just 2% of those given traditional radiation. Despite the hope that less radiation for a shorter duration would produce fewer side effects, the brachytherapy patients also reported more infections, hospitalization, broken ribs and breast pain.
What other lessons did we learn?
- With current cut backs to government funding, Pharma funding increasingly drives and influences breast cancer research. This is not an acceptable alternative. We need increased government funding to ensure independent research and we need to not rely on Pharma funded research to meet our needs.
- Several researchers made a plea for tissue samples and a national bio-specimen collection, as a standard part of future studies. This would require significant infrastructure investment and planning as well as addressing medical privacy issues.
- Patient-reported outcomes need more attention because, as we’ve always argued they matter. We need to ask patients directly and include their response regarding side effects if we want to accurately understand women’s experiences with treatment. It’s no surprise side effects are correlated to treatment “adherence”— when side effects are too bad, women stop taking the drugs. When women are asked about side effects, there are always more side effects than clinicians report. Yet, side effects are tremendously important because they negatively affect health-related quality of life.
- Many researchers and clinicians continue to be hopeful about the promise of Avastin, despite lack of evidence that the drug benefits patients. The official SABCS Newsletter 3, placed on every seat each morning, opened with a piece titled “Understanding Results from AVEREL as a Positive Way Forward” despite the fact that AVAREL was a negative study–it did not reach its endpoints. AVAREL was a randomized Phase III trial that looked at Avastin in combination with Hercptin and docetaxil as a treatment for metastatic HER2+ breast cancer. The investigators did not find a statistically significant reduction in progression free survival after an average of 26 months. However, after engaging an independent review committee to re-evaluate (and re-classify) the data, there was a statistically significant finding of a 2.9 month gain in progression free survival with the re-analyzed data.
- Even though we are learning more about the different characteristics of different breast cancers, tens of thousands of women continue to be overtreated each year because we just don’t know who will benefit from which treatment and so, to be on the “safe side” (which may not be all that safe), we subject all women within a particular diagnostic profile to the same treatment. It was interesting to hear a number of researchers and clinicians talk about the issue of overtreatment in various contexts, noting that after many years of tying to help women by adding therapies, for some women it may be time to think about less treatment.