The San Antonio Breast Cancer Symposium is the largest scientific meeting devoted to breast cancer, attracting national and international attention. It is attended by clinicians, researchers and advocates. “The Symposium aims to achieve a balance of clinical, translational, and basic research, providing a forum for interaction, communication, and education for a broad spectrum of researchers, health professionals, and those with a special interest in breast cancer.”
Dr. Julie Gralow is a Breast Cancer and Global Oncology Specialist at the University of Washington and Seattle Cancer Care Alliance, and is also regular participant in the #BCSM tweet chats, attended the conference. Here are some of the studies she felt were most relevant to our community, with her interpretation of the results.
S1-04 The APT Study: Combining paclitaxel (Taxol) and trastuzumab (Herceptin) as adjuvant treatment for small, lymph node-negative, HER2+ breast cancer
[Article link: http://www.ascopost.com/ViewNews.aspx?nid=10846]
Several large, randomized clinical trials have shown that the addition of the HER2-targeted therapy trastuzumab to chemotherapy in early stage (non-metastatic), HER2+ breast cancer decreases the risk of recurrence by 50% and improves survival. The chemotherapy given in these trials varied, but it was generally intensive, with most patients receiving anthracyclines (such as doxorubicin – Adriamycin – or epirubicin) along with taxanes. These trials included very few patients with small breast cancers that were lymph node negative, and virtually no patients with tumors < 1 cm. While patients with small HER2+ disease have a lower risk of recurrence than those with higher stage tumors, the presence of HER2 is an aggressive enough feature that some combination of chemotherapy and HER2 targeted therapy is often recommended. Such treatment has not been tested in many women with small tumors, and there has been no standard approach to reducing disease recurrence in this group.
The APT study (Adjuvant Paclitaxel and Trastuzumab) was designed to address the need to balance risks and benefits in a group of patients who would likely derive a small treatment benefit, because of their lower risk of recurrence, using a chemotherapy regimen that would be more tolerable than is often combined with trastuzumab. It included 406 women with HER2+, lymph node-negative tumors that were < 3 cm in size. Patients received paclitaxel as the only chemotherapy agent, plus trastuzumab for 12 weeks, followed by 9 months of trastuzumab alone. The study was a non-randomized trial, based on the rationale that a prospective trial that randomized to trastuzumab or not, or to different types of chemotherapy, would have required thousands of patients and been difficult to accrue to.
The results showed that this was an effective and well-tolerated regimen. After 3.6 years of average follow-up, 10 patients had experienced a recurrence or death, about 2.5% of the patients enrolled. Only two of these were distant recurrences. Of the remaining events, 4 were local/regional (in the breast or axilla on the same side as the primary cancer), 3 were new breast cancers in the opposite breast (all were HER2-negative), and 1 was a non-breast cancer death (due to ovarian cancer). 3-year disease-free survival (meaning patients were alive and without recurrence) was very high at 98.7%. As for toxicity, 2 patients developed symptomatic congestive heart failure (which normalized after discontinuing trastuzumab), and 13 had asymptomatic drops in their cardiac function (11 were able to resume trastuzumab after a brief interruption). Few other serious side effects were reported.
BOTTOM LINE: This study has limitations, since it was a single-arm, non-randomized trial, and about 20% of its patients had tumors < 0.5 cm that are already associated with a very favorable prognosis. Also, two-thirds were estrogen receptor–positive, and recurrences with these tumors may be occur beyond 3.6 years (virtually all of these patients also received endocrine therapy such as tamoxifen or an aromatase inhibitor). Nevertheless, paclitaxel plus trastuzumab can be considered a reasonable and fairly well-tolerated approach for the majority of patients with small, lymph node negative, HER2+ breast cancer, and more aggressive and toxic chemotherapy regimens can be avoided. For small HER2 positive tumors that are also ER+, it will be important to test a regimen of HER2- and ER-targeted therapy that omits the chemotherapy entirely.
S3-03 The HOPE (HOrmone and Physical Exercise) trial: A randomized trial of exercise versus usual care in women experiencing arthralgias (joint aches) associated with aromatase inhibitors
Aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, play an important role in reducing recurrence in ER+, early stage (non-metastatic), postmenopausal breast cancer patients. Joint complaints are common side effects, and up to 50% of patients on aromatase inhibitors report arthralgias, or joint pain and stiffness, within 6 months of starting therapy. Arthralgia is the most common reason for drug discontinuation and poor adherence to aromatase inhibitors.
In this randomized trial, the impact of a year-long exercise program was compared with usual care in 121 women with stage I-III breast cancer who had been taking AIs for at least 6 months. All reported at least mild joint pain and were not exercising at the time of enrollment, but they were physically able to exercise and agreed to random assignment. Sixty-one participants were randomly assigned to an exercise program that included twice-weekly resistance and strength training sessions and 150 minutes per week of at least moderate-intensity aerobic exercise, such as brisk walking. The usual care group was provided with written information about physical activity recommendations, received monthly phone calls to asses AI adherence, and was offered an end-of-study visit with an exercise trainer.
Measures of worst pain, pain severity, and pain interference dropped 20 % among participants who were assigned to the exercise program, compared with modest increases or no change in joint pain among participants who were assigned to usual care. Exercisers experienced these improvements regardless of age, tumor stage, whether they received chemotherapy or radiation, and how long they had been taking AIs. There was also a dose-response effect: Women who attended at least 80% of the exercise sessions experienced a 25% decrease in pain scores, while women who attended fewer than 80% of the exercise sessions experienced a 14% decrease. The HOPE study investigators plan future studies to explore mechanisms that may be influencing the effect of exercise on AI-associated joint pain, including body weight, inflammation, and muscular strength.
BOTTOM LINE: The HOPE study showed that exercise can significantly improve joint pain associated with aromatase inhibitors. In addition, numerous studies have shown that physical activity can improve many aspects of physical and emotional health in breast cancer survivors. Exercise also can have an impact in reducing a recurrence or second cancer. Healthy lifestyle choices, including exercise and physical activity, should be a part of the survivorship care plan for all women with breast cancer!
S4-07 The affect of bisphosphonates on recurrence and death in early stage breast cancer: A meta-analysis from randomized trials
Bisphosphonates are a class of drugs that inhibit bone resorption, or breakdown. They are commonly used to help strengthen bone and reduce fractures in patients with osteoporosis or low bone mineral density. Bisphosphonates are also frequently used in patients with bone metastases, reducing pain and fractures and lessening the need for surgery or radiation therapy to manage bone complications in these patients.
In breast cancer, bone is the most common site of distant recurrence (metastasis). In many breast cancers, the bone environment is felt to be a “reservoir” where cancer cells can hide in a dormant (resting) state until they may eventually be triggered by some signal to grow and spread. Complex interactions take place between breast cancer cells and the bone environment. This has been described as a “vicious cycle” in which cancer cells stimulate bone resorption, which in turn causes release of many factors from the bone that can fuel the cancer cells. It has been hypothesized that disrupting the interaction between breast cancer cells and bone at the time of initial diagnosis, by inhibiting bone breakdown before cancer cells have a chance to fully integrate into the bone environment, might prevent recurrences in bone and improve survival.
Many trials have attempted to test this hypothesis, using bisphosphonates such as clodronate, ibandronate and zoledronic acid, to inhibit bone breakdown at the time of breast cancer diagnosis. The results reported to date have been mixed and controversial, with some trials showing positive results with reduced recurrences and deaths, and others showing no effect. These trials have included a mix of breast cancer patients, tumors, and treatments and it has been difficult to sort out whether certain patients or tumor subsets might have benefit. Some of the trials suggested that bisphosphonates reduced distant metastases, predominantly in bone, but that this effect was largely confined to postmenopausal women. This population of women has ongoing bone loss, irrespective of their breast cancer diagnosis, as a result of low estrogen levels that occur at menopause. It is felt that this low estrogen environment may result in a chronic state of low-level bone resorption, releasing factors that enhance the ability of circulating cancer cells to stabilize in the bone.
A meta-analysis is a statistical method that focuses on combing results from multiple similar trials in order to identify patterns among study results, sources of disagreement among those results, or other interesting relationships that may come to light in the context of multiple studies. For the past several decades, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), coordinated by the University of Oxford, has performed many meta-analyses of randomized treatment trials in operable, early stage breast cancer in conjunction with the study investigators that have changed clinical practice.
The EBCTCG presented a large meta-analysis evaluating the use of bisphosphonates in over 22,000 women with early stage breast cancer based on 36 randomized trials comparing adjuvant use of a bisphosphonate versus no bisphosphonate or a placebo. Seven of the trials evaluated the oral non-aminobisphosphonate clodronate, which is approved in much of the world for osteoporosis and treatment of bone metastases, but is not available in the U.S. Twenty-nine trials evaluated newer generation aminobisphosponates (including zoledronic acid and ibandronate).
In the overall analysis of all of the women in the study, breast cancer recurrence was nonsignificantly decreased by 1.1% at 10 years in those on bisphosphonates, and distant recurrences were reduced by 1.4%. In this whole cohort, bone recurrences were reduced by 1.5%, which was statistically significant by a small difference. Among 11,306 postmenopausal women (including women age > 55 if menopausal status was unknown, as well as premenopausal women receiving ovarian suppression as part of their breast cancer therapy), adjuvant use of bisphosphonates reduced the risk of bone recurrence by 34% and the risk of breast cancer death by 17%. The study found a highly significant difference in distant recurrence and in bone recurrence, with reductions of 5.9% and 8.8%, respectively. Breast cancer deaths were reduced by 3.1%, from 18.3% among postmenopausal women not on bisphosphonates to 15.2% for those on the therapy. Adjuvant bisphosphonates achieved reductions in bone recurrence and breast cancer deaths in postmenopausal women regardless of the tumor’s estrogen receptor status, lymph node status, and whether or not they received chemotherapy. No significant effect of bisphosphonates was observed on non-bone recurrence. Additionally, no effects on disease outcome were observed in premenopausal women.
BOTTOM LINE: The EBCTCG meta-analysis showed that adjuvant bisphosphonates reduce bone metastases and improve survival in postmenopausal breast cancer patients. There is still some concern that we haven’t truly identified exactly which subsets of patients and tumors benefit most, but these drugs seem to have effect predominantly in a low estrogen setting. While several bisphosphonates were included in these trials, zoledronic acid is the main drug approved and available in the US. Although different regimens were studied, the recommended dosing schedule of zoledroinc acid is an intravenous infusion every 6 months for 3-5 years, starting shortly after breast cancer diagnosis. It is not known, because it has not been studied, whether starting bisphosphonates several years after a breast cancer diagnosis will impact recurrence. However, bisphosphonates also have a proven role in osteoporosis, and many breast cancer treatments accelerate bone loss and increase osteoporosis and fractures, including aromatase inhibitors. It is reasonable to monitor changes in bone density in all breast cancer patients, and add bisphosphonate therapy to improve bone density and reduce fractures when bone loss is seen.
Platinum agents in triple negative breast cancer: promising data in the preoperative therapy setting
S5-01 CALGB C40603: Addition of carboplitin and/or bevacizumab (Avastin) to preoperative weekly paclitaxel (Taxol) followed by dose dense AC in triple negative breast cancer
S5-02 I-SPY2 Trial: Veliparib (a PARP inhibitor) and carboplatin plus standard preoperative therapy for high risk breast cancer
The phase II CALGB 40603 study enrolled 454 patients with stage II or III triple negative breast cancer, randomly assigning participants to standard preoperative chemotherapy or chemotherapy plus either carboplatin, bevacizumab, or the combination. After completion of the chemotherapy, patients underwent surgery and the amount of cancer remaining in the breast and the lymph nodes in the axilla (armpit) was evaluated. The primary endpoint of the study was complete pathologic response at the time of surgery (no cancer remaining following preoperative therapy).
The addition of carboplatin to standard preoperative chemotherapy significantly increased the rate of pathologic complete response. For patients receiving carboplatin, 60% achieved a pathologic complete response in the breast, compared to 46% of those not receiving carboplatin, an increase of 76%. If evealuation of the lymph nodes in the axilla were included with the breast, pathologic complete response rates were 54% with carboplatin versus 41% without carboplatin, a 71% increase. Patients receiving carboplatin were more likely to experience neutropenia (low white blood cell counts) and thrombocytopenia (low platelet counts).
Bevacizumab was also evaluated and had some effect when added to chemotherapy, but, due to its toxicity, was felt to be less promising. The addition of bevacizumab resulted in a statistically significant difference in the breast but not the axilla. Among patients receiving bevacizumab, 59% achieved a pathologic complete response in the breast, while 48% achieved this without bevacizumab. Absence of residual disease in both breast and axilla was observed in 52% of patients receiving bevacizumab, and in 44% of those not receiving this drug, a 36% nonsignificant increase. Bevacizumab was associated with more grade 3 hypertension (high blood pressure), infections, and postsurgical complications, with a slight increase in thrombosis (clotting) and bleeding problems.
The I-SPY 2 trial is an innovative phase II trial using an adaptive design, based on tumor biomarker subtypes, to evaluate a series of investigational drugs added to standard preoperative therapy. The aim is to indentify potentially promising drugs matched to selected subsets of breast cancer to move into phase III testing. This first presentation from the I-SPY2 trial reported on a combination of the chemotherapy agent carboplatin and the oral PARP inhibitor veliparib, added to standard preoperative chemotherapy, in triple-negative breast cancer.
Veliparib/carboplatin improved pathologic complete response rates in women with triple-negative breast cancer, thus qualifying the drugs to move to the next round of clinical trial testing. The estimated pathologic complete response rate was 52% with veliparib/carboplatin, versus 26% with chemotherapy alone. The investigators reported on the combination’s potential after testing only 71 women, and after only 6 months of treatment. The combination was predicted to be far less successful in other breast cancer subtypes. In the estrogen receptor-positive/HER2-negative group, the estimated pathologic complete response rate was only 14% for the combination and 19% for controls who received standard chemotherapy.
BOTTOM LINE: Several studies, including the C40603 trial and the I-SPY2 trials reported at San Antonio as well as the previously reported GeparSixto study, show that the addition of carboplatin to standard preoperative chemotherapy increases pathological complete responses in patients with triple negative breast cancer. A long-term impact on recurrence and overall survival (the most important endpoints for patients) has not yet been observed, largely due to short follow-up and lack of statistical power. For triple negative breast cancer patients beginning preoperative chemotherapy, it is reasonable to consider incorporating carboplatin in the treatment regimen to achieve the best pathologic response at the time of surgery. Carboplatin should not be considered the standard of care in the post-operative setting for triple negative breast cancer patients, however, because we have yet to prove it decreases recurrences or deaths and it does add some toxicity. Bevacizumab in C40603 did slightly increase pathologic complete response, but with significant toxicities and therefore it is not recommended in this setting. The I-SPY2 trial did not separate out the addition of carboplatin from the PARP inhibitor, veliparib, so there is no ability to say whether the veliparib contributed to the improvement in pathologic complete response. The design of I-SPY2 is a new way of testing drugs in different breast cancer subtypes more rapidly, which is very important as our number of new drug treatment options expands.
Many thanks to Dr. Gralow for this post! Feel free to leave comments or ask for clarification of any of the studies summarized here. For more from Dr. Miller, follow her on Twitter.