The most positive news from the San Antonio Breast Cancer Symposium relates to the potential benefit of platinum agents for women with triple-negative breast cancer (TNBC). The rationale for the use of carboplatin comes from a number of sources, including The Cancer Genome Atlas (TCGA) data suggesting genomic similarities between basal-like breast cancer and high-grade serous ovarian cancer. Platinum agents are the most active drugs in the treatment of high-grade serous ovarian cancer.
Carboplatin in TNBC
Two trials presented at the symposium—CALGB 40603 and I-SPY2—investigated the addition of neoadjuvant carboplatin for the treatment of triple-negative breast cancer (TNBC).
Abstract S5-01, CALGB 40603, evaluated the impact of the addition of carboplatin and/or bevacizumab to neoadjuvant taxane and anthracycline therapy in patients with stage 2 or 3 TNBC. Using a 2 × 2 factorial design, patients were randomized to one of four arms: weekly paclitaxel × 12 followed by dose-dense doxorubicin plus cyclophosphamide × 4 with or without carboplatin and with or without bevacizumab. Adding carboplatin to paclitaxel in the neoadjuvant setting for TNBC significantly improved pathologic complete response (pCR) rates (inclusive of both the breast and axilla) of 54 percent with carboplatin versus 41 percent without carboplatin (odds ratio 1.76, p=0.0018).
While bevacizumab was associated with an improvement in pCR rates in the breast, it failed to improve pCR rates significantly when both the breast and axilla were considered. The addition of bevacizumab also came at the cost of a significant increase in serious toxicities, including hypertension, bleeding, thromboembolism, and surgical complications. This led Dr. William Sikov, the lead author, to recommend that carboplatin, but not bevacizumab, be considered for the neoadjuvant treatment of TNBC.
Abstract S5-02, the I-SPY2 trial, also investigated the addition of carboplatin—but this time with the PARP inhibitor veliparib—to a control regimen of neoadjuvant taxane followed by doxorubicin/cyclophosphamide. The I-SPY2 Phase II trial uses an adaptive design to screen novel agents by assessing whether they improve response when added to neoadjuvant chemotherapy, with the goal of also identifying the appropriate signature for which the treatment applies.
Because of the fluid design, actual pCR rates are biased by continuous adaptation, and are thus not reported. Rather, the results reported are the estimated pCR rates—the likelihood that the experimental arm is superior to the taxane and anthracycline-based control arm, and the probability of success in a 300-patient randomized Phase III trial.
Dr. Hope Rugo and colleagues reported that although the addition of veliparib and carboplatin was studied in various breast cancer subgroups, only those with TNBC demonstrated a significant improvement in estimated pCR rates as compared with standard chemotherapy (52% vs. 26%). This experimental arm has a 99 percent probability of being superior to the control arm for TNBC, and a 90 percent predicted probability of being successful in a randomized 300-patient Phase III neoadjuvant clinical trial for TNBC.
Given the correlation between pathologic complete response and overall survival seen in women with TNBC, the results of these two trials incorporating carboplatin into neoadjuvant therapy are exciting, and will hopefully lead to new treatment paradigms with improved outcomes for this subset of breast cancer patients. The role of veliparib is uncertain, and is being addressed in other trials.
No Benefit to Postop-RT in Low-Risk Older Patients
Abstract S2-01, the PRIME II study, was the second randomized trial to investigate whether radiation after breast-conserving therapy improves outcomes in older, low-risk breast cancer patients. The CALGB 9343 trial had previously demonstrated that women over 70 years who had a lumpectomy for ER-positive breast cancer had similar overall survival, regardless of whether they received adjuvant radiation therapy. In PRIME II, investigators studied 1,326 patients over the age of 65 to assess the impact of omitting postoperative radiation therapy in low-risk patients undergoing breast-conserving therapy. While there was a slight increase in locoregional recurrence rates for those who did not receive adjuvant radiation therapy (3.2% vs. 0.8%), there was no significant difference in overall survival at a median of five years of follow-up.
Investigators concluded that omitting postoperative radiation therapy is a reasonable option in women 65 years and above with node-negative, hormone-receptor-positive tumors under 3 cm in size.
The National Comprehensive Cancer Network (NCCN) has already amended its clinical practice guidelines to suggest that omitting radiation is a reasonable alternative in older patients with ER-positive, clinically node-negative T1 tumors who receive hormone therapy. However, the vast majority of older women—even those with good-prognosis ER positive tumors—continue to receive radiotherapy after breast-conserving therapy. Perhaps the results of a second randomized trial will be able to change practice.
Abstract S4-07: Adjuvant Bisphosphonate Treatment Associated with an Improvement in Breast Cancer Mortality
Bisphosphonates have long been used to treat osteoporosis and to prevent skeletal-related events in patients with bone metastases. Numerous studies have also been performed to assess a potential benefit of bisphosphonates on preventing breast cancer recurrence, with mixed results. For example, the NaTan (neoadjuvant trial add-on) study, presented at SABCS13 by Dr. Gunther von Minckwitz on behalf of the German Breast Group (Abstract S5-05), revealed that zoledronic acid did not improve outcomes in patients with primary breast cancer who failed to achieve a pathologic CR after neoadjuvant chemotherapy. A nonsignificant trend towards benefit in disease-free survival was seen in women over the age of 55.
Given the discrepant results of published studies, clinicians have been reluctant to routinely incorporate the use of adjuvant bisphosphonates into their practice. One hypothesis was that bisphosphonates are of benefit only in the “low estrogen” setting, for women who are postmenopausal or treated with ovarian-function suppression. A meta-analysis of 36 different trials including almost 23,000 patients presented at SABCS13 appeared to confirm this.
The authors reported that in premenopausal women, there is no significant effect on bone recurrence (hazard radio [HR], 0.93), whereas in postmenopausal women, there was a 34 percent reduction. There was no effect on non-bone recurrence, but there was an absolute reduction in mortality from 18.3 to 15.2 percent (HR 0.83, p=0.004) in postmenopausal women. There was no effect on mortality in premenopausal women, with a hazard ratio of 1.0.
These data will undoubtedly increase bisphosphonate use in the adjuvant setting. However, significant uncertainties remain about which bisphosphonates and what dosage are appropriate for whom. Moreover, although rates of advanced osteonecrosis of the jaw appear to be relatively low in the adjuvant setting, higher rates of stage 0 disease (fistulas and abnormal radiological signs) have been noted when patients receive comprehensive dental examinations (Rugani et al: Clin Oral Inv 2013: DOI 10.1007/s00784-013-1012-5), and adjuvant IV bisphosphonate treatment should likely be reserved for higher-risk patients.
Benefits of Locoregional Therapy Questioned in Stage IV Breast Cancer
Several retrospective series have suggested that women presenting with metastatic breast cancer may benefit from removal of the primary tumor, but there have been no randomized trial data available to date. Results of two small studies were reported at SABCS.
In Abstract S2-2, from Tata Memorial Hospital in Mumbai, 350 women with metastatic breast cancer who had a response to initial chemotherapy were enrolled to a trial testing the hypothesis that increased locoregional therapy would improve outcomes. Those who underwent resection of the primary tumor and axillary lymph nodes plus radiation therapy did not have a better overall survival than women treated with systemic therapy alone.
A second study, the Turkish MF07-01 trial (Abstract S2-03) randomized 293 women presenting with stage IV breast cancer to receive systemic therapy with or without initial local therapy of the breast and axilla. This study also found no difference in overall survival with locoregional therapy, although the data are not yet mature.
Dr. Seema Khan, who discussed these trials, noted that these results indicate that the benefit of local therapy to the primary site (if any) is certainly smaller than suggested by the retrospective analyses. Primary site local therapy probably should not be offered to women with asymptomatic primary tumors unless they are participating in a clinical trial, she said. However, completion of ongoing trials, including the ECOG-E2108 study in the U.S. (“Phase III Randomized Study of Early Local Therapy Comprising Surgery versus Standard Palliative Therapy for the Intact Primary Tumor in Patients with Stage IV Breast Cancer”) remains important to provide a definitive answer.
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