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At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2014), held May 30 through June 3 in Chicago, specialists discussed the latest cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to cover key presentations at the conference. Here, William J. Gradishar, MD, reviews new findings in breast cancer research.
Strategies to preserve ovarian function fertility in young women undergoing early-stage breast cancer treatment have included egg retrieval, embryo freezing, and concurrent use of gonadotropin-releasing hormone (GnRH) agonist drugs and chemotherapy, the latter strategy of which has shown mixed results in previous small studies. To further evaluate whether a GnRH agent can reduce premature ovarian failure, Moore and colleagues conducted the phase III Prevention of Early Menopause Study (POEMS) (abstract LBA505), in which premenopausal women with ER-negative, stage I–IIIa breast cancer were randomized to receive standard chemotherapy plus goserelin (66 patients) or chemotherapy alone (69 controls). The primary endpoint was ovarian failure, defined as amenorrhea for the prior 6 months and levels of follicle-stimulating hormone in the postmenopausal range. Secondary endpoints included pregnancy rates.
At 2 years, the ovarian failure rate was 22% among controls and 8% among goserelin recipients. Pregnancy was successful in 12 of 18 controls and 22 of 25 of goserelin recipients (odds ratio, 2.45). Numerically, more babies were born to goserelin recipients (18) than controls (12). Interesting and unexpected was the observation that disease-free survival (DFS) and overall survival (OS) were improved with goserelin. Although this study was modest in size, the use of goserelin in this setting appears safe and promising.
Piccart-Gebhart and colleagues conducted the randomized, phase III ALTTO trial (abstract LBA4) to determine if dual anti-HER2 therapy with trastuzumab and lapatinib would improve survival in HER2-positive breast cancer in the postoperative setting. The promise of this strategy was based on findings from multiple trials conducted in the preoperative setting, including the NeoALTTO study, in which dual-HER2 blockade improved the rate of pathologic complete response (pCR).
The ALTTO trial comprised early-stage patients who received chemotherapy prior to anti-HER2 therapy or concurrently with adjuvant chemotherapy. Anti-HER2 therapy was either: (1) every-3-weeks trastuzumab for 1 year, (2) lapatinib for 1 year, (3) weekly trastuzumab weekly for 12 weeks followed by lapatinib for 34 weeks, or (4) lapatinib plus trastuzumab for 1 year. Fewer events occurred during the trial than were anticipated (555 instead of 850). Consequently, the primary analysis was triggered with 4.5 years of follow-up. A total of 40% of patients had axillary-node–negative disease, 57% had hormone-receptor–positive tumors, and 46% had tumors ≤2 cm.
An earlier analysis determined that lapatinib alone was inferior. With 6281 patients randomized, no statistical difference in DFS (the primary endpoint) was found between the three remaining treatment arms, analyzed as a whole, by ER status, or by concurrent or sequential administration of chemotherapy. No difference in OS was observed. Due to toxicity, significantly fewer patients receiving lapatinib were able to receive ≥85% of the planned dose compared with trastuzumab. A doubling of pCR in the preoperative NeoALTTO study with the combination of trastuzumab and lapatinib did not translate into an improved survival in the ALTTO study.
The FDA recently provided guidelines that could serve as a pathway for drug approval in the preoperative setting. The basic idea is that an improved pCR may translate into a significant improvement in event-free survival (EFS), DFS, and OS. However, the magnitude of the pCR improvement and correlation with improvement in EFS and DFS has been a source of controversy. The results of the adjuvant ALTTO trial were disappointing and may have implications for the strategy of rapid drug approval using the preoperative setting as a substitute for conducting large, randomized trials in the postoperative setting for patients with early-stage breast cancer.
Bevacizumab took another hit with an ECOG 5103 report by Miller and colleagues (abstract 500) of 4994 patients with early-stage, HER2-negative breast cancer (64% ER positive; 26% lymph-node negative). All patients received doxorubicin and cyclophosphamide followed by weekly paclitaxel. Patients were randomized to one of three treatment arms in a 1:2:2 ratio: placebo, bevacizumab during chemotherapy treatment, and bevacizumab during chemotherapy and continued for 10 cycles after completion of chemotherapy. With a median follow-up of 4 years, invasive DFS and OS were not statistically different between treatment arms, and no subset could be identified that gained benefit from bevacizumab. Along with the previously reported negative BETH and BEATRICE trials evaluating bevacizumab in the adjuvant setting of early breast cancer, no compelling evidence exists for the routine use of this drug for treatment of breast cancer.
Contrary to reports suggesting that inadequate vitamin D levels lead to an increase in breast cancer or a higher risk for recurrence, Lohmann and colleagues described the lack of correlation between 25-hydroxy vitamin D levels and breast cancer prognosis in the phase III NCIC MA.21 study (abstract 504). Patients with early breast cancer were randomized to one of three adjuvant chemotherapy regimens. With follow-up of 9.2 years, 25-hydroxy vitamin D levels were not associated with OS, relapse-free survival, or breast cancer–specific survival. Only a single 25-hydroxy vitamin D level was obtained, and the study population was homogenous (white, young, with high risk for recurrence). Nevertheless, based on these data, evaluating vitamin levels for anything other than bone health cannot be supported.
An issue that is frequently discussed with patients is what measures they can take to combat breast cancer. The discussion often focuses on diet, exercise, supplements, and efforts to reduce stress. Pan and colleagues analyzed 70 clinical trials involving 80,000 women (abstract 503) and found no correlation between obesity and long-term survival among postmenopausal women with ER-positive or ER-negative disease; the only exception was a slight increase in breast cancer mortality in postmenopausal women with ER-positive or ER-negative disease who were extremely obese (body-mass index ≥40 kg/m2). In obese, premenopausal women (BMI ≥30 kg/m2), breast cancer mortality was 21.5%, compared with 16.6% among those with normal BMI (20–25 kg/m2). These effects were independent of the treatment administered.