There is now a large body of data that is building for the use of bone-modifying agents in early breast cancer, and this should definitely help our patients.
—Jame Abraham, MD
The 2015 San Antonio Breast Cancer Symposium (SABCS), hosted by the American Association for Cancer Research, the Cancer Therapy & Research Center at The University of Texas Health Sciences Center at San Antonio, and Baylor College of Medicine, was held in December 2015. As has been true for the past 38 years, SABCS featured the most up-to-date breast cancer research and was attended by a global mix of clinicians, investigators, and advocates.
Jame Abraham, MD, Director of the Breast Oncology Program at the Taussig Cancer Institute of the Cleveland Clinic, Ohio, presents here his “top picks” from this meeting in an interview with The ASCO Post. Below are Dr. Abraham’s comments on these key studies (in italics), which are detailed at more length in this and other issues of The ASCO Post.
10-Year Follow-up of BCIRG-006
After 10 years of follow-up, BCIRG-006, which randomized 3,222 early HER2-positive high-risk breast cancer patients to one of three treatment arms, found sustained benefit for trastuzumab (Herceptin) and showed that woman can be effectively, and more safely, treated without an anthracycline.1 BCIRG-006 compared doxorubicin plus cyclophosphamide followed by docetaxel (AC-T); AC-T plus trastuzumab (AC-TH); and a nonanthracycline-containing arm, docetaxel, carboplatin, and trastuzumab (TCH). Trastuzumab was given for 1 year.
The two trastuzumab-containing arms significantly improved disease-free survival, which was 74.6% with AC-TH (P < .0001), 73.0% with TCH (P = .0011), and 67.9% with AC-T. Overall survival at 10 years was 85.9% (P < .0001), 83.3% (P = .0075), and 78.7%, respectively. The anthracycline arms were associated with significantly more toxicity, including a fivefold increase in congestive heart failure, compared with the nonanthracycline arm, and more leukemias.
The BCIRG-006 follow-up is extremely important for several reasons. When the trial was initially presented, AC-TH was slightly favored over TCH. Now we know there is essentially no difference—only 10 events separated the two arms. The overall survival and disease-free survival rates were basically the same.
This is good news for our patients. The most important thing is that TCH was associated with much less toxicity. In my practice, for very low–risk HER2-positive patients, I will use paclitaxel plus trastuzumab. For moderate-risk patients (ie, those with one or two positive lymph nodes), I’ll often use TCH. And then for the very high–risk patient, I’ll still use AC followed by TH, but this study tells me that I am actually fine in using TCH, even in the high-risk subset. I think this is potentially practice-changing information, or at least it should be convincing to physicians who may not have been convinced before.
TH3RESA Solidifies Ado-Trastuzumab Emtansine Benefit
For women with advanced, HER2-positive breast cancer previously treated with a taxane, trastuzumab, and lapatinib (Tykerb), treatment with ado-trastuzumab emtansine (formerly T-DM1; Kadcyla) improved overall survival by nearly 7 months, compared with physician’s choice of therapy, in the phase III TH3RESA trial of 602 patients.2 After a median follow-up of 30.5 months, median overall survival was 22.7 months in the ado-trastuzumab emtansine arm vs only 15.8 months in the control arm (hazard ratio [HR] = 0.68; P = .0007). The benefit was seen despite half the control arm crossing over to receive ado-trastuzumab emtansine and was observed regardless of patient age, hormone-receptor status, visceral metastases, and number of prior treatment regimens.
At this point, the [U.S. Food and Drug Administration] approval of ado-trastuzumab emtansine is for second-line HER-2 positive metastatic breast cancer patients, based upon the results of the EMILIA trial.3 However, this trial is clearly showing the efficacy of ado-trastuzumab emtansine in pretreated patients also. So this is good news for our heavily pretreated patients with HER-2 positive disease, who could still benefit from ado-trastuzumab emtansine.
Ado-Trastuzumab Emtansine as Neoadjuvant Chemotherapy
In the international phase II WSG-ADAPT trial, neoadjuvant treatment with ado-trastuzumab emtansine significantly improved pathologic complete response rates over trastuzumab plus endocrine therapy; the addition of endocrine to ado-trastuzumab emtansine did not further enhance the benefit.4 The study enrolled 376 patients with HER2-positive, hormone receptor–positive early breast cancer, randomizing them to 12 weeks of neoadjuvant treatment with one of three regimens: ado-trastuzumab emtansine, ado-trastuzumab emtansine plus endocrine therapy, or trastuzumab plus endocrine therapy, followed in essentially all patients by surgery and 1 year of trastuzumab. Rates of pathologic complete response were 41% for ado-trastuzumab emtansine alone, 41.5% for ado-trastuzumab emtansine plus endocrine therapy, and only 15.1% for trastuzumab plus endocrine therapy. The differences between either ado-trastuzumab emtansine arm and trastuzumab/endocrine therapy were highly significant (P < .001).
The ADAPT trial was the first large prospective randomized trial specifically conducted within this distinct subtype of HER2-positive/hormone receptor–positive early breast cancer. For the first time, it showed a clinically meaningful pathologic complete response rate after a short duration of ado-trastuzumab emtansine, with or without endocrine therapy and completely without systemic chemotherapy. The single-agent regimen achieved pathologic complete responses in 40% of patients. This gives us tremendous information about ado-trastuzumab emtansine, and I think this is part of the theme of tailoring treatment based on risk. Can we start using this approach in the clinic? The answer is probably not yet, as ado-trastuzumab emtansine is approved only in second-line metastatic disease.
Patients with advanced breast cancer who had received multiple lines of therapy were treated with single-agent immune checkpoint inhibitors in two trials presented at the 2015 SABCS. The phase Ib JAVELIN study evaluated the anti–PD-L1 (programmed cell death ligand 1) antibody avelumumab in 168 patients.
Treatment led to responses in 4.8% of patients, but this number rose to 8.6% in the triple-negative subgroup.5 One patient achieved a complete response, and 23.2% achieved stable disease. Response to avelumumab was not associated with the level of PD-L1 expression at specified cutoffs, but for patients with ≥ 10% of PD-L1 in immune cells, response rates were 33.3% overall and 44.4% in triple-negative patients.
The anti–PD-1 antibody pembrolizumab (Keytruda) was evaluated in the phase Ib KEYNOTE 028 trial, which included 25 patients with confirmed expression of PD-L1.6 The objective response rate was 12%, and 16% achieved stable disease on pembrolizumab.
Although there’s been a lot of interest in evaluating immune checkpoint inhibitors in breast cancer, the activity of these two anti–PD-1/PD-L1 agents was not very impressive in the JAVELIN and KEYNOTE trials. We know that the immunotherapy approach is producing impressive results in other refractory cancers, such as lung and melanoma, and the breast cancer community is trying to catch up. I am sure future breast cancer clinical trials will identify patients who will benefit from this approach.
Denosumab Reduces Recurrence Risk
Targeting the bone in breast cancer may have more than bone-preserving effects. Results from the randomized, phase III ABCSG-18 trial, which followed 3,425 patients for 4 years, showed that denosumab (Xgeva) reduces the risk of recurrence by about 18% among postmenopausal women with early, hormone receptor–positive breast cancer who are taking aromatase inhibitors.7 Disease-free survival was 83.5% in the denosumab arm and 80.4% in the control arm (HR = 0.816; P = .0515). In the sensitivity analysis, which censored patients at crossover, the disease-free survival was 84.3% with denosumab and 80.3% with aromatase inhibitors alone (P = .0419). Exploratory subgroup analyses suggested that the benefit is greater when denosumab is started early, along with the aromatase inhibitor, and that the benefit is greatest in patients with larger tumors and ductal histology. Risk of fracture was also reduced.
Denosumab at 60 mg, administered just every 6 months, reduced the risk of fracture and at the same time improved survival. The result mirrors findings from the Early Breast Cancer Trialists’ Group’s meta-analysis of bisphosphonates in early breast cancer, which showed a 14% reduction in risk among postmenopausal patients (P = .002) and a 17% reduction in the risk of bone recurrence overall (P = .004).8 The results are also in line with a meta-analysis of the similar bone-modifying agent zoledronic acid, showing a 15% reduction in mortality (P = .047) and a 34% reduction in fracture risk (P < .001).9 The good news is that denosumab also demonstrates this benefit and has less toxicity than zoledronic acid. There is now a large body of data that is building for the use of bone-modifying agents in early breast cancer, and this should definitely help our patients.
Capecitabine Useful for Residual Disease
The phase III CREATE-X trial investigated whether the drug capecitabine, given for up to eight cycles, could improve disease-free survival among 455 HER2-negative patients who had residual disease after neoadjuvant chemotherapy.10 At 5 years, disease-free survival rates were 74.1% in the capecitabine arm vs 67.7% in the control arm (HR = 0.70; P = .00524), and overall survival rates were 89.2% and 83.9% (HR = 0.40; P < .01), respectively. The benefit was observed across subgroups, with hazard ratios ranging from 0.54 to 0.84; a 42% reduction was shown in the hormone receptor–negative subset.
The CREATE-X trial showed that in high-risk HER2-negative patients with residual disease after neoadjuvant chemotherapy, capecitabine can reduce the risk of recurrence. This trial used capecitabine at a dose of 1,250 mg/m2 twice a day, whereas in the United States, we tend to use 1,000 mg/m2 mg twice a day—a dose that is associated with less toxicity. The findings from CREATE-X could be useful for a subset of patients with significant disease burden after neoadjuvant chemotherapy, especially triple-negative patients. We have several trials in the neoadjuvant and postneoadjuvant settings. For high-risk patients who not eligible for enrollment in these trials, capecitabine could be discussed.
Neoadjuvant Carboplatin in Triple-Negative Disease
CALGB 40603 and GeparSixto evaluated the benefit of adding carboplatin to neoadjuvant chemotherapy in patients with triple-negative breast cancer. CALGB 40603, in 443 patients, showed that rates of pathologic complete response could be increased with the addition of carboplatin, but there was no association between carboplatin use and disease-free or overall survival.11 GeparSixto, in 595 women, on the other hand, found that carboplatin improved pathologic complete response rates and also increased event-free survival rates by approximately 10%.12
CALGB 40603 evaluated carboplatin (area under the curve [AUC] of 6) and/or bevacizumab (Avastin; 10 mg/kg) as a component of neoadjuvant chemotherapy for triple-negative breast cancer. In the overall population, 3-year event-free survival was 74%, and 3-year overall survival was 83%. For patients achieving a pathologic complete response, event-free survival was 86%, compared with 62% for patients not achieving a pathologic complete response (P < .0001), and 3-year overall survival was 93% and 73%, respectively (P < .0001). These improved outcomes, however, could not be specifically tied to treatment with carboplatin or bevacizumab.
In GeparSixto, 595 patients were randomized to receive neoadjuvant therapy with liposomal paclitaxel and doxorubicin, with or without carboplatin (AUC of 2, later reduced to 1.5). The triple-negative subset also received concurrent bevacizumab, whereas those with HER2-positive tumors received trastuzumab and lapatinib. Although pathologic complete response rates in all patients were not improved with carboplatin, a benefit was observed in the triple-negative subgroup, whose pathologic complete response rates improved from 17% to 53% with carboplatin (P = .005) and disease-free survival improved from 76.1% to 85.8% (HR = 0.56; P = .0350).
CALGB 40603 and GeparSixto are important trials looking at the role of carboplatin in patients with triple-negative disease, but I think the story of carboplatin in breast cancer is still evolving. Perhaps in young patients with high-risk disease, one might consider using neoadjuvant carboplatin, but we are awaiting results of the important NSABP B56 trial, which is evaluating the role of carboplatin in the neoadjuvant setting. It is using anthracycline/cyclophosphamide (AC) followed by paclitaxel (T) plus carboplatin, vs AC-T plus carboplatin or the PARP (poly [ADP-ribose] polymerase) inhibitor veliparib. The study is currently enrolling and should help us answer this question.
Sustained Benefit of Neratinib in ExteNET
An unplanned exploratory analysis of 3-year invasive disease–free survival was conducted on the ExteNET population of 2,840 HER2-positive patients who received neratinib for 12 months after chemotherapy and 1 year of trastuzumab.13 The addition of neratinib improved invasive disease–free survival by 2.1%, compared with placebo. Grade 3 diarrhea occurred in about 40% of patients, but this was before the protocol-mandated use of a prophylactic regimen.
At 3 years, invasive disease–free survival rates were 90.5% for the neratinib arm and 88.6% in the placebo arm (HR = 0.74; P = .023). In the hormone receptor–positive subgroup, risk was reduced by 43% (P = .003), whereas hormone receptor–negative patients did not significantly benefit. Patients who enrolled within 1 year of trastuzumab and were centrally confirmed to be HER2-positive had an invasive disease–free survival of 92.8% vs 86.7% without the drug (HR = 0.43; P < .001).
Patients received neratinib after completing chemotherapy and 1 year of trastuzumab in the ExteNET trial. This was not an easy study to accrue, due to inclusion criteria and side effects of neratinib. However, the activity of neratinib in patients who received trastuzumab for 1 year is very promising. I think neratinib is a very active anti–HER2-targeted drug. The ongoing trials will help us determine several important things: how to manage the diarrhea effectively, where this drug fits into our armamentarium, and what agents can be used in combination with neratinib. ■
Disclosure: Dr. Abraham reported no potential conflicts of interest.