X. Ma, Cynthia MD, PhD
The following are my “best of ASCO” for the treatment of breast cancer in the areas of triple-negative breast cancer, hormone receptor-positive breast cancer, HER2-positive breast cancer, adjuvant cytotoxic therapy, and local therapy.
Triple-Negative Breast Cancer (TNBC)
• GeparSixto Trial (Abstract 1004): Addition of carboplatin is beneficial in the neoadjuvant setting for TNBC.
GeparSixto was a randomized Phase II study comparing neoadjuvant weekly paclitaxel and nonpegylated liposomal doxorubicin with and without the addition of weekly carboplatin for 18 weeks before surgery in patients with centrally confirmed triple-negative or HER2+ early-stage breast cancer. In addition, trastuzumab and lapatinib were administered concomitantly for HER2+ disease and bevacizumab in TNBC.
CYNTHIA X. MA, MD, PHD
A total of 588 patients were enrolled, including 315 with TNBC (53.6%) and 273 with HER2+ disease (46.4%). An increase of more than 20 percent in pathologic complete response rate (pCR: no invasive disease in the breast and lymph nodes) was seen in the TNBC patients (58.7% with carboplatin and 37.9% without carboplatin, p < 0.05), but not in those with HER2+ disease (33.1% with carboplatin and 36.3% without carboplatin, not significant). Further studies of platinum in early-stage TNBC are needed.
Hormone Receptor Positive Breast Cancer
• aTTom (Abstract 5): Extending adjuvant tamoxifen from five to 10 years is beneficial in reducing breast cancer recurrence and death.
The U.K. aTTom trial randomized 6,953 women with early breast cancer (40% ER+, 60% ER status unknown) who completed five years of tamoxifen to receive an additional five years of tamoxifen (n=3,468) or discontinuation of tamoxifen (n=3,485). The updated analysis demonstrated that 10 years of tamoxifen reduced breast cancer recurrence by 15 percent compared with five years of treatment (RR=0.85 [95% CI 0.76-0.95]; p=0.003). The difference between the two arms was not significant until year 7 of follow-up.
In addition, compared with five years of treatment, 10 years of tamoxifen reduced breast cancer mortality by 25 percent after year 10. There was an increased incidence of endometrial cancer (2.9% vs. 1.3%; RR: 2.2 [95% CI 1.31-2.34]; p<0.0001), and risk of death from endometrial cancer (1.1% vs. 0.6%; RR: 1.83 [95%CI 1.09-3.09]; p=0.02) associated with longer duration of therapy. Combined analysis of aTTom and the ATLAS trial confirmed the benefit of 10 years over five years of tamoxifen in reducing recurrence and survival.
HER2-Positive Breast Cancer
• BOLERO 3 (Abstract 505): Addition of everolimus to trastuzumab and vinorelbine resulted in small but significant improvement in PFS in trastuzumab-resistant metastatic HER2+ breast cancer.
BOLERO-3 was a randomized Phase III study of weekly trastuzumab plus vinorelbine plus daily everolimus at 5 mg (n=284) or weekly trastuzumab plus vinorelbine plus placebo (n=285) in patients with locally advanced or metastatic HER2+ breast cancer resistant to trastuzumab, defined as recurrence within 12 months of adjuvant trastuzumab or metastatic progression within four weeks of trastuzumab, and who had received prior paclitaxel.
Approximately 55 percent of patients had hormone receptor-positive (HR+) disease. The addition of everolimus led to a significant improvement in progression-free survival (PFS) (placebo arm: 7.78 months; everolimus arm: 7.0 months; HR=0.79, 95% CI 0.65-0.95, p=0.0067). Interestingly, the benefit of everolimus appeared to be restricted to the HR- population (HR 0.65, 95% CI 0.48-0.87).
The most common adverse events were stomatitis, pyrexia, and decreased appetite in the everolimus arm, but the overall quality of life was not affected. Data was not yet mature for overall survival (OS) analysis.
• CALGB 40601 (Abstract 501): Dual HER2 targeting with trastuzumab and lapatinib did not significantly improve pCR rate.
CALGB 40601 evaluated neoadjuvant trastuzumab and lapatinib, either alone or in combination, administered concomitantly with weekly paclitaxel for 16 weeks (THL: paclitaxel, trastuzumab, lapatinib; TH: paclitaxel, trastuzumab; TL: paclitaxel and lapatinib) prior to surgery in patients with newly diagnosed clinical stage II or III HER2+ breast cancer.
The primary endpoint of the study was pathologic complete response (pCR) (no invasive disease in the breast). The TL arm was closed early due to lower efficacy observed in other studies. The addition of lapatinib to the trastuzumab-plus-paclitaxel regimen led to an increase in pCR rate but did not reach statistical significance (56% in THL and 46% in TH; p=0.12). This is in contrast to results reported from a similar study, neoALLTO, which demonstrated a significantly higher pCR rate in the THL arm compared with the TH arm. The interpretation of these results awaits data from the adjuvant ALLTO trial.
Similar to other studies, higher pCR rates were noted in the HR- than in the HR+ population (77% [THL]/55% [TH] in HR- and 42% [THL]/39% [TH] in the HR- population). Strikingly, the HER2-enriched subtype represented only 52 percent in HR- and 18% in HR+ subgroups by molecular subtyping in this trial and was associated with the highest pCR rate (89% in THL and 80% in TH), important information for future trial designs in HER2+ breast cancer.
• ACOSOG Z1041 (Abstract 502): Combining anthracycline and trastuzumab not necessary in an anthracycline and taxane plus trastuzumab regimen.
ACOSOG Z1041 compared four cycles of FEC (5-FU, epirubicin, cyclophosphamide) followed by 12 weeks of paclitaxel/trastuzumab (Arm 1: n=140) with 12 weeks of paclitaxel/trastuzumab followed by four cycles of FEC/trastuzumab (Arm 2: n=142) as neoadjuvant treatment for HER2+ operable breast cancer. No difference was observed in the rate of pCR (no invasive disease in breast) (56.5% in Arm 1 and 54.2% in Arm 2; p=0.72) or cardiac toxicity.
A significantly higher rate of pCR was observed in the HR- population (72.4% in Arm 1 and 76.7% in Arm 2) compared with the HR+ population (45% in Arm 1 and 37.8% in Arm 2).
The study concluded that concurrent anthracycline and trastuzumab is not necessary as part of the anthracycline and sequential taxane/trastuzumab regimen.
• NOAH (Abstract 503): Neoadjuvant/adjuvant trastuzumab improves pCR rate and long-term outcome for HER2+ breast cancer.
The NeOAdjuvant Herceptin (NOAH) trial compared the addition of trastuzumab or not to the neoadjuvant chemotherapy regimen (doxorubicin/paclitaxel q3w × 3 cycles followed by paclitaxel q3w × 4 cycles followed by CMF (cyclophosphamide, methotrexate, 5-FU) q4w × 3 cycles) followed by surgery for HER2+ breast cancer (n=117 trastuzumab arm, n=118 in chemo only arm). Additionally, trastuzumab was administered to week 52 in the adjuvant setting in the trastuzumab arm. The study had previously reported a significant improvement of pCR in the breast by the addition of trastuzumab to chemotherapy (43% versus 22%, p=0.0007).
Updated analysis at a median follow up of 5.4 years demonstrated a significant improvement in event-free survival (EFS) (HR 0.64, 95% CI 0.44-0.93; p=0.016) and a non-significant trend for longer overall survival (HR 0.66, 95% CI 0.43-1.01, p=0.055) in the trastuzumab arm for the HER2+ population.
Interestingly, the benefit of trastuzumab was statistically significant only in the pCR group (HR 0.29, 95% CI 0.11-0.78, p=0.135) and not in the non-pCR group. The p value for interaction between treatment and pCR effect = 0.037. The study confirms that benefit of trastuzumab for patients with early-stage breast cancer.
Adjuvant Cytotoxic Therapy
• S0221 (Abstract CRA1008): Weekly paclitaxel (80 mg/m2) × 12 is equivalent to the every-two-week (175 mg/m2) with pegfilgrastim support × 6, in reducing breast cancer in the adjuvant setting and with less toxicity.
The phase III S0221 trial, which compared two schedules of paclitaxel following dose-dense AC (doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2) as adjuvant therapy for high-risk early-stage breast cancer, demonstrated no difference between weekly paclitaxel × 12 (n=1, 653) or Q2 week paclitaxel × 6 (n=1,641) in five-year DFS and OS. Allergy and musculoskeletal pain and neurologic toxicities were significantly greater in the Q2 week arm.
• CALGB 40101 (Abstract 1007): Single-agent paclitaxel not as good as doxorubicin/cyclophosphamide.
CALGB 40101 randomized patients with zero to three positive lymph nodes in early-stage breast cancer to receive either AC (Q3w then changed to Q2w) or paclitaxel (weekly then changed to Q2w) for four to six cycles as adjuvant treatment. Adjuvant hormonal therapy and trastuzumab were administered as indicated. Previous analysis of this trial demonstrated no difference between four or six cycles of therapy in relapse-free survival (RFS).
Data presented at ASCO 2013 indicated that paclitaxel is not equivalent to AC in RFS (HR: 1.26, favoring AC, 95% CI 1.05-1.53, p=0.02) and OS (HR: 1.27, favoring AC, 95% CI 1.00-1.62, p=0.05). Therefore, single-agent paclitaxel is not recommended in the adjuvant setting based on this study.
• 10-year update of NSABP B32: Axillary lymph node dissection is not needed in patients with negative sentinel lymph node.
NSABP B32 was a Phase III trial that randomized patients with clinically node-negative breast cancer to either the sentinel node (SN) resection with axillary lymph node dissection (AD) (group 1) or SN alone without AD unless SN was found to be positive by intraoperative cytology or postop H&E. The 10-year follow-up data were reported.
In the SN-negative population, no difference was observed between the two groups in local and regional recurrences rates (4.25% in the SN+AND arm and 4.03% in the SN-only arm, HR=0.96, p=0.77), DFS (HR=1.02, p=0.72) or OS (HR=1.09, p=0.35), reassuring the current practice that the SN-negative population does not need AD.
Among the 3,268 patients with negative SN, central analysis by IHC and detailed pathologic exam of the SN were performed. 616 (15.9%) patients were found to have occult metastases, including 430 with isolated tumor cells, 172 with micrometastases, and 14 with macrometastases.
The presence of an occult metastases was associated with an insignificant decrease in overall survival (HR=1.26, p=0.06) and a significant decrease in disease-free survival (HR=1.25, p=0.01), but likely not clinically significant. Therefore, routine use of IHC for SN evaluation is not recommended.
• Final analysis of the EORTC AMAROS trial (Abstract LBA1001): Axillary radiation provides local control and survival comparable to axillary lymph node dissection (AD) with fewer side effects in women with clinical node-negative but found to have a positive sentinel node.
In this trial, patients with a positive SN, were randomized to AD (n=744) and axillary radiation (A×RT: level I + II + III + supraclavicular area) (n=681). Patients with four or more positive lymph nodes identified in the AD group were offered radiation therapy.
The five-year axillary recurrence rates were low in both groups—0.43 percent in the AD group and 1.19 percent in the AxRT group. There was no difference in DFS and OS between the two groups.
Note that ALND identified no additional lymph nodes in 67.1 percent, one to three nodes in 25 percent, and more than four in 7.8 percent of patients. There was a significantly higher rate of lymphedema in the AD group, and therefore, radiation rather than AD is recommended.