Gelber, Richard D.

Background Limited data exist on the safety of using anti–human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2‐positive patients. Methods The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2‐positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease‐free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time‐varying covariates to account for a guarantee‐time bias. Results Ninety‐two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52‐2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307). Conclusions For patients with HER2‐positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.

502 Background: Pre-specified 5-year analyses of the phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial defined in Amendments 11&12. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. In 2011, due to futility the L arm was closed and is not included in this analysis. The primary end point is disease-free survival (DFS). Secondary objectives include treatment comparisons with respect to overall survival (OS), time to recurrence (TTR), time to distant recurrence (TDR), cardiac and overall safety and tolerability. Primary analysis results of the study were published in JCO 2015 34:1034-1042. This updated analysis occurs at a 6.9 yrs median follow up (MFU). Results: All patients have reached 5-years of follow-up. 705 DFS events for L+T vs T have been observed. HR for DFS was 0.86 (95% CI, 0.74-1.00; 6-yr DFS%=85% vs 82%) for L+T vs T and 0.93 (95% CI, 0.81-1.08; 6-yr DFS%=84% vs 82%) for T→L vs. T. The 6-year OS was 93%, 92%, and 91% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T vs. T and 0.88 (95% CI, 0.71-1.08) for T→L vs. T. DFS differences for L+T vs. T were slightly higher for the hormone-receptor(ER)-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS%=84% vs. 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS%=83% vs.79%)] subgroups. There were no differences in sites of first DFS events according to treatment arm for CNS, loco-regional, or distant recurrences. There were more AEs related to study treatment (L+T 93% vs T 64%). The incidence of primary cardiac end points was low: 1% for L+T, 0.5% for T→L and 0.9% for T. Conclusions: The HRs for this updated analysis are similar to those from the Primary Analysis and the event rate remains lower than anticipated (705 vs 850 planned). Cardiac toxicity remains low. This analysis suggests that HER2+/ER- tumors may have a different biology than HER2+/ER+ and may benefit more from dual HER2 blockade. Long-term follow up continues. Clinical trial information: NCT00490139.

LBA4 Background: Lapatinib (L) is a HER1-HER2 tyrosine kinase inhibitor. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised, phase III trial comparing 3 oral L-containing regimens with T, each given for 1 year. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. Anti-HER2 therapy was initiated after completing all chemotherapy (N=4613), concurrently with a taxane following anthracycline (N=3337), or concurrently with a non-anthracycline, platinum-containing regimen (N=431). The L arm was closed in Aug 2011 for futility and is not presented. The primary endpoint is invasive disease-free survival (DFS). L+T vs. T is tested for superiority and T→L vs. T is tested for non-inferiority at 1.11 margin. P≤0.025 is required for statistical significance. 850 DFS events in the L+T vs. T comparison would provide 80% power to detect a true hazard ratio (HR) of 0.80 with experiment-wide alpha=0.05. The current analysis was planned to occur either after observing these 850 events or at 4.5 yrs median follow up (MFU). Results: Pt and disease characteristics were well balanced. 40% were node-negative and 57% were hormone receptor positive. Only 555 DFS events for the L+T vs. T comparison were observed at 4.5 years MFU. HR for DFS was 0.84 (97.5% CI, 0.70-1.02; P=0.048; 4-yr DFS%=88% vs. 86%) for L+T vs. T and 0.93 (97.5% CI, 0.76-1.13; non-inferiority P=0.044; 4-yr DFS%=87% vs. 86%) for T→L vs. T. Diarrhoea (75% vs. 20%), rash (55% vs. 20%) and hepatobiliary (23% vs. 16%) adverse events were more frequent in L+T vs. T. Primary cardiac endpoints were infrequent (<1%) in all arms. Conclusions: L+T has lower risk of a DFS event compared with T, and T→L appeared non-inferior to T, but neither finding was statistically significant. The first DFS results of dual HER2 blockade in the adjuvant ALTTO at 4.5 years MFU are unexpected considering the effect shown by doubling the pCR rate with L+T vs. T in the NeoALLTO trial. Follow up continues. Clinical trial information: NCT00490139.

LBA1 Background: Adjuvant endocrine therapy with AI vs T improves outcomes in postmenopausal HR+ BC. TEXT and SOFT were designed to test whether adjuvant AI improves outcomes in premenopausal women with HR+ BC treated with OFS (AI question) and to determine the value of OFS in women who remain premenopausal and are suitable for adjuvant T (OFS question). Methods: TEXT and SOFT, randomized phase 3 trials, enrolled 5,738 premenopausal women with HR+ early BC from Nov03 to Apr11 (2672 TEXT; 3066 SOFT). TEXT randomized women within 12wk of surgery to 5y E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5y E+OFS vs T+OFS vs T alone, either within 12wk of surgery if no CT planned, or within 8mo of completing (neo)adjuvant CT. OFS was by choice of 5y triptorelin, oophorectomy, or ovarian irradiation. The primary endpoint is disease-free survival (DFS: randomization until invasive local, regional, distant recurrence, or contralateral breast; 2nd malignancy; death). Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the AI question (E+OFS vs T+OFS) by joint analysis of TEXT and SOFT. By Q3’2013 with >5y median follow-up, 436 DFS events were projected, providing 84% power for HR=0.75 with E+OFS vs T+OFS (stratified logrank 2-sided α=0.05). Results: At 5.7y median follow-up, 514 (11%) DFS events were reported in the ITT population comparing E+OFS (n=2346) vs T+OFS (n=2344). Patients assigned E+OFS had significantly reduced DFS hazard (HR=0.72; 95% CI, 0.60-0.86; P=0.0002) vs T+OFS; 5y DFS was 91.1% vs 87.3%. Reductions were similar for secondary endpoints of BC-free interval (HR=0.66 (0.55-0.80) 5y BCFI 92.8% vs 88.8%) and distant recurrence-free interval (HR=0.78 (0.62-0.97)), though not overall survival (HR=1.14 (0.86-1.51)) at this early follow-up (194 (4%) deaths). Grade 3-4 targeted AEs were reported in 31% E+OFS vs 29% T+OFS patients. Conclusion: In premenopausal women with HR+ BC, adjuvant treatment with E+OFS significantly reduced the risk of recurrence compared to T+OFS. Clinical trial information: NCT00066703 / NCT00066690 .

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Purpose We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) –positive breast cancer treated in randomized trials. Methods A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) –positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. Results Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively. Conclusion Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.

Purpose For nearly two decades, multiple retrospective reports, small prospective studies, and meta-analyses have arrived at conflicting results regarding the value of timing surgical intervention for breast cancer on the basis of menstrual cycle phase. We present the results of a multi–cooperative group, prospective, observational trial of menstrual cycle phase and outcome after breast cancer surgery, led by the North Central Cancer Treatment Group (NCCTG) in collaboration with the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the International Breast Cancer Study Group (IBCSG). Patients and Methods Premenopausal women age 18 to 55 years, who were interviewed for menstrual history and who were surgically treated for stages I to II breast cancer, had serum drawn within 1 day of surgery for estradiol, progesterone, and luteinizing hormone levels. Menstrual history and hormone levels were used to determine menstrual phase: luteal, follicular, and other. Disease-free survival (DFS) and overall survival (OS) rates were determined by Kaplan-Meier method and were compared by using the log-rank test and Cox proportional hazard modeling. Results Of 1,118 women initially enrolled, 834 women comprised the study cohort: 230 (28%) in luteal phase; 363 (44%) in follicular phase; and 241 grouped as other. During a median follow-up of 6.6 years, and in analysis that accounted for nodal disease, estrogen receptor status, adjuvant radiation therapy or chemotherapy, neither DFS nor OS differed with respect to menstrual phase. The 5-year DFS rates were 82.7%, 82.1%, and 79.2% for follicular, luteal, or other phases, respectively. Corresponding OS survival rates were 91.9%, 92.2%, and 91.8%, respectively. Conclusion When menstrual cycle phases were strictly defined, neither DFS nor OS differed between women who underwent surgery during the follicular phase versus the luteal phase. Nearly 30% of the patients did not meet criteria for either follicular- or luteal-phase categories.