Ellis, M. J.

Abstract Background: Survivor plots permit adjustment by baseline demographics and clinical characteristics; log-normal survival analysis may be more robust than a Cox model under departures from model assumptions. We depicted distant disease-free survival (DDFS) for statistically standardized quantitated ER, PgR, and HER2. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER, PgR, and HER2 HSCORE were centrally assessed by machine image quantitation, and statistically standardized to mean of 0, standard deviation (SD) of 1 following Box-Cox variance stabilization transformations of square for ER, natural logarithm (ln) and square root for PgR, and ln for HER2. For the ln transformation, 0.1 was added to 0 HSCOREs for a stable transformation. The primary endpoint was DDFS at the longest trial follow-up of 4.1 years. For log-normal survival analysis, ln(time) is a linear function of covariates and had a normal distribution; the Cox models were log-linear for covariates. Survival was depicted with log-normal and Cox survivor plots adjusted at the means of age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics. We examined ER and PgR ASCO/CAP cut-points at (0; >0), HER2 cut-points at (IHC 0, 0 stain; IHC 0, (0,10%] stain; IHC 1+; IHC 2+; IHC 3+), and ER/PgR/HER2 standardized cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1). P was based on the likelihood ratio criterion (∼Χ2 (1)) for the addition of ER/PgR/HER2 to the model of baseline covariates, and had nominal significance if P<0.05. Log-normal and Cox multivariable regressions with unstandardized and standardized categorical, and continuous, ER, PgR, and HER2 were adjusted by baseline covariates; 2-sided Wald tests had nominal significance if P<0.05. Results: Of 7576 MA.27 patients, 2325 patients had quantitated image analysis assessments for ER, PgR, and HER2; 113 of 2325 (4.9%) patients experienced a DDFS event during follow-up. Multivariable log-normal survival analysis indicated DDFS was significantly longer for patients with T1 (p=0.01), N0 (p=.002), and grade 1/2 tumors (p=0.01); similar significance levels were found with a Cox model. Log-normal survivor plots were smooth, while Cox survivor plots were step-wise discontinuous at events. Adjusted log-normal survivor plots indicated similar 5-year DDFS for patients by standardized ER categories (p=0.43): 95.4% for those with ER <-1.0 (n=401); 95.8%, for (-1.0,0.0] (n=737); 96.1%, for (0.0,1.0] (n=737); and 96.4%, for >1.0 (n=450). The log-normal standardized PgR survivor plots indicated patients had significantly different 5-year DDFS (p<.001) by categories, with both ln and square root transformations of HSCORE: with a ln transformation, 93.7% for <-1.0 (n=607); 95.4%, for (-1.0,0.0] (n=390); 96.8%, for (0.0,1.0] (n=826); and 97.8%, for >1.0 (n=502). Patients had similar 5-year DDFS by standardized HER2 categories (p=0.71): 96.2% for <-1.0 (n=83); 96.0%, for (-1.0,0.0] (n=1201); 95.9%, for (0.0,1.0] (n=527); and 95.7%, for >1.0 (n=514). In full fit multivariable log-normal survival analyses, DDFS was not significantly different for ER (p=0.51-0.89) and HER2 (p=0.12-0.98); higher PgR was associated with significantly better DDFS (p=0.01 to <.001). Adjusted Cox survival analyses had similar results. Conclusions: Survivor plots adjusted for baseline demographic and clinical characteristics provided similar indications of significance for standardized ER, PgR, and HER2 as those seen in multivariable models with both log-normal and Cox survival analyses. Higher PgR was associated with significantly better DDFS. Citation Format: J. W. Chapman, J. Bayani, S. SenGupta, J. M. S. Bartlett, T. Piper, M. A. Quintayo, S. Virk, P. E. Goss, J. N. Ingle, M. J. Ellis, G. W. Sledge, G. T. Budd, M. Rabaglio, R. H. Ansari, R. Tozer, D. P. D'Souza, H. Chalchal, S. Spadafora, V. Stearns, E. A. Perez, K. A. Gelmon, T. J. Whelan, C. Elliott, L. E. Shepherd, B. E. Chen, K. J. Taylor. Survivor plots for quantitated adjunctive statistically standardized ER, PgR, and HER2 in adjuvant postmenopausal breast cancer: Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-07-23.

Abstract Background: While there are abundant data on the surgical management of BC after neoadjuvant chemotherapy (NAC), there is less guidance regarding surgical management of BC after NET, particularly with respect to lymph node (LN) surgery. While pathologic complete response (pCR) is common with NAC, it is a rare event with NET. In this analysis we assess the surgeons’ approach in the context of NET. Methods: The ALTERNATE trial is a phase III study that randomized postmenopausal patients (pts) with clinical stage II/III ER+ HER2- BC to receive neoadjuvant anastrozole (A), fulvestrant (F), or both for 6 mos. before surgery. The primary objective was to determine if neoadjuvant F or A+F increases the rate of pCR or ypT1-2N0/N1mic/Ki67 <2.7% residual disease over A alone. Breast surgery was per standard of care. Sentinel lymph node biopsy (SLNB) with or without axillary lymph node dissection (ALND) was required to determine preoperative endocrine prognostic index PEPI score and residual cancer burden (RCB). Surgeons were required to indicate if the patient would be eligible for breast- conserving surgery (BCS) prior to NET. Patient accrual occurred from 2014-2018. The surgical outcomes are reported for the entire group. Results: Among the 3 treatment arms, 933 patients completed 6 cycles of NET. The clinical T stage at diagnosis was 73.6% T2, 22.6% T3and 3.8% T4. Initial tumor size was assessed by mammogram and ultrasound. Primary tumor histology was ductal in 64.8% and lobular in 25.4%.568 pts (60.9%) were clinically node negative (cN0), 36.2% cN1, 2.6% cN2 with 0.3% cN3. LNs were palpable in 25.2%. 383 had LN needle biopsy pre NET, of which 80.9% were positive. The surgeons’ initial impression of the patient’s eligibility for BCS was 74% while 0.6% were considered inoperable.75.5% of pts had post-NET imaging performed. Of those with tumor size recorded, 52.9% were T1 or not visible. Overall, 69.9% of the 933 patients had BCS. Of those 330 pts without post-NET imaging or who had post-NET imaging without a size noted, 64.8% underwent BCS. For pts undergoing BCS, 80.2% required only one surgery for margin clearance. Of the 690 pts deemed eligible for BCS pre NET, 79% had BCS. Of the 240 pts deemed ineligible for BCS pre-NET, 43.8% had BCS. Of the pre-NET cT2 tumors, 79% had BCS while only 45.5% of T3 tumors and 37.1% of T4 tumors had BCS. On surgical pathology, 474 (50.8%) pts were LN+ compared to pre-NET cN+ 39.1% and needle biopsy-proven 33.2%. For pts with pN0, 93.3% had SLNB alone. 6.7 % of pN0 had ALND alone or SLNB+ALND. For those with pN1-3 , 36.3% had SLN only; 37.3% SLN+ ALND; 26.4% ALND alone. Only 0.8% of the patients had no ALND or SLNB performed. Pts undergoing BCS were more likely to have SLNB alone for a +SLN compared to mastectomy pts (62.9% vs. 37.6%; chi-square p<0.0001). For pts with pre-NET +LN on needle biopsy, only 26.8% underwent SLNB alone, while 37.4% underwent ALND alone. Of the 204 LN-positive pts having SLNB alone, 55.9% had only 1 + LN and 27% had only 2+ LNs. For pN+ pts who underwent SLNB +ALND, 42.1% had 1-2 + LNs. Conclusion: With NET, 69.9% of pts achieved BCS, including 43.8% deemed ineligible pre-NET. Given the low rate of pCR to NET, there should not be the expectation of pCR in +LNs. Based on the procedures performed in pts with +SLNs, it appears that surgeons were applying ACOSOG Z0011 criteria for pts having BCS, but were less likely to omit ALND for +LN in pts having mastectomy. The finding of only 1-2 +LNs in many of the LN+ pts suggests that omission of ALND may be a reasonable approach post-NET. Longer follow-up is required to assess local-regional recurrence. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: A. M. Leitch, T. Dockter, V. suman, A. Weiss, G. W. Unzeitig, J. Guenther, S. Sanati, K. Vij, J. Hoog, A. Caudle, A. Tiersten, M. Mita, W. Razaq, T. J. Hieken, Y. Wang, M. Rimawi, M. J. Ellis, E. Winer, K. K. Hunt, A. H. Partridge, L. A. Carey. Surgical outcomes in the ALTERNATE trial (Alliance A011106) -a randomized phase 3 neoadjuvant endocrine therapy (NET) trial in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF1-02.