Guenther, J. Michael

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.

504 Background: For PM patients (pts) with locally advanced ER+ HER2- BC, NET improves breast conservation surgery (BCS) rates, and modified preoperative endocrine prognostic index (mPEPI) 0, defined as pT1-2 pN0 Ki67< 2.7%, or pathologic complete response (pCR: no invasive disease in breast or lymph node) is associated with low risk of recurrence without adjuvant chemotherapy (CT). The ALTERNATE trial was initiated to assess if the endocrine-sensitive disease rate (ESDR: number of mPEPI 0 pts/number of eligible pts initiating NET) with fulvestrant (F) or F+anastrozole (A) is improved relative to A alone (reported here) and if the 5-year (yr) recurrence-free survival (RFS) rate for pts with mPEPI 0 on A alone without CT is ≥ 95% (awaits further follow-up). Methods: PM pts with clinical stage II/III ER+ HER2- BC were randomized 1:1:1 to 1 mg A po daily, 500 mg F IM every 4 week (wk)s after loading dose, or A+F for 6 months. Ki67 was tested centrally on biopsies acquired prior to NET, wk 4, wk 12 and at surgery. Pts with Ki67 >10% at wk 4 or 12 were recommended to go off protocol-directed ET and switch to CT. Pts with mPEPI 0 at surgery were recommended to continue assigned ET for 1.5 yrs followed by A for a total of 5 yrs ET (and not to receive CT). The primary endpoint of the neoadjuvant phase was ESDR. ESDR of each F arm was compared to that of the A alone arm. With 425 pts per arm, a one-tailed alpha = 0.025 chi-square test of two independent proportions has 84% power to detect an increase of ≥10% in ESDR for F or F+A compared to the A arm, assuming ESDR ≤30% in A. Results: 1362 pts (A 452; F 454; A+F 456) were enrolled Feb 2014 to Nov 2018. 63 pts were excluded (did not start NET). Of the remaining 1299 pts (A 434; F 431, A+F 434), 42% were cN1-3 and 73% were considered candidates for BCS. ESDR was 18.6% (95%CI: 15.1-22.7%) with A, 22.7% (95%CI: 18.9-27.0%) with F, and 20.5% (95%CI: 16.8-24.6%) with A+F. No significant difference in ESDR was found between A and F (p=0.15) or A and A+F (p=0.55). Among the 825 pts with wk 4 Ki67 < 10% who completed NET and surgery, ESDR and the BCS rate were 27.7% and 70.3% with A; 29.6% and 68.1% with F, and 26.8% and 69.9% with A+F, respectively. Conclusion: Neither F nor F+A significantly improved ESDR compared to A alone in PM pts with locally advanced ER+ HER2- BC. RFS data are awaited. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org ; NCI BIQSFP, BCRF, Genentech, AstraZeneca. Clinical trial information: NCT01953588 .

Abstract Background: Standard treatment for ductal carcinoma in situ (DCIS) consists of surgery, often followed by adjuvant radiation therapy or endocrine therapy. This current approach is thought to represent overtreatment for some patients. This study was undertaken to determine whether an alternate approach of primary endocrine therapy alone could result in measurable radiographic changes in unresected estrogen receptor (ER)-positive DCIS. Methods: A phase II open-label single arm multi-center cooperative group trial (CALGB 40903) was conducted for postmenopausal patients diagnosed with ER-positive DCIS. All eligible patients underwent baseline mammography and MRI, followed by 6 months of preoperative therapy with letrozole. Follow up breast MRI was obtained at 3 and 6 months of treatment. The primary endpoint was change in total MRI volume of DCIS enhancement from baseline to 3 months and from baseline to 6 months. Secondary endpoints were change in MRI maximum diameter over baseline and change in mammographic extent of disease over baseline. Endpoints were analyzed via 2-sided paired t-tests (a=0.05). Results: From 8/1/12 to 2/1/16 108 patients were enrolled; Of the 77 patients who completed letrozole treatment per protocol, 66 patients were assessable. 2 additional patients who did not complete treatment per protocol were considered assessable and thus included in the analysis for a total of 68 patients. Median age of the cohort was 62.7 years. DCIS nuclear grade was low in 10% of patients, intermediate in 49%, and high in 40%. 82% of patients had ER-positive, PR-positive DCIS. The total mean MRI volume decreased from baseline to 3 months by 1.93 cm3 (p&lt;0.001) and from baseline to 6 months by 1.82 cm3 (p&lt;0.001). There was no significant difference in tumor volume between 3 and 6 months. Mean total mammographic tumor diameter decreased from baseline to 6 months by 3.31 mm2 (p=0.078). Conclusions: In a cohort of postmenopausal women treated with 6 months of preoperative endocrine therapy for ER-positive DCIS, MRI volume decreased markedly by 3 months, while mammographic extent of disease was not altered significantly. Correlation of imaging changes with pathology and baseline biomarkers will be conducted. These results will help determine whether MRI could be an effective modality for monitoring treatment response in some patients treated with primary endocrine therapy for ER-positive DCIS. Citation Format: Hwang ES, Duong S, Bedrosian I, Allred J, Wisner D, Hyslop T, Caudle A, Guenther J, Hudis C, Winer E, Esserman L, Hylton N. Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-05.

LBA513 Background: Neoadjuvant aromatase inhibitor (AI) therapy is a rational and effective approach to improving the breast conservation surgery (BCS) rate for postmenopausal patients with large, estrogen receptor (ER) rich breast cancers. Barriers to adopting this strategy include lack of experience in this management approach in the US and uncertainty regarding the comparative effectiveness of the three approved aromatase inhibitors for this indication. Methods: ACOSOG Z1031 is a multicenter, open-label, neoadjuvant phase III screening study that randomized postmenopausal women with clinical stage II/III ER rich (Allred score 6-8) breast cancer to 16 weeks of either exemestane (EXE) 25 mg daily, letrozole (LET) 2.5 mg daily, or anastrozole (ANA) 1 mg daily. At baseline study participants were either marginal for BCS (MBCS), candidates for mastectomy only (MO), or inoperable (IO). Planned enrolment was 125 patients per arm in order that the likelihood of the treatment with the “best” 16-week clinical response rate (based on caliper measurements) by WHO criteria (cRR) was included among the subset of treatments with “similar” cRR (90% power). Secondary endpoints included: extent of surgery, radiologic and pathologic response rates. Results: From 4/1/2006 to 10/1/2009, 377 postmenopausal women with clinical stage II or III ER rich breast cancer were enrolled. 374 women began treatment and were included in an intent-to-treat analysis. Median age was 66 yrs (range: 43-90 yrs), Median tumor size was 4.0 cm (range: 2-13 cm). The 16-week cRR was 60.5% (95%CI: 51.3-69.1%) for EXE; 70.9% (95% CI: 62.2-78.6%) for LET, and 66.7% (95% CI: 57.6-74.9%) for ANA. Seventeen patients did not have surgery due to refusal (12 pts), progression (3 pts) or other medical conditions (2 pts). The BCS rate was 78% (163/207) in MBCS group; 42% (77/163) in MO group; and 75% in IO group (3/4). Surgeons made the decisions regarding procedure choice 75% of the time in both the MBCS and the MO categories. Conclusions: This large multicenter screening trial selected non-steroidal AIs for further development due to their higher observed cRR. The study demonstrates that high response and breast conservation rates and low rates of disease progression can be achieved through patient selection based on high ER expression. We are currently refining our approach for early detection of poor response to AIs through an assessment of the tumor Ki67 proliferation index at 2 to 4 weeks (Z1031 Cohort B). [Table: see text]

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Abstract Background: Estrogen receptors are over-expressed in around 70% of breast cancer cases. The genetic changes that occur during aromatase inhibitor (AI) treatment are not well understood and may differ depending upon the patient's response phenotype. Methods: We performed whole genome sequencing (WGS) of matched blood, pre-treatment, and post-treatment biopsy samples from 22 estrogen receptor positive breast cancer patients treated with neoadjuvant aromatase inhibitors. For 5 cases, we performed the whole genome sequencing (WGS) on patients’ matched normal, two pre AI-treatment, and two post AI-treatment DNA isolates from biopsy samples. We validated all putative coding and non-coding somatic mutations using deep sequencing. By comparing the validated somatic mutations from pre- and post- AI treatment biopsy samples, we were able to determine the alterations in the tumor genomes. In every case we defined the clonal architecture of each pair of pre-treatment and post-treatment biopsy samples by comparing the variant allele frequencies from thousands of validated somatic mutations. Results: Comparisons of the two pre AI-treatment biopsy samples from the same patient indicates that the variant allele frequencies of mutations showed high concordances in all 5 cases, 0.74 to 0.95 range of correlation coefficient. Only a small percentage of somatic mutations were detected in one pre-treatment sample and not the other (4.65% overall). In comparing the somatic variations between pre-treatment and matched post-treatment biopsy samples in 22 cases, we found that patients with good clinical response to AI treatment retained known driver mutations only in their pre-treatment tumors. Conversely, those patients with poor clinical response presented new driver mutations in their post-treatment samples. Furthermore, the variant allele frequency for most mutated genes decreased in post AI treatment samples for patients with good AI treatment response; on the contrary, the variant allele frequency increased for patients with poor clinical response. Conclusions: From WGS of matched normal, pre-treatment, and post-treatment biopsy samples, we identified new driver genes mutated in patients with poor clinical response, while patients with good clinical response had lost mutated driver genes in their post-treatment biopsy samples. The genetic landscape revealed by WGS of pre-treatment and post-treatment biopsy samples reveals mutational repertoires are remodeled by AI therapy. This finding suggests deep sequencing of AI treated samples will be necessary to reveal the complete complement of mutations present in a patient's tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-423. doi:1538-7445.AM2012-LB-423