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Introduction: PIK3CA mutations, seen in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC), are associated with treatment (Tx) resistance and shorter survival. Alpelisib (ALP) is an α-selective PI3K inhibitor and degrader indicated for treating this population in combination with fulvestrant (FUL) after endocrine therapy (ET). Previous results from the SOLAR-1 study showed that progression-free survival (PFS) ≥18 mo is achievable for pts treated with ALP on/after prior Tx with aromatase inhibitor (AI). Here, we analyze pts from BYLieve study Cohort A who achieved long-term (LT) and very-long-term (VLT) disease control with ALP + FUL after prior Tx with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and AI. Methods: BYLieve was a Phase II, nonrandomized, open-label, 3-cohort study of ALP + ET in pts with PIK3CA-mutated, HR+, HER2– ABC whose disease progressed on/after prior CDK4/6i. In Cohort A, median (m) PFS was 7.26 mo. LT disease control was defined as ≥12 mo PFS and VLT disease control as ≥18 mo PFS. Pts with < 12 mo PFS were defined as non-LT. Baseline characteristics are summarized by duration of disease control. Incidence rate (IR) per 100 patient-treatment years (PTY) was calculated to assess exposure-adjusted adverse events (AE). To assess tumor complexity in LT/VLT pts, median circulating tumor DNA (ctDNA) fraction, chromosome (chr) 8/11 amplification, and ESR1 mutations were determined by next-generation sequencing. Results: In BYLieve Cohort A, 31 of 121 pts (25.6%) achieved LT disease control with an mPFS of 24.8 mo (95% CI 18.2 mo to not estimable [NE]) and 20 of 121 pts (16.5%) achieved VLT disease control (mPFS NE; 95% CI 22.1 mo to NE). Pts with LT/VLT disease control had lower BMI and ECOG score, longer time from initial diagnosis to first recurrence/relapse, more frequent bone-only lesions, and fewer liver metastases than non-LT pts (Table). Median ALP relative dose intensity was 86.7%, 91.7%, 85.0%, and 85.1% for all Cohort A pts (n=127), non-LT (n=96), LT (n=31), and VLT disease control (n=20), respectively, whereas median ALP exposure was 5.13 mo, 3.61 mo, 21.29 mo, and 25.25 mo respectively. The IRs per 100 PTY of diarrhea, hyperglycemia, and rash were lower in LT (IR 128.4, n=24; IR 78.0, n=20; IR 21.6, n=10 respectively) and VLT (IR 93.5, n=15; IR 51.2, n=11; IR 24.9, n=8 respectively) pts than non-LT pts (IR 250.5, n=57; IR 251.5, n=56; IR 85.4, n=30 respectively). In LT and VLT pts ctDNA fraction was 2% and 5% respectively, whereas ctDNA fraction in non-LT pts was 14%. Incidence of chr 8/11 amplification was 10% in both LT and VLT pts and 20% in non-LT pts; incidence of ESR1 mutations was 26%, 25%, and 27% in LT, VLT, and non-LT pts respectively. Conclusions: In pts with PIK3CA-mutated, HR+, HER2– ABC treated with ALP + FUL after CDK4/6i, LT and VLT disease control was observed in 25.6% and 16.5% of patients, respectively. Visceral disease, development of AEs, and ESR1 mutations did not preclude LT/VLT disease control. These data confirm that targeting the PIK3CA driver mutation with ALP + FUL post-CDK4/6i Tx may lead to LT disease control. Table Baseline characteristics in BYLieve Cohort A overall and by duration of disease control Citation Format: Hope Rugo, Stephen K. Chia, Javier Cortés, Giuseppe Curigliano, Patrick Neven, Rebecca Dent, Sara Tolaney, Eva Ciruelos, Yeon H. Park, Estelle Roux, Yogesh Chattar, Heather Patino, Murat Akdere, Dejan Juric. PD13-06 Long-Term and Very-Long-Term Disease Control in Patients From BYLieve Study Cohort A With PIK3CA-Mutant, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-06.

Introduction Neuroendocrine tumours (NET) are thought to arise from cells throughout the diffuse endocrine system and can occur almost everywhere in the body. Most NETs arise from the gastrointestinal tract, lung, thymus, and pancreas. Primary neuroendocrine carcinoma (NEC) of the breast is a rare and under-recognized subtype, accounting for less than 1% of breast carcinomas. Only a few small studies and case reports have been reported and there are no clear diagnostic criteria and established treatment options. World Health Organization (WHO) classification of tumor series’ fifth edition was published in 2019 and adopted ‘Neuroendocrine neoplasm (NEN)’ as a term encompassing all tumour classes with predominant neuroendocrine differentiation. NENs of the breast are classified into invasive ductal carcinoma (IDC) with neuroendocrine differentiation (NED), NET, and NEC of small cell or large cell types. Thus we aim to report pathologic reviews and treatment outcomes of patients with NENs of the breast at a single center. Methods We retrospectively screened the medical record of 34,370 patients diagnosed with breast cancer from 2007 to 2022 by Corporate Data Warehouse (CDW) and revealed there were 22 patients diagnosed with primary breast NEN. The pathologist reviewed the pathology slides and reclassified the diagnosis according to the WHO classification of tumor series’ fifth edition. Clinical characteristics, treatment modalities, and therapeutic outcomes were reviewed retrospectively. Results We reviewed pathology slides of 22 patients with histologically proven diagnoses of primary breast NEN from 2007 to 2022. We found only 8 patients meet the criteria of primary breast NEC (large cell 2, small cell 6), 3 patients with NET, and 3 patients with IDC with NED. We excluded 8 patients who did not fulfill the criteria of NEN. The median age of NEN was 48.5 years (range, 31-70) and 6 patients (42.9%) were postmenopausal women. The median follow-up duration was 25.3 months (Interquartile range(IQR), 15.0-54.7). All patients underwent surgery, 3 patients underwent a mastectomy and 11 patients underwent breast-conserving surgery (BCS) with a curative aim. Five patients had lymph node metastasis. There was no expression of the human epidermal growth factor receptor 2 (HER2) in all 14 cases. Hormone receptor expression was shown in 4 of NECs (50%) and all NETs or IDC with NED patients. Patients with primary breast NEC had a median recurrence-free period (RFP) of 14.6 months (95% confidence interval (CI), 11.0-18.2) and median overall survival (OS) of 52.1 months (95% CI, 0.0-120.0). Patients with NET or IDC with NED had an overall favorable outcome, none of the patients died and only one patient with IDC with NED experienced disease progression. The median PFS and OS were not reached in NET or IDC with NED subgroups. Conclusion NETs are rare tumours with a wide range of clinical presentations according to the site of involvement. Primary breast NENs are extremely rare and there are no specific guidelines for treatment. NENs are often underdiagnosed, as neuroendocrine markers are not routinely tested in breast cancer. In this retrospective single-center study, the incidence of primary breast NENs was 0.04% (14 of 34,370 patients) and primary breast NEC was associated with poor prognosis compared with breast NET or IDC with NED. Identifying innovative treatment strategies is needed to overcome poor outcomes of primary breast NEC. Citation Format: Young Kyung Jeon, Ji-Yeon Kim, Jin Seok Ahn, Young Hyunk Im, Kyue-Hee Choi, Sun Young Jeong, Yeji Jung, Jae Yeon Jang, Daeho Choi, Joohyun Hong, Hyo Jung Kim, Soo Youn Cho, Yeon H. Park. Primary neuroendocrine carcinoma of the breast: A case series by WHO classfication in 2019 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-07.

BACKGROUND Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader (SERD) that was found to be well tolerated and active as a monotherapy and in combination therapy in Phase I/II studies in early BC and pretreated locally advanced/metastatic BC (LA/mBC). Dual HER2 blockade with pertuzumab + trastuzumab (PH) + a taxane (induction therapy) followed by maintenance PH is the first-line standard of care for most patients (pts) with HER2+ LA/mBC. Despite HER2–ER blockade synergy, paucity of Phase III data evaluating maintenance PH + endocrine therapy (ET) vs. PH in pts with ER+/HER2+ LA/mBC leads to variable use of ET in this setting. Adding giredestrant to the maintenance phase could improve outcomes. TRIAL DESIGN This is a Phase III, randomized, two-arm, open-label, multicenter study evaluating the efficacy and safety of giredestrant + the fixed-dose combination of PH for subcutaneous injection (PH FDC SC) vs. PH FDC SC after induction therapy with PH FDC SC + a taxane in pts with ER+/HER2+ LA/mBC. In the induction phase, pts will receive 4–6 PH FDC SC cycles (1200 mg P/600 mg H in the first cycle, followed by 600/600 mg every 3 weeks) + a taxane (investigator choice of docetaxel/paclitaxel). Pts deriving clinical benefit may receive two additional cycles per investigator’s discretion. Pts completing ≥4 induction therapy cycles, achieving at least stable disease, and with a left ventricular ejection fraction (LVEF) ≥50% will be randomly assigned 1:1 to maintenance giredestrant 30 mg/day + PH FDC SC every 3 weeks or PH FDC SC only, until disease progression (PD). ET (aromatase inhibitor/tamoxifen) will be allowed in the PH FDC SC-only arm. Study treatment will continue until PD, limiting toxicity, death, or consent withdrawal. ELIGIBILITY Enrolled pts must have ER+/HER2+ LA/mBC, disease-free interval from completion of (neo)adjuvant non-ET ≥6 months, Eastern Cooperative Oncology Group performance status 0/1, LVEF ≥50%, and adequate organ function. Pts with prior SERD treatment or presence of symptomatic central nervous system metastases will be excluded. All men and pre-/perimenopausal women must be eligible for a luteinizing hormone-releasing hormone agonist. AIMS The primary endpoint is investigator-assessed, maintenance progression-free survival. Secondary endpoints include overall survival (OS), objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim OS analysis is planned, and an independent data monitoring committee will be in place. ACCRUAL The study is open for enrollment. Approximately 812 pts will be enrolled in the induction phase, to allow for approximately 730 pts to be randomized in the maintenance phase. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number: NCT05296798. Citation Format: Sherko Küemmel, Catherine Harper-Wynne, Yeon H. Park, Fábio Franke, Michelino De Laurentiis, Eva Schumacher-Wulf, Daniel Eiger, Sarah Heeson, Mahesh Shivhare, Eleonora Restuccia, Joyce O’Shaughnessy. heredERA Breast Cancer: Phase III study of first-line, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection ± giredestrant (GDC-9545) for estrogen receptor+, HER2+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-01.

Background: Endocrine therapy remains the mainstay treatment for ER+ BC. CDK4/6 inhibitors induce cell cycle arrest and decrease tumor cell proliferation, as measured by the biomarker Ki67, when used in combination with aromatase inhibitors (AI) such as anastrozole (A). Giredestrant is an oral, well-tolerated, and highly potent selective ER degrader (SERD) that achieves robust ER suppression and has demonstrated antitumor activity in the metastatic setting either as monotherapy or in combination with the CDK4/6 inhibitor palbociclib. The randomized, phase 2 coopERA Breast Cancer study (NCT04436744) evaluated giredestrant in postmenopausal women with untreated ER+/HER2- early BC and met its primary endpoint, demonstrating superior Ki67 suppression with giredestrant vs A after two weeks of single agent treatment. This suppression was maintained at surgery where giredestrant vs A was evaluated in combination with palbociclib. Here, we present gene expression analysis and associations with Ki67 response. Methods: 221 eligible patients with measurable ER+/HER2– untreated early BC and baseline Ki67 ≥ 5% were randomized 1:1 to receive 30 mg oral daily (PO QD) giredestrant or 1 mg PO QD A on Days 1–14 of a neoadjuvant window-of-opportunity phase, followed by four 28-day cycles of PO QD giredestrant or A with 125 mg PO QD palbociclib on Days 1–21 before surgery. FFPE specimens were collected at baseline, week 2 and surgery; and RNA-sequencing (seq) was performed. Gene expression analysis included ER pathway activity, PAM50 intrinsic subtypes, and other pathway analyses, assessed by Ki67 response. Results: 112 and 92 patients had paired tumor samples at baseline/week 2 and baseline/surgery, respectively, that were evaluable for RNA-seq and Ki67. The trend for greater Ki67 protein suppression by giredestrant vs A from baseline to week 2 was maintained in the RNA-seq evaluable subset. Interestingly, the same subset revealed similar suppression of both proliferation gene signatures and ER pathway activity between A and giredestrant. PAM50 subtyping showed that 69% of tumors were luminal (Lum) A and 29% were LumB at baseline. Less than 1% were classified as basal or HER2. Interestingly, giredestrant (G) showed greater suppression of both Ki67 and ER pathway activity vs A in LumB tumors (Ki67: -82% [G] vs -62% [A]; ER activity: -0.83 [G] vs -0.66 [A]) compared to LumA at week 2 (Ki67: -74% [G] vs -71% [A]; ER activity: -0.60 [G] vs -0.70 [A]). Moreover, at week 2, 83% (13/18) of LumB tumors at baseline transitioned into a LumA subtype after giredestrant treatment compared to 46% (5/11) of A-treated tumors. Giredestrant-treated tumors also achieved lower mean ER pathway activity compared to those treated with A at surgery (p=0.023). Gene set enrichment analysis showed downregulation of cell-cycle and ER-related pathways at week 2 and surgery in both treatment arms. A subset of cytokine signaling and immune response pathways were increased at week 2 compared to baseline after treatment with A but not with giredestrant. These pathways were also associated with Ki67 resistance (Ki67 ≥ 7.4%) in A-treated tumors. This was consistent with differential expression analysis of samples collected at week 2, in which cytokine signaling pathways were enriched in A compared to giredestrant. Notably, IL12 signaling was enriched in tumors resistant to A but not giredestrant. Conclusions: Giredestrant has a greater effect on Ki67 protein suppression in ER+/HER2- early BC compared to A, which is more pronounced in LumB tumors. This benefit may involve differential regulation of cytokine and immune responses. These exploratory findings reveal novel mechanisms that may differentiate the activity of SERDs vs AIs, which warrant further validation. Citation Format: Alejandro M. Chibly, Tharu M. Fernando, Ciara Metcalfe, Marc Hafner, Gilbert Owusu-Manu, Sara Hurvitz, Aditya Bardia, Peter A. Fasching, Yeon H. Park, Vanesa Quiroga, Jutta Steinseifer, Pablo Perez-Moreno, Heather M. Moore. PD13-02 Exploratory gene expression analysis of coopERA Breast Cancer (BC): a study evaluating neoadjuvant giredestrant versus anastrozole alone and in combination with palbociclib in ER-positive, HER2-negative untreated early BC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-02.

In DESTINY-Breast01 (NCT03248492) and DESTINY-Breast03 (NCT03529110), trastuzumab deruxtecan (T-DXd) demonstrated unprecedented activity in patients (pts) with HER2+ (immunohistochemistry 3+; immunohistochemistry 2+/in situ hybridization+) advanced metastatic breast cancer (mBC), leading to regulatory approvals in several countries for HER2+ unresectable/mBC after a prior anti–HER2-based regimen. DESTINY-Breast02 (NCT03523585) is a phase 3 trial of T-DXd vs treatment of physician’s choice (TPC) in patients with centrally confirmed HER2+ mBC previously treated with trastuzumab emtansine (T-DM1). It acts as a confirmatory study for the pivotal phase 2 DESTINY-Breast01 trial. Here we report the primary results of DESTINY-Breast02. Methods: Pts with HER2+ mBC were randomized 2:1 to receive T-DXd or TPC (trastuzumab + capecitabine or lapatinib + capecitabine) and stratified by hormone receptor (HR) status (HR+/HR-), prior pertuzumab treatment, and history of visceral disease. The primary endpoint of this time-driven primary analysis was progression-free survival (PFS) as determined by blinded independent central review (BICR). The powered secondary endpoint was overall survival (OS). Other secondary endpoints included confirmed objective response rate (ORR) by BICR, duration of response (DoR) by BICR, PFS by investigator assessment, safety, and others. Results: 608 pts were randomized to receive T-DXd (n = 406) or TPC (n = 202). Pts receiving T-DXd and TPC had a median age of 54.2 years (range, 22.4-88.5 years) and 54.7 years (range, 24.7-86.5 years), respectively, with a median of 2 (range, 0-10 and range,1-8) prior lines of systemic therapy (excluding hormone therapy) in the metastatic setting. Median treatment duration was 11.3 mo in the T-DXd arm and ~4.5 mo in the TPC arm. Efficacy and safety results are shown in the table below. T-DXd significantly improved PFS (HR, 0.36; 95% CI, 0.28-0.45; P Conclusions: Results from DESTINY-Breast02 confirmed the clinical benefit and superiority of T-DXd over conventional chemotherapy-based regimens in pts with HER2+ mBC previously treated with T-DM1, as evidenced by significant and clinically meaningful improvements in PFS and OS. These data, together with earlier reported results from the DESTINY-Breast03 study of T-DXd vs T-DM1 solidify T-DXd as an optimal treatment option in pts with progressive HER2+ mBC across broad settings. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Caylin Bosch, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy and Safety Results for T-DXd and TPC in Patients With HER2+ mBC Previously Treated With T-DM1 Citation Format: Ian Krop, Yeon H. Park, Sung-Bae Kim, Giuliano Borges, Sercan Aksoy, Joaquin Gavila Gregori, Rebecca Roylance, Elgene Lim, Rinat Yerushalmi, Flora Zagouri, Francois P. Duhoux, Tanja Fehm, Toshimi Takano, Anton Egorov, Iris Wu, Jillian Cathcart, Changan Chu, Fabrice Andre. GS2-01 Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-01.

Intestinal ischemia can occur from mesenteric artery (MA) occlusion and portal vein (PV) occlusion. The degree and mechanisms of ischemia/reperfusion (I/R) injury in these conditions may differ. Metabolic changes are seen early in I/R. This study compares tissue histology, inflammation, and metabolic response during small bowel I/R due to superior MA or PV occlusion.Anesthetized male Wistar rats (250-300 g) underwent laparotomy followed by MA or PV occlusion for 40 min. After 120 min of reperfusion, small bowel tissue was collected. The expression of heat shock protein (HSP)-32 and HSP70 was evaluated to compare physiological stress responses between groups. Metabolic profiles were obtained using (1)H-nuclear magnetic resonance spectroscopy (NMR)-based quantitative metabolomics. Histological injury of small bowel was graded from 0 (normal) to 4 (extensive ischemic damage).Protein expression of HSP32 and HSP70 increased when compared to sham but was not different in the MA I/R and PV I/R groups. Metabolic profiles demonstrated decreased glucose levels and highly elevated tissue lactate and amino acids and fatty acids following I/R, with more pronounced changes with PV occlusion. Lipid peroxidation was equally increased in both groups, while depletion of reduced glutathione (GSH) was more severe with MA occlusion. The epithelial necrosis score was higher with MA (3.5 ± 0.6) than with PV occlusion (2.3 ± 0.8).Histological injury of the intestine is less pronounced following PV occlusion, most likely due to higher oxygen and substrate availability during I/R by PV occlusion. This conclusion is supported by a more pronounced metabolic synthetic response (increased glycolysis and fatty acid and amino acid accumulation) with PV occlusion, while oxidative stress was higher with MA occlusion. The inflammatory response showed little difference between the groups.