Metastatic Setting Research Articles

Abstract RF02-03: Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is approved in over 40 countries for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (a score of 1+ on immunohistochemistry [IHC] analysis or an IHC score of 2+ and negative results on in-situ hybridization) breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. DESTINY-Breast08 (DB-08) was designed to establish the safety, tolerability, and preliminary activity of T-DXd in combination with widely used standard of care therapies in HER2-low hormone receptor (HR)+ metastatic breast cancer (mBC). Results reported here are from the dose-expansion stage of the Phase 1b, multicenter, open-label, parallel-assignment DB-08 study arms investigating T-DXd–endocrine therapy (ET) combinations [NCT04556773]. Methods: Eligible patients had centrally confirmed HER2-low advanced/mBC with measurable disease per RECIST 1.1 and were documented as HR+. Among patients with mBC, ≤1 prior line of ET ± a targeted therapy was allowed, and prior chemotherapy in the mBC setting was exclusionary. Patients received T-DXd 5.4 mg/kg intravenously (IV) every three weeks (Q3W) + anastrozole 1 mg orally daily (T-DXd + ANA) or T-DXd 5.4 mg/kg IV Q3W + fulvestrant 500 mg intramuscularly Q4W, with a 500 mg loading dose on Cycle 1 Day 15 (T-DXd + FUL). Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival, duration of response (all evaluated by investigator per RECIST 1.1), and overall survival (OS). Data cutoff (DCO) was ~24 weeks after the last patient in each arm had received study treatment. Results: As of February 20, 2023, 21 patients in the T-DXd + ANA arm and 20 patients in the T-DXd + FUL arm had received study treatment. Median age was 55 and 66 years, 67% and 75% of patients received a prior line of ET ± a targeted therapy for mBC, 33% and 25% had no prior line of treatment for mBC, and median follow up in censored patients was 12.1 months (range 4.0, 17.3) and 8.5 months (range 1.3, 15.1) in the T-DXd + ANA and T-DXd + FUL arms, respectively. Adverse events (AEs) occurred in 95.2% (20/21) of patients in the T-DXd + ANA arm and 100% (20/20) of patients in the T-DXd + FUL arm, with AEs ≥Grade 3 occurring in 47.6% (10/21) and 55.0% (11/20) of patients in each arm, respectively. The most common any-grade AEs, occurring in ≥30% of patients in either arm, are reported in the Table. Three (15%) adjudicated drug-related interstitial lung disease/pneumonitis events were reported in the T-DXd + FUL arm (all Grade 2; at DCO, one case had resolved, one was resolving, and one was not resolved); none were reported in the T-DXd + ANA arm. AEs were manageable by drug interruption and dose reduction. Confirmed ORR was 71.4% (15/21; 95% confidence interval [CI] 47.8, 88.7) in the T-DXd + ANA arm, and 40.0% (8/20; 95% CI 19.1, 64.0) in the T-DXd + FUL arm (Table). OS data were not mature at this DCO. Conclusions: Safety profiles for T-DXd-ET combinations were generally comparable to T-DXd monotherapy and manageable with dose modification and routine clinical practice. T-DXd in combination with anastrozole or fulvestrant was active in first- or second-line treatment of patients with HER2-low HR+ mBC. Citation Format: Komal Jhaveri, Fabrice André, Erika Hamilton, Peter Schmid, Carey Anders, Laura Testa, Inna Ganshina, Yen-Shen Lu, Seock-Ah Im, Robyn Young, Magdalena Wrona, Caron Lloyd, Yiwen Zhang, Sherene Loi. Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-03.

Abstract PO4-15-07: ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact

Abstract Background Neoadjuvant endocrine therapy (NET) is currently used in several clinical trials to select patients for chemotherapy de-escalation. However, exposure to NET may induce/select endocrine-resistant tumor cell clones harboring ESR1 mutations (ESR1mut), which are well known to confer poor prognosis and ET resistance to aromatase inhibitors in the metastatic setting. In this study, we sought to determine the frequency and prognostic significance of ESR1mut after NET in postmenopausal patients with HR+/HER2- early breast cancer. Materials and methods We conducted a retrospective study in postmenopausal patients with ER+/HER2-early breast cancer diagnosed between 2000 and 2012 and treated with NET for at least three months at Institut Curie Hospitals (Paris and Saint Cloud, France). Exclusion criteria were: stage IV breast cancer, no surgery of the primary tumor, neoadjuvant radiation therapy, chemotherapy or targeted therapies. DNA from post-NET surgical samples was extracted using the phenol-chloroform DNA isolation method. ESR1mut were detected with multiplex drop-off ddPCR assay previously used in the PADA-1 trial (targeting clustered hotspot mutations in exon 8 and 5, using a BioRad QX100 system and analyzed with QuantaSoft v.1.7.4 software). Associations between ESR1mut detection and patient outcomes, distant relapse-free interval (DRFI) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results N=143 patients treated with NET were eligible for this study, of whom N=136 had interpretable ESR1mut detection results. Median age at NET initiation was 75.4 (IQR 66.6-81.3) years. The median duration of NET was 6.6 months (IQR 5.8 – 7.6). Most patients were treated with aromatase inhibitors (n=107, 75.9%), while 24.1% (n=34) received tamoxifen. The median time between diagnosis and surgery was 7.6 (IQR 6.4 – 8.7) months. ESR1mut were detected in post-NET surgical samples in N=7 patients (5.2%). Baseline clinicopathological characteristics were not associated with post-NET ESR1mut detection status. The median follow-up for DRFI and OS was 11.0 (IQR 7.7 – 13.8) and 18.7 (IQR 13.3 – 18.7) years, respectively. The median DRFI was 6.7 (95%CI [4.9-NR]) vs 14.0 [10.7-NR] years in ESR1mut and ESR1wt patients, respectively (HR=1.9 [0.6-6.2], p=0.29). Similarly, median OS was numerically shorter in patients with post-NET ESR1mut (6.8 [3.7-NR] vs 9.8 [8.5-NR]; HR=2.0 [0.9-4.7], p=0.09). Conclusions Post-NET tumors are enriched in ESR1mut subclones, which represent a potentially lethal threat in the context of aromatase inhibitor-based adjuvant endocrine therapy. Although the limited sample size of our study did not allow reaching statistical significance, our results suggest, for the first time, worse survival outcomes for patients with a ESR1mut detected in post-NET primary tumors. The role of next-generation oral SERDs as neoadjuvant or adjuvant endocrine therapy to prevent ESR1mut-related relapses remains to be determined. Citation Format: José Luis Sandoval, Helene Salaun, Shufang Renault, Marcela Carausu, Aurore Rampanou, Caroline Hego, Matthieu Carton, Luc Cabel, Jean-Yves Pierga, Romain Geiss, Francois-Clement Bidard, Florence Lerebours. ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-07.

Abstract PS17-06: A phase I trial of the PI3K inhibitor (PI3Ki) copanlisib and fulvestrant in combination with continuous or intermittent abemaciclib in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer

Abstract Background: Activation of the phosphoinositide 3-kinase (PI3K) pathway is a prominent resistance mechanism to endocrine therapy and CDK4/6 inhibition (CDK4/6i) in ER+, HER2- breast cancer. There is reciprocal crosstalk between PI3K and cell cycle regulatory pathways. Triplet therapy that targets ER, CDK4/6, and PI3K prevents or delays disease progression in preclinical models of ER+, HER2- breast cancer. However, the toxicities of triplet therapy hinder its clinical development. Copanlisib (COP) is an intravenous (IV) PI3Ki with potent activity against α and δ isoforms. Intermittent high-dose PI3Ki is expected to be less toxic and more effective than continuous daily dosing. We set out to determine the recommended phase 2 dose (RP2D) for the COP/Fulvestrant (FUL)/Abemaciclib (ABE) combination. Methods: Eligible patients (pts) included men or women with ER+, HER2- metastatic breast cancer (MBC), with no more than 1 prior chemotherapy in the metastatic setting, and no limits on prior endocrine or targeted therapy. Prior FUL, CDK4/6i and PI3K/mTORi were allowed. Pts with HbA1c >8.5% were excluded. Pts received FUL 500 mg IM standard dosing and COP/ABE at assigned doses. Premenopausal women also received a GnRH agonist. Dose-limiting toxicity (DLT) was assessed during the first 28-day cycle. Adverse events (AEs) were graded according to NCI-CTCAE v5.0. Dose escalation/de-escalation was based on continual reassessment (CRM) and the RP2D was defined as the dose with the highest probability of the DLT rate within the acceptable 25~35%. Results: Between June 2020 and June 2023, 24 pts with ER+, HER2- MBC were enrolled. Table 1 shows the dose levels (DLs) and DLTs. The first 10 pts were enrolled to Part A on two consecutive DLs of COP (DL1: 45 mg IV D1 and D15, n=7; DL2: 45 mg IV D1, D8, and D15, n=3), with ABE fixed at 100 mg PO BID continuously. DL2a exceeded the maximum tolerated dose (MTD). DL1a was tolerable based on Cycle 1 AEs. However, during subsequent cycles, only 1 of the 7 pts in DL1a maintained the intended dose of ABE due to neutropenia, others reduced ABE to 50mg bid (n=5) or discontinued (n=1). This triggered a protocol amendment, adding Part B with ABE administered 5 days on and 2 days off (5-on/2-off) intermittent schedule. 14 pts were enrolled to Part B in 2 consecutive DLs of COP (DL1b: n=7; DL2b: n=7), the same as in Part A. ABE was fixed at 100 mg PO Bid 5-on/2-off. DL2b exceeded the MTD. DL1b was tolerable based on Cycle 1 AEs. In addition, in subsequent cycles, only 1 of 7 pts on DL1b required dose reduction of ABE to 50mg bid. RP2D is therefore defined as DL1b. Grade (G) 4 AEs were rare. The most common all cycle G3 AEs included transient hypertension (45%), rash (30%), anemia (25%), neutropenia (25%), and AST elevation (20%). As of 6/14/2023, 22 pts, with a median of 1 prior metastatic regimen (range 0-5), prior CDK4/6i in 18 (82%), liver mets in 8 (36%), and PIK3CA mutation in 8 (50%) of 16 pts with known mutation status, were evaluable for response. There were 5 partial responses and 3 stable diseases lasting for ≥24 weeks. Clinical benefit rate was 36.4% (8/22, 95%CI: 17.19% ~ 59.34%). Responses were observed in pts regardless of prior CDK4/6i, FUL, or PIK3CA mutation. Conclusion: COP/FUL/intermittent ABE can be safely administered with fair overall tolerability. Preliminary anti-tumor activity was observed, which will be further examined in the randomized phase II trial (NCT 03939897). Table 1 Dose-limiting Toxicities by Dose Level Citation Format: Cynthia Ma, Jingqin Luo, Jessica Moss, Maryann Kwa, Ritesh Parajuli, Katia Khoury, Emily Douglas, Ashley Frith, Caron Rigden, Foluso Ademuyiwa, Shana Thomas, Brittney Haas, Gerburg Wulf, Claire Dees, Rabih Said. A phase I trial of the PI3K inhibitor (PI3Ki) copanlisib and fulvestrant in combination with continuous or intermittent abemaciclib in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-06.

Abstract PO2-05-04: ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC)

Abstract Background: ER+/HER2- breast cancer (BC) is the most prevalent BC subtype. Endocrine therapy (ET) is the mainstay of treatment; however, development of resistance to this therapeutic approach is common in the metastatic setting. After progression on first-line treatment, both ET monotherapy and combination therapy options are available. Combinations such as everolimus + exemestane and alpelisib + fulvestrant can be associated with higher efficacy, but also significant toxicity with discontinuation rates around 25%. Also, for second-line treatment, pts who did not receive prior treatment with a CDK4/6i, the combination of fulvestrant with a CDK4/6i (palbociclib, abemaciclib, and ribociclib) are among the recommended treatment options for this pt population (NCCN, 2022). However, fulvestrant has low bioavailability and an IM injection burden. The crosstalk between the three pathways ER, PI3K/AKT/mTOR and cyclin-dependent kinases (CDK4/6) provide a rationale for the combination of elacestrant, a next-generation oral SERD, with inhibitors of these pathways that are natural targets to overcome endocrine resistance. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC ET in pts with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following disease progression on prior ET (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. The replacement of the fulvestrant backbone with elacestrant in combination with targeted agents enabling oral-oral combinations is of therapeutic interest. Methods: ELEVATE (NCT05563220) is a phase 1b/2 clinical trial that will evaluate the safety and efficacy of elacestrant combined with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. Eligible pts must be adults with confirmed ER+/HER2− advanced or mBC, > 1 measurable lesion as per RECIST v1.1, and adequate bone marrow or organ function. The main objectives for Phase 1b are to determine the RP2D of elacestrant combined with other targeted agents. The RP2D of elacestrant and abemaciclib will be determined in the ELECTRA study (NCT05386108). The Phase 2 portion will evaluate the efficacy of elacestrant combined with other study drugs for PFS; secondary objectives include PK of the various combinations, ORR, DoR, CBR, PFS, and OS. Here we report the initial dosing from the Phase 1b portion. Results: As of June 2023, 11 pts were enrolled in the phase 1b portion of the trial, cohort 1 for all combinations: 5 pts in the elacestrant and everolimus (300 mg elacestrant QD/everolimus 5 mg QD) and 3 pts in the elacestrant and alpelisib (300 mg elacestrant QD/alpelisib 250 mg QD) and 2 patients for palbociclib and 1 patient in the ribociclib combinations. Further patient accrual is expected in phase 1b cohorts of various combinations during the second half of 2023; both safety and PK data will be provided. Conclusion: In the Phase 1b portion of ELEVATE, elacestrant is being combined with various targeted agents enabling oral-oral combinations to determine a RP2D. Recruitment is actively ongoing; safety and PK results will be presented at the meeting from the completed phase 1b cohorts. Citation Format: Hope Rugo, Aditya Bardia, Javier Cortés, Giuseppe Curigliano, Erika Hamilton, Sara Hurvitz, Sibylle Loibl, Sara Tolaney, Virginia Kaklamani, Giulia Tonini, Shannon Matheny, Kathy Puvana Theall, Joyce O'Shaughnessy. ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-04.

Abstract PO4-19-11: A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer

Abstract Background The androgen receptor (AR) is expressed in approximately 30% of breast cancers. Phase I and II trials of bicalutamide in HR-negative and enzalutamide in both triple negative breast cancer (TNBC) and hormone receptor (HR) positive populations have shown safety and favorable clinical benefit rates (CBR). Additionally, cell cycle (CC) inhibitors, such as abemaciclib, have demonstrated improved progression free survival (PFS) for patients with HR-positive metastatic breast cancer (MBC) in combination with ET in the first line and subsequent lines of therapy. A preclinical study showed that anti-androgen therapies enhanced CKD4/6 induced cytostatic effect in AR-positive TNBC cell lines. We performed a retrospective, institutional study evaluating metastatic HR+ tumor samples with immunohistochemistry (IHC) from patients treated with CDK4/6 inhibitor, palbociclib. We found a statistically significant increase in event free survival (EFS) for those that had any expression of AR (>0%, median EFS 19 months vs 5 months, HR 0.26, p=0.01). Additionally, AR expression was associated with intact phosphorylated retinoblastoma (Rb) expression (100%, P=0.02), which may represent a mechanism by which CC inhibition is effective in AR+ MBC. Trial Design NCT 05095207 is an ongoing, Phase Ib/II, open label, multi-center study. The primary objective for the phase I portion is to determine the recommended phase II dose (RP2D) of abemaciclib in combination with bicalutamide. The primary objective for the phase II portion is to determine the disease control rate (DCR) at 6-month treatment with abemaciclib and bicalutamide. Patients with HER2-negative MBC who are AR+ (IHC >1%) are eligible. HR-positive participants must have had one prior line of ET in the metastatic setting and no more than 2 prior lines of cytotoxic chemotherapy. HR-negative participants may have had up to 4 prior lines of cytotoxic chemotherapy. In the Phase I portion, up to 12 patients are given abemaciclib 100 mg oral, twice daily on days 1 to 28 and bicalutamide 150 mg oral, daily on days 1 to 28. If there is no toxicity after cycle 1 for the first 3 patients, the dose of abemaciclib will increase to 150 mg twice daily. However, if there is a dose limiting toxicity (DLT) within the first cycle (28 days) of therapy, the dose will decrease to 50 mg twice daily. In the Phase II portion, 51 patients will receive abemaciclib at the RP2D twice daily in addition to bicalutamide 150 mg daily on days 1 to 28. The estimated study duration is 36 months. The drugs will be administered until disease progression or unacceptable toxicity. The primary end points include the DLT and the RP2D for abemaciclib administered with bicalutamide and the DCR at 6 months. The secondary end points include the frequency of adverse effects, the DCR stratified by HR status, and PFS. Exploratory endpoints are to determine whether Ki67, cyclin D1, p16, and phosphorylated Rb expression at baseline are predictors of response to abemaciclib and to determine potential mechanisms for resistance to treatment. For Phase Ib, we will utilize the Bayesian optimal interval (BOIN) design, the RP2D will be selected as the dose closest to the target toxicity rate of 0.3. The observed DLT rate at the current dose is ≤ 0.236, the next cohort will be treated at the next higher dose level, if it is ≥ 0.359 the next cohort will be treated with the next lower dose level. For Phase II, we will assess the DCR using a Simon 2 stage optimal design. If among the 46 evaluable patients, 12 or fewer achieve disease control, the treatment will be rejected, however if 13 or more have disease control, the treatment will be considered worthy for further study. We define inactivity as DCR of 0.20 and activity as DCR of 0.35. To date, the study has recruited 21 participants, the goal accrual is 60 patients. Citation Format: Nicole Casasanta, Chrystal Landry, Theresa Shao, Paula Klein, Julie Fasano, Aarti Bhardwaj, Natalie Berger, Erin Moshier, Gargi Atul Joshi, Rita Vaccaro, Joseph Sparano, Amy Tiersten. A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-11.

Abstract PO1-19-08: Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer

Abstract Background: Only a subset of patients with metastatic triple-negative breast cancers (TNBC) demonstrate response to FDA approved PD-1 immune checkpoint blockade (ICB), and few have durable responses. Data suggests that breast cancers have defects in antigen presentation and that antigen presenting cells especially the cDC1 subtype of dendritic cells (DCs) are required for response to ICB. CD40 agonists activate antigen presenting cells including DCs and B cells and repolarize macrophages to an anti-tumor phenotype. Flt3 ligand is a growth factor that increases differentiation and expansion of DCs. We recently demonstrated in pre-clinical TNBC models that the combination of liposomal doxorubicin chemotherapy, a CD40 agonist, and a Flt3 ligand improves outcomes compared to alternate combinations. Methods: This is a single arm phase I pilot study of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Patients will be randomized to 3 lead-in arms (triplet therapy, doublet immunotherapy only, or liposomal doxorubicin only) for one cycle prior to receiving triplet therapy with tissue biopsies done before and after the lead-in treatment. CDX-301 will be given for only two cycles; liposomal-doxorubicin and CDX-1140 will be continued until disease progression or clinically limiting toxicities. Primary endpoint is determination of a recommended phase II dose based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune response after triplet therapy, after immunotherapy alone, and after liposomal doxorubicin alone; median progression-free survival, overall response rate, duration of response, and clinical benefit rate. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line treatment for metastatic disease (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999) and is currently open at University of Texas Southwestern Medical Center, Texas Oncology, University of Chicago, University of Texas San Antonio, Sarah Cannon Research Institute, and Johns Hopkins. Citation Format: Sangeetha Reddy, Joyce O'Shaughnessy, Navid Sadeghi, Samira Syed, Cesar Santa-Maria, Virginia Kaklamani, Nan Chen, Denise Yardley, Yisheng Fang, Isaac Chan, Nisha Unni, Sarah Kashanian, Namrata Peswani, Shahbano Shakeel, Meredith Carter, Kelly Kyle, Farjana Fattah, Chul Ahn, Ina Patel, Joshua Gruber, Dawn Klemow, Glenda Delgado, Nicole Sinclair, Michael Yellin, Heather McArthur, Rita Nanda, Suzanne Conzen, Carlos Arteaga. Phase I trial of pegylated liposomal doxorubicin chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-08.

Abstract PO1-04-02: ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan

Abstract Background: HER2 overexpression and/or amplification confers aggressive tumor behavior and decreased survival in patients with breast cancer. Targeting of HER2 is a validated therapeutic strategy, and trastuzumab deruxtecan (T-DXd) has emerged as a preferred treatment in the second-line setting. However, effective treatment following progression on T-DXd remains a major unmet medical need. ARX788 is a next-generation antibody-drug conjugate (ADC) using a technology platform whereby a HER2-specific monoclonal antibody is conjugated to amberstatin 269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to the slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells, at a lower effective dose compared with other HER2 ADCs. Methods: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety in approximately 40 patients with unresectable or metastatic HER2 positive breast cancer who have been previously treated with T-DXd. Eligibility criteria include measurable disease by RECIST v1.1, radiographically stable brain metastases, no more than three prior lines of treatment in the metastatic setting, and HER2 positivity as determined by central review. If recently progressed on T-DXd or trastuzumab emtansine (T-DM1), a new biopsy for HER2 status is required. Patients will be administered 1.5 mg/kg of ARX788 every three weeks. Efficacy will be assessed using RECIST v1.1 at nine-week intervals after starting ARX788 until progression or start of new cancer treatment. Objective response rate is the primary endpoint, with disease control rate, progression-free survival, overall survival, best overall response, duration of response, and time to response as additional endpoints. The safety and tolerability profile will also be evaluated. PK analysis will determine serum concentrations of ARX788, total antibody, and pAF-AS269. Potential predictive and/or prognostic biomarkers will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Citation Format: Kashif Ali, Laila Agrawal, Anu Thummala, Kevin Kalinsky, Sami Ali, Sibel Blau, Margaret Block, Michael Danso, Denise Yardley, Jay Andersen, Adrienne Gropper-Waks, Priya Jayachandran, Igor Makhlin, Petros Nikolinakos, Joyce O'Shaughnessy, Sandra Aung, Colin Hessel, Hope Rugo, William Gradishar, Debu Tripathy. ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-02.

Abstract PO1-05-14: Outcomes of first-line chemotherapy for visceral crisis in metastatic breast cancer

Abstract Background: Visceral crisis (VC) in metastatic breast cancer (BC) is defined as severe organ dysfunction, as assessed by signs and symptoms, laboratory tests, and rapid disease progression. The management of this condition is currently based on limited retrospective evidence and expert opinions, since VC has been a common exclusion criterion in clinical trials. There is a paucity of real-world data regarding the management of BC VC. We aim to evaluate the survival outcomes and prognostic factors of first-line palliative chemotherapy for VC in a tertiary cancer center in Brazil. Methods: Data were retrospectively collected from patients with metastatic BC diagnosed with VC between 2017 and 2022 in a single cancer center. Our analysis focused on patients receiving first-line chemotherapy for VC. Patients with hormone receptor-positive BC could have been previously treated with endocrine therapy for metastatic disease. CDK4/6 inhibitors were not available in the cancer center during the study period. Prognostic factors associated with survival were evaluated through univariate and multivariable analyses, using the Cox regression model. Results: A total of 106 patients with VC were evaluated. Among them, 58.5% (62 patients) had not received any previous line of chemotherapy in the metastatic setting before the diagnosis of VC (1st line cohort). Median overall survival (mOS) in the total population was 1.7 months, significantly distinct from the 1st line cohort, which had a mOS of 4.9 months (p < 0.001). Focusing on the 1st line cohort, the most common type of VC was pulmonary (40.3%), followed by hepatic (24.2%), and medullary infiltration (21%). 66.1% of patients had HR+HER2- (mOS 9.3 months), 19.3% HER2+ (mOS 4.5 months), and 11.3% triple-negative BC (TNBC) (mOS 1.5 months). Most patients were treated for VC based on systemic therapy combinations (59.7%), while 32.2% received monochemotherapy, and 8.1% were managed with best supportive care (BSC) alone. In the population receiving multidrug therapy, the mOS was 9.3 months, compared to 4.9 months with monochemotherapy and 0.7 months in patients undergoing BSC. Nevertheless, the type of treatment received was not associated with OS in the multivariable analysis. In the multivariable analysis, the prognostic factors associated with worse mOS were TNBC subtype, hepatic VC), and ECOG-PS > 2. (Table). Among patients with hepatic VC, 73.7% died during the same hospitalization and 60.5% received chemotherapy within 30 days prior to death. Conclusions: Patients with VC due to BC have a poor prognosis, even in the context of first-line chemotherapy. Factors such as ECOG-PS, BC subtype, and VC type should be taken into account when discussing the expected outcomes of this life-threatening condition. Taking these factors into account can help physicians to differentiate patients who are more likely to benefit from systemic oncologic treatment from those for whom such therapy would be futile or potentially harmful. Median overall survival according to baseline characteristics and multivariable analysis (1st line cohort, n=62) Citation Format: Matheus de Oliveira Andrade, Vitor Hugo Felix, Renata Colombo Bonadio, Laura Testa. Outcomes of first-line chemotherapy for visceral crisis in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-14.

Abstract PO1-19-12: VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. Vepdegestrant directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study (NCT04072952), vepdegestrant monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The global, randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of vepdegestrant vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Trial design: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N≈560) are randomized 1:1 to receive vepdegestrant 200 mg orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation subpopulation. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Citation Format: Mario Campone, Cynthia Ma, Michelino de Laurentiis, Hiroji Iwata, Sara Hurvitz, Seth Wander, Michael Danso, Dongrui Lu, Julia Perkins Smith, Yuan Liu, Lana Tran, Sibyl Anderson, Erika Hamilton. VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-12.

Abstract PO5-13-04: Breast Cancer Index (BCI) results from a HER2 low breast cancer community cohort of operable stage I-II hormone receptor positive (HR+) breast cancer

Abstract Background Hormone receptor positive (HR+) breast cancer (BC) traditionally included HER2-negative or HER2-positive classifications. The BCI test is a quantitative RNA profile assay applied to HR+ early-stage breast cancers from archival pretreatment surgical specimens. The BCI assay estimates the likelihood of distant recurrence (DR) during years 5-10 (prognostic result) and predicts extended endocrine therapy benefit (ETT)(i.e., BCI (H/I)-High, yes benefit) or no benefit (i.e., BCI (H/I)- Low) for patients who have completed 5 years of adjuvant endocrine therapy (AET). Based on the Destiny Breast 04 trial, an antibody drug conjugate (ADC) anti-HER2 therapy was recently approved for treating metastatic HR+HER2 low BCs, which are currently defined as tumors with either HER2 immunohistochemical (IHC) staining of 1+ or IHC 2+ without HER2 gene amplification. Primary archival specimens were eligible for enrollment on the Destiny Breast 04 trial (35%). Quality control of IHC result categories is needed due to new clinical implications in the metastatic setting. To date, BCI results for tumors classified as HER2 low has not been reported. Objectives Determine the average BCI distant DR risk (prognostic result) and the proportion of tumors with BCI (H/I)-High, yes benefit versus BCI (H/I)-Low, no benefit (predictive result) from a small community-based retrospective study of pretreatment samples from a cohort of HER2 low, HR+ breast tumors. Methods Around completion of 5 years of AET, BCI testing was applied to 110 surgically excised archived stage I and 2 HR+ untreated tumors that were collected between 2017 and 2022. Specimens had paired HER2 local pathology IHC and in-situ hybridization (ISH) results. Results 32 tumors were identified as HER2-low including 26 specimens with HER2 IHC 1+ results and six HER2 IHC 2+ tumors with non-amplified HER2 ISH results. Given this was a small exploratory analysis, statistical significance was deliberately not evaluated. Prognostic Results: The average estimated DR risk during years 5-10 was 8% for tumors classified as HER2-low (Range 1.3-17.5%). For 26/32 patients with HER2 IHC1+, the average DR risk was 7.4% (Range 1.3-17.5%). For 6/32 patients with HER2 IHC 2+ and non-amplified HER2 ISH results, the average DR risk was 4.6% (Range 1.6-8.6%). Predictive Results: Of the 32 HER2-low tumors, 15/32 (47%) were BCI (H/I)-High (yes benefit) compared to 17/32 (53%) which were BCI (H/I)-Low (no benefit). Conclusions The prevalence of HER2 low tumors appears to be as high as 67% in reports to date. In this small series, the prevalence of HR+ HER2 low tumors was 29% (32/110). The average DR risk in these HR+ HER2 low cases was roughly 8% which represents a DR risk that is very similar to the average DR risk of 7.4% for HR+ HER2 negative tumors reported from one of the large BCI validation studies (TransATAC). In this series of HER2 low BCs, the proportions of BCI (H/I)-High (yes benefit) and BCI (H/I)-Low (no benefit) tumors were 47% and 53%, compared with 46% and 54%, respectively, in three large BCI validation studies (Trans-aTTom, B42, IDEAL) for HER2 negative tumors. Although this is a small retrospective series, these results suggest that HER2 low tumor are, by BCI testing, very similar to HER2 negative tumors in DR risk (prognostic results). Also, it appears that BCI (H/I)-High (yes benefit) and BCI (H/I)-Low (no benefit) proportions (predictive results) for HER2 low tumors appear similar to reported results for HER2 negative tumors. Follow-up data from larger series are needed to determine if BCI testing is prognostic and predictive for HER-2 low BCs. Citation Format: Milana Dolezal, Mark Pegram. Breast Cancer Index (BCI) results from a HER2 low breast cancer community cohort of operable stage I-II hormone receptor positive (HR+) breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-04.

Abstract PO2-08-09: Prevalence of germline genetic variants in breast cancer susceptibility genes among patients with metaplastic breast cancer

Abstract Background: Pathogenic or likely pathogenic variants (PV) in breast cancer (BC) susceptibility genes are present in approximately 5-10% of individuals with breast cancer and approximately 13-15% of those with triple-negative breast cancer (TNBC). Identifying patients with PV in BRCA1 and BRCA2 can inform selection of appropriate candidates for poly(ADP-ribose) polymerase inhibitors (PARPi), which have improved progression-free and overall survival in the metastatic and adjuvant settings, respectively. Metaplastic breast cancer (MpBC) is a rare, aggressive subtype of breast cancer that is often triple-negative and refractory to chemotherapy. To date, limited data describe germline genetic findings in patients with MpBC. Methods: We conducted a retrospective chart review including patients with pathology results at the Hospital of the University of Pennsylvania from 2021 through May 2023 demonstrating MpBC. Germline genetic test results and tumor histopathologic characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were evaluated. Descriptive statistics as well as two-tailed t tests were used for data analysis. Results: Of 89 patients identified with MpBC, 51 had germline genetic testing results available for review. Nine patients (17.6%) had MpBC with PV in BC predisposition genes (PV-MpBC) and 42 (82.4%) had PV-negative MpBC (PVneg-MpBC). Seven patients (13.7%) had a PV in BRCA1, 1 (2.0%) in BRCA2, and 1 (2.0%) in CHEK2. Median age at diagnosis was 45 years for patients with PV-MpBC and 56.5 years for those with PVneg-MpBC (p=0.005). Among patients with PV-MpBC, 6 (66.7%) had ER and PR negative disease by ASCO-CAP guidelines and 3 (33.3%) had ER and/or PR positive disease. Among patients with PVneg-MpBC, 31 (73.8%) had ER and PR negative disease and 11 (26.2%) had ER and/or PR positive disease. All 9 patients with PV-MpBC had HER2-negative disease, one (11.1%) of whom had HER2-low disease. Among patients with PVneg-MpBC, 40 (95.2%) had HER2-negative disease, two (4.8%) of whom had HER2-low disease, and 2 (4.8%) had HER2-positive BC. Conclusions: The frequency of PV in breast cancer susceptibility genes among patients with MpBC is comparable to, and possibly higher than, the reported rates of such PV in patients with TNBC, for whom genetic testing is recommended. If confirmed in a larger dataset, germline testing should be considered for all patients with MpBC regardless of ER, PR, and HER2 status, as findings may help identify candidates for PARPi therapy and genetically-directed clinical trials. Citation Format: Kaitlin Demarest, Anupma Nayak, Payal Shah. Prevalence of germline genetic variants in breast cancer susceptibility genes among patients with metaplastic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-09.

Abstract PO5-24-03: Breast cancer intrinsic subtypes predict outcomes in primary and metastatic samples

Abstract Background: The prognostic and predictive value of the PAM50 intrinsic subtypes, namely Luminal A, Luminal B, Her2, and Basal-like subtypes, is well-studied in primary as well as metastatic breast cancer settings. Prosigna has emerged as a rapid PAM50 subtype predictor based on the NanoString nCounter assay. However, assay reproducibility across various RNASeq or qRT-PCR platforms can be challenging, especially when applying the predictor on metastatic breast cancer tumors. Here, we used SpinAdapt to create an intrinsic subtype predictor that works on RNA sequencing data, and validates on multiple tumor-sites. We evaluate real-world outcomes for our intrinsic subtype predictions across various immunohistochemical (IHC) labels and metastatic sites. Methods: We trained the subtype predictor on a cohort of 2,497 breast cancer patients using the PAM50 genes, profiled using Nanostring RNA nCounter assay (GSE148426). Approximately 5,423 de-identified records of breast cancer patients sequenced using whole-exome capture RNA-seq were included in our reference dataset. The reference dataset contained samples collected from various sites including breast (n=2440), liver (n=936), lymph node (n=577), lung (n=540), and bone (n=304). For subtype classification, we first batch-corrected the external dataset to Tempus RNA-seq reference dataset using SpinAdapt, then trained a Support-Vector Classifier (SVC) on the corrected data. A 10-fold CV experiment was performed on the corrected dataset to analytically validate the intrinsic subtype predictions. We retrospectively analyzed 7,021 de-identified breast cancer patients with known hormone receptor (HR) or HER2 status and a matched RNASeq sample. The concordance between HR/HER2 status and PAM50 prediction was analyzed, and these patients were excluded from training. Real-world overall survival (rwOS) was evaluated from the time of first diagnosis. The outcomes across intrinsic subtypes were further assessed according to tumor collection site and HR/HER2 IHC status. Results: The 10-fold CV experiment on the Tempus-adapted GSE148426 dataset achieved F-1 scores of 0.97, 0.86, 0.94, and 0.87 on Basal, HER2-like, Luminal A, and Luminal B PAM50 subtypes, respectively. On the Tempus evaluation dataset, 85.3% of HR+/HER2- patients (n=4,366), 65.4% of HR-/HER2+ patients (n=240), and 75.4% of HR-/HER2- patients (n=1,930) were classified as Luminal, HER2-like, and Basal, respectively. Evaluating outcomes on Tempus patients for each PAM50 group, the rwOS for the basal group was significantly shorter than patients not predicted to be basal (n=5,845, p< 2e-90). The rwOS for the predicted PAM50 basal patients remained significantly shorter than non-basal patients even when stratified by site of metastasis: breast (n=2,405; p< 1e-27), lymph node (n=577, p< 1e-7), liver (n=936; p< 1e-25), lung (n=540, p< 1e-13), and bone (n=304, p< 1e-3). Interestingly, within both HR+/HER2- (n=3,653) and HR-/HER2- (n=1,664) IHC cohorts with available outcomes data, the predicted PAM50 basal subtype could further stratify each of these populations with basal-subtype showing significantly worse prognosis than the non-basal subtype (p< 1e-27 and p< 1e-7, respectively). Conclusions: We retrospectively analyzed Tempus multimodal RWD to validate an in-house breast intrinsic subtype predictor that is agnostic to the site of metastasis. The prognostic value of the basal subtype was significant for breast cancer patients across various sites of metastasis including lymph node, liver, lung, and bones and IHC groups. For patients in each of the HR+/HER2- and triple negative IHC groups, the intrinsic molecular subtypes provided an additional level of prognostic detail with statistical significance. These data emphasize the importance of combining molecular subtypes with IHC-based diagnostics to fully characterize clinically relevant subpopulations and risk. Citation Format: Talal Ahmed, Mark Carty, Kaveri Nadhamuni, Raphael Pelossof. Breast cancer intrinsic subtypes predict outcomes in primary and metastatic samples [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-03.

Abstract PO1-27-07: Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative

Abstract Background: Overexpression of HER2 is a significant prognostic and predictive factor in early breast cancer. HER2 positive tumors are those scored by immunohistochemistry (IHC) 3+ or 2+ with amplification by in situ hybridization (ISH). These tumors may benefit from HER2-targeted treatment and additionally, in early HER2-positive BC, achieving a complete pathological response after neoadjuvant treatment improves patient survival. In recent years, new anti-HER2 antibody-drug conjugates have proven effective for HER2 low BC (defined as IHC score 1+ or 2+ not amplified) in the metastatic disease setting; however, in HER2-low early BC, studies testing novel anti-HER2 antibody-drug conjugates as neoadjuvant therapy (NAT) are ongoing. Currently, we don´t know exactly whether HER2 expression can influence the pathological response rate after NAT or disease-free survival (DFS) in these patients compared to HER2-zero (IHC 0). The aim of our study is to determine the impact on response rate to NAT and survival outcomes in early HER2-negative BC. Methods: We conducted a retrospective study in two hospitals in Andalucia, Spain. Patients with early HER2 negative BC treated with NAT from January 2015 to June 2022 were included. Patients were divided into HER2 low patients (IHC 1+ or 2+ not amplified) and HER2 0 (IHC 0). We collected clinical and pathological characteristics, pathological response rate using the Residual Cancer Burden (RCB) system where a complete pathological response (pCR) was defined as ypT0/ypTis and ypN0, and survival outcomes. The primary objective of the study was to analyze the pCR rate after NAT according to HER2 score, and secondary objectives were to assess disease-free survival and overall survival (DFS and OS rates). Results: 574 patients were included (100% women). 397 patients had hormone receptors (luminal BC) on these tumors, and 177 did not have them, i.e., triple-negative BC (TNBC). 225 patients were HER2-zero, and 312 patients were HER2-low (253/312 patients had luminal BC and 59/312 patients were TNBC). The pCR in HER2-low patients was 17.3% and 23.1% in HER2-zero patients (p=0.047). For luminal BC patients, the pCR was 16.7% in HER2-low tumors and 13.7% in HER2-zero tumors (p=0.29). Similarly, there was no difference in pCR rates in TNBC patients (45.8% in HER2-low and 53.8% in HER2-zero tumors, respectively, (p=0.958). The overall survival (OS) at 96 months was 88.7% (95% CI 85.6%-92%). Regarding survival outcomes, neither HER2 expression level was associated with higher 8-year DFS: 81.1% in HER2-low patients (95% CI 75.7%-86.8%) and 74.9% in HER2-zero patients (95% CI 62.3%-90.1%) p=0.64. There was no difference between histological subtypes at 8-years regarding DFS rate: 80.5% (95% CI 74.3%-87.2%) in luminal HER2-low patients and 76.3% (95% CI 60.8%-95.7%) in luminal HER2-zero patients, p=0.22; 83.8% in TNBC HER2-low (95% CI 74.5%-94.2%) and 77.5% in TNBC HER2-zero patients (95% CI 69.4%-86.6%) p=0.26. We also didn´t find significant differences in terms of OS. For HER2-low patients, the 8-year OS was 90.9% (95% CI 87%-94.9%) and for HER2-zero patients, it was 86.4% (95% CI 80.8%- 92.5%) p=0.46. There were also no differences in OS for different histological subgroups with an 8-year OS in luminal HER2-low breast cancer patients of 92.5% (95% CI 88%-96.7%) and 87% in HER2-zero (95% CI 78.9%-96.1%) p=0.91. In patients with triple-negative breast cancer phenotype, the OS was 84.2% for HER2-low (95% CI 74.5%-95.2%) and 85.3% for HER2-zero (95% CI 77.9%-93.4%) p=1. Conclusions: We found no difference in survival outcomes and response rate to conventional NAT between HER2-low and HER2-zero expression levels. Therefore, our data do not support the hypothesis of HER2-low as a biologically specific breast cancer subtype. Further research on this approach with HER2 antibody-drug conjugate schemes as an alternative to traditional NAT schemes is warranted. Citation Format: Ana Gil-Torralvo, Yeray Rodriguez, Alejandro Falcon, David Morales, Mónica Cejuela, Isabel Miras, Marta Amérigo, Manuel Ruíz - Borrego, Juan Bayo, Francisco Javier Salvador Bofill. Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-07.

Abstract PO3-25-07: Characterization of tertiary lymphoid structures and its association with response to immune checkpoint inhibitors in triple negative breast cancer using spatial transcriptomics

Abstract Background Tertiary lymphoid structures (TLS) are ectopic lymphoid organs playing a role in adaptive antitumor immune response. They were shown to be associated with favorable outcome and appears to be a promising biomarker for response to immune checkpoint inhibitors (ICI). Yet, there is no consensus for their detection and quantification. Here we aimed to derive a specific TLS signature using high resolution spatial transcriptomics data from a large series of triple negative breast cancer (TNBC) samples and to assess its clinical relevance including response to ICI. Methods Spatial transcriptomics (ST) was performed on a series of 94 early-stage TNBC surgical samples with detailed clinicopathological and outcome data. TLS and tumor infiltrating lymphocytes (TILs) were scored using hematoxylin and eosin and double immunohistochemistry (CD3/CD20) stained slides by a dedicated breast pathologist. Regression based on morphological annotations and deconvolution methods estimated the fraction of gene expression related to TLS in each ST spot allowing to derive specific TLS signature. Its prognostic and predictive value of response to ICI was assessed using publicly available breast cancer (METABRIC, SCAN-B, and I-SPY2) and other tumor type datasets treated with ICI (Bareche et al. Ann Oncol, 2022) from bulk gene expression data. Results Deconvolution of the TLS compartments using the ST gene expression data showed that TLS are enriched in all B cell subsets, CD4+ (central) memory and naïve T cells, as well as mast cells. A functional analysis showed an enrichment of ‘vascular endothelial cell proliferation’, ‘mitotic G2/M transition checkpoint’, ‘V/D/J recombination’ and ‘regulation of cell chemotaxis to fibroblast growth factor’ suggesting that TLS aggregates are associated with angiogenesis, immune cell proliferation, adaptative humoral response and tissue remodeling. A comparison of gene expression data between TLS and non-aggregated TILs led to the development of a specific TLS gene signature comprising B and T cell-specific genes, immunoglobulin genes as well as genes associated with TLS initiation. Its projection on tumor slides overlapped with the regions annotated as TLS by the pathologist, demonstrating its specificity for TLS detection. As expected, the highest levels of the TLS signature were observed in the immunomodulatory TNBC molecular subtype and fully inflamed tumors, whereas the lowest levels were observed in the mesenchymal molecular subtype and immune desert tumors (p< 0.05). Of note, high levels of the TLS signature were associated with better prognosis in TNBC patients from METABRIC (p=6.5 10−5) and SCAN-B datasets (p=1.6 10−3) as well as with higher pathological complete response rates in all breast cancer patients treated with neoadjuvant pembrolizumab in the I-SPY2 study (p=0.026). Similar results were found in other tumor types treated with immunotherapy in the metastatic setting including metastatic melanoma, pancreatic and bladder cancers (PFS, p=6 10−6). Of interest, the TLS signature outperformed the predictive value of other immune-related signatures including TILs suggesting a key role of TLS in obtaining a sustainable, adaptive antitumor immune response in the vicinity of the tumor area. Conclusion By leveraging the potential of spatial transcriptomics, we have successfully developed a unique TLS gene signature that demonstrates a strong correlation with the response to ICI in breast cancer and various other tumor types. This TLS gene signature outperforms other immune biomarkers, underscoring the pivotal role of TLS in eliciting a robust antitumor immune response. The universality of this TLS signature makes it a potent biomarker capable of identifying patients who would benefit from immunotherapy, pending further validation. Citation Format: Xiaoxiao Wang, David Venet, Frédéric Lifrange, Denis Larsimont, Mattia Rediti, Linnea Stenbeck, Floriane Dupont, Ghizlane Rouas, Andrea Joaquin Garcia, David Gacquer, Ligia Craciun, Laurence Buisseret, Nayanika Bhalla, Yuvarani Masarapu, Kim Thrane, Eva Gracia Villacampa, Lovisa Franzén, Sami Saarenpää, Linda Kvastad, Joakim Lundeberg, Françoise Rothé, Christos Sotiriou. Characterization of tertiary lymphoid structures and its association with response to immune checkpoint inhibitors in triple negative breast cancer using spatial transcriptomics [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-07.

Abstract PO1-19-05: COGNITION/-GUIDE – Implementation of Precision Oncology in Early High-Risk Breast Cancer

Abstract Background: The concept of precision oncology is nowadays increasingly implemented into clinical practice but is predominantly restricted to the metastatic setting limiting the benefits to prolongation of progression-free-survival (PFS). Implementation of precision oncology at an earlier disease stage with less tumor burden, heterogeneity and a higher capacity of tumor lesions to inform on the molecular tumor landscape holds the promise to impact cure rates. Methods: The prospective COGNITION/-GUIDE precision oncology platform encompasses the COGNITION diagnostic multi-omics biomarker screening platform (NCT05906407) linked to the multi-arm phase II COGNITION-GUIDE umbrella trial (NCT05332561). Based on a two-step consenting procedure, patients with early breast cancer (eBC) and poor response towards standard-of-care (SOC) neoadjuvant chemotherapy (NACT) are first enrolled into the COGNITION diagnostic platform. Residual bulk tumors are subjected to whole-genome- (WGS)/whole exome- (WES) and RNA-sequencing to enable streamlined detection of a rigorous biomarker-framework for subsequent genomics-guided arm allocation. Pilot analyses revealed that 78% (81/104) of high-risk tumors (TNBC or HER2+ BC with non-pCR or HR+/HER2- BC with non-pCR and CPS-EG score ≥ 3, or ypN+ and CPS-EG score ≥ 2) can be successfully sequenced and discussed within an interdisciplinary molecular tumor board. In 67% (70/104) eligible biomarker-profiles could be identified for potential biomarker-guided therapeutic intervention. In a second step, having completed all standard-of-care neoadjuvant and post-neoadjuvant treatments (except endocrine therapy, which can be administered simultaneously to the experimental therapy), patients can be enrolled into one of 6 biomarker-based arms in the COGNITION-GUIDE phase II trial (atezolizumab, inavolisib, ipatasertib, olaparib, sacituzumab govitecan or trastuzumab/pertuzumab). Primary end point is invasive disease-free survival (IDFS) at 4 years after surgery in the whole study population. Secondary endpoints are overall survival (OS), IDFS in each treatment arm, distant disease-free survival (DDFS) and patient-reported outcomes (PROs). Enrollment in COGNITION-GUIDE started in Q2/2023 and 240 patients will be enrolled in 5 German sites until Q2/2027. A comprehensive biomarker discovery program is integrated on longitudinal tumor tissue and liquid biopsies for exploratory analyses. Further clinical work and accrual will be reported at the meeting. Conclusion: The theranostic COGNITION/-GUIDE platform moves the concept of precision oncology to a potentially curative but still high-risk stage of eBC following SOC NACT. Hence, this novel application in the field of precision oncology harbours the prospect to increase cure rates. Citation Format: Verena Thewes, Luise Strassl, Marc Zapatka, Mario Hlevnjak, Constantin Pixberg, Christian Maurer, Katharina Smetanay, Carlo Fremd, Laura Michel, Sabine Heublein, Celina V. Wagner, Jan-Philip Suppelna, Lars Buschhorn, Albrecht Stenzinger, Renate Haidinger, Eva Schumacher-Wulf, Sibylle Loibl, Pauline Wimberger, Jens-Uwe Blohmer, Peter A. Fasching, Wolfgang Janni, Richard F. Schlenk, Peter Lichter, Andreas Schneeweiss. COGNITION/-GUIDE – Implementation of Precision Oncology in Early High-Risk Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-05.

Abstract GS01-05: Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) showed statistically significant improvements in PFS and OS vs placebo + chemo in patients (pts) with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) whose tumors expressed PD-L1 with a combined positive score (CPS) ≥10 in the phase 3 KEYNOTE-355 study. Tolerable and effective maintenance regimens after induction therapy are needed to sustain clinical benefit. The PARP inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumor types and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect. KEYLYNK-009 (NCT04191135) is a randomized open-label phase 2 study to evaluate the efficacy and safety of maintenance pembro + olaparib vs pembro + chemo in pts with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with 1L pembro + platinum-based chemo. Methods: Eligible pts with measurable, locally recurrent inoperable or metastatic TNBC that had not been previously treated with chemo in the metastatic setting received induction therapy for up to 6 cycles of pembro 200 mg + chemo (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8) every 3 wk (Q3W). Pts with complete response (CR), partial response (PR), or stable disease (SD) after 4-6 treatment cycles were randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or pembro + chemo (continued induction regimen). Olaparib or chemo was continued until progression or unacceptable toxicity; pembro was continued for up to 35 cycles (including induction treatment), progression, or unacceptable toxicity. Pts were stratified by induction response (CR or PR vs SD, by RECIST v1.1), tumor PD-L1 status (CPS ≥1 vs CPS < 1), and tumor genomic status (tBRCAm vs tBRCAwt). Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS from randomization in all pts. Secondary endpoints included PFS and OS from randomization in pts with PD-L1 CPS ≥10 tumors and in pts with tBRCAm, and safety. Results: Of the 460 pts who received induction therapy, 271 were randomly assigned to pembro + olaparib (n=135) or pembro + chemo (n=136). At the Dec 15, 2022 data cutoff, median follow-up was 17.2 mo. Maintenance pembro + olaparib did not significantly improve PFS or OS vs pembro + chemo after induction therapy (Table). Median PFS was longer with pembro + olaparib vs pembro + chemo in pts with tBRCAm, but not in pts with PD-L1 CPS ≥10 tumors; a similar trend was observed for OS (Table). In 268 treated pts, treatment-related AEs (TRAEs) occurred in 114 of 135 pts (84.4%) for pembro + olaparib and in 128 of 133 pts (96.2%) for pembro + chemo. Grade ≥3 TRAEs occurred in 44 pts (32.6%) for pembro + olaparib (0 deaths) and in 91 pts (68.4%) for pembro + chemo (2 [1.5%] deaths), with 12 (8.9%) vs 26 (19.5%) discontinuations for TRAEs, respectively. Conclusions: The primary endpoints of PFS and OS were not met in an unselected population of pts with advanced TNBC. However, directionally favorable improvements in PFS and OS were observed in pts with tBRCAm with pembro + olaparib vs pembro + chemo, representing a potential maintenance strategy. Further data are required to confirm this effect. No new safety signals were observed, and there were fewer TRAEs in the pembro + olaparib group vs the pembro + chemo group. PFS and OS were evaluated from the time of randomization. *Based on stratified Cox regression model with Efron’s method of tie-handling with treatment as a covariate. NR = not reached. Citation Format: Hope Rugo, Mark Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Nadia Harbeck, Li Fan, Jaime Mejia, Vassiliki Karantza, David Cescon. Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-05.

Abstract PS08-03: Sequencing Antibody-Drug Conjugate after Antibody-Drug Conjugate in Metastatic Breast Cancer (A3 study): Multi-Institution Experience and Biomarker Analysis

Abstract Background: Antibody-drug conjugates (ADCs) improve survival in patients with metastatic breast cancer (MBC) and offer the potential for targeted delivery of highly potent therapy. Many patients are now candidates for multiple ADCs, but optimal strategies for sequencing are unknown. We previously reported on a single institution experience of patients receiving multiple ADCs for MBC (Abelman, ASCO 2023). Here we report a multi-institution update with biomarker analysis. Methods: We included all patients treated at three academic medical institutions who received multiple ADCs for MBC. Patients were included if they had hormone receptor positive, HER2-negative (HR+/HER2-) breast cancer or triple-negative breast cancer (TNBC); patients with HER2+ metastatic breast cancer were excluded. Clinical information was determined by chart review. The metric of “cross-resistance” to the second ADC was defined as patients with progressive disease on first restaging assessment or progression within 60 days of treatment initiation. Every subsequent ADC beyond the first was compared against the prior ADC for presence of identical “antibody target” and “payload”. Comparisons across ADCs were performed using Fisher’s exact test. Significance was determined to be a type I error less than 0.05. A subset of patients had available whole exome tissue sequencing through commercially available sequencing platforms (BostonGene and Caris) performed around the time of receipt of ADC. All sequencing reports were examined for presence of pathogenic variants, variants of uncertain significance, and currently undefined variants and fusions as defined by each sequencing platform. Results: 68 patients were identified who received two or more ADCs for metastatic HR+/HER2- breast cancer or TNBC from August 2014-June 2023. 30 patients (44.1%) had HR+/HER2- disease and 38 patients (55.9%) had TNBC; 50 patients (73.5%) had HER2-low disease. Median age at time of second ADC was 59.6 (range 29.9-88.6). Patients had received a median of 4 lines of treatment in the metastatic setting prior to initiation of the second ADC. At time of first restaging, cross-resistance was present in 38/64 evaluable cases (59.4%). When the antibody target of the latter ADC was the same as the prior, cross-resistance was present in 11/14 cases (78.5%) compared to 26/49 cases (53.1%) when the later ADC targeted a different tumor-associated antigen. Relatively similar patterns of cross-resistance were observed regardless of whether the later ADC contained an identical payload to prior (6/10 cases, 60%) versus a different payload (22/42, 52.4%). Sequencing information was available for 20 patients who received multiple ADCs with 15 unique reports performed at the time of resistance to ADC1, prior to initiation of ADC2, or after ADC2 if presence of cross-resistance. Variants in topoisomerase-I associated genes (TOP1, TOP2A, TOP3A, TOP3B) were identified in a subset of patients mediating cross-resistance to the second ADC with a topoisomerase-I inhibitor payload. Conclusions: In this multi-institution study, cross-resistance to the second ADC appears to be driven by the antibody target in some patients versus the payload in others, highlighting the heterogeneity of mechanisms related to ADC resistance. Tumor sequencing revealed candidate resistance mutations that may guide optimal sequencing for patients with MBC. Citation Format: Rachel Occhiogrosso Abelman, Laura Spring, Geoffrey Fell, Andrew Davis, Whitney Hensing, Phoebe Ryan, Neelima Vidula, Seth Wander, Arielle Medford, Jennifer Shin, Elizabeth Abraham, Steven Isakoff, Beverly Moy, Leif Ellisen, Aditya Bardia. Sequencing Antibody-Drug Conjugate after Antibody-Drug Conjugate in Metastatic Breast Cancer (A3 study): Multi-Institution Experience and Biomarker Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-03.

Abstract PO5-16-11: Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers

Abstract The third-generation antibody-drug conjugates, Trastuzumab-Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG), have been approved for the treatment of metastatic breast carcinoma in various subtypes and therapeutic settings based on compelling Phase III study data. (DESTINY-Breast03 (T-DXd; HER2-positive), DESTINY-Breast04 (T-DXd; HER2-low), ASCENT (SG; triple-negative), and TROPiCS-02 (SG; HR+/HER2-negative). The aim of this retrospective study conducted at two major German Breast centers was to evaluate the tolerability, adherence, and efficacy of both substances in the real-world setting. All patients treated outside of clinical trials with T-DXd or SG at the Department of Gynecology and Obstetrics, Ulm University Hospital and the Department of Women’s Health, Tuebingen University Hospital between November 2020 and May 2023 were included in this retrospective analysis. Seventy-five patients were included [T-DXd: 46; SG: 29]. The mean duration of therapy was 5.4 months [T-DXd: 6.2; SG: 4.2]. The real-world cohort was more heavily pretreated than the corresponding study cohorts, with a mean of 4.2 systemic therapies in the metastatic setting prior to T-DXd therapy and 3.6 systemic therapies prior to SG therapy. The administered cumulative dose on average was 87.9% [T-DXd: 94%; SG: 79%] of the theoretical full dose or 95.3% [T-DXd: 98%; SG: 92%] when considering dose reductions that occurred. Hematotoxicities of CTC ≥ 3° occurred in 11% of patients treated with T-DXd and in 41% of patients treated with SG. Neutropenia was the predominant severe hematotoxicity (CTC≥III°) observed during SG therapy, occurring in 38% of patients. The occurrence of neutropenia during SG therapy was reduced with primary prophylactic administration of Granulocyte-Colony Stimulating Factor (GCSF), with a rate of 29% (21/29) of patients experiencing neutropenia ≥CTC-III°, compared to 63% (8/29) without primary prophylactic GCSF. Therapy-associated pneumonitis under T-DXd occurred in 5 out of the 46 included patients and was successfully treated with corticosteroids in all cases (CTC II° in 4 cases, CTC III° in 1 case). The median progression-free survival (PFS) from initial administration was 7.7 months under T-DXd [HER2-positive: 9.0; HER2-low: 6.1], and 4.8 months under SG [TNBC 4.8; HR+/HER2-negative: 2.8]. The median overall survival from initial administration was 27.1 months under T-DXd [HER2-positive: 27.1; HER2-low: not reached], and 11.9 months under SG therapy [TNBC: 11.0, HR+/HER2-negative: not reached]. This analysis provides evidence of the efficacy and tolerability of T-DXd and SG in a heterogeneous and heavily pretreated cohort in a real-world setting. However, a conclusive assessment of progression-free survival (PFS) and overall survival (OS) is not feasible yet, as a substantial number of patients are still under treatment. Updated PFS and OS data, with a specific focus on the therapy indication, will be presented at the meeting. Citation Format: Henning Schäffler, Dominik Dannehl, Kristina Veselinovic, Franziska Mergel, Kerstin Pfister, Brigitte Rack, Visnja Fink, Elena Leinert, Lea Volmer, Tobias Engler, Sara Brucker, Wolfgang Janni, Andreas Hartkopf. Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-11.

Abstract PO4-19-08: Randomized phase II study of talazoparib vs talazoparib plus atezolizumab for patients with premenopausal HR+/HER2- metastatic breast cancer harboring homologous recombination deficiency scar (Young-PALETTA, KCSG BR21-09)

Abstract Background Cyclin D kinase-4/6(CDK4/6) inhibitor combined with endocrine treatment have significantly increased progression free survival(PFS) and overall survival(OS) of patients with hormone receptor(HR)-positive/HER2-negative metastatic breast cancer, and currently is a standard 1st line endocrine treatment option. Homologous recombination deficiency(HRD) including germline(g) BRCA1/2 pathogenic mutation is known to be prevalent among young premenopausal patients. Recently several retrospective data suggested that patients with germline BRCA1/2 pathogenic mutation or HRD have poorer outcome with CDK4/6 inhibitor treatment, however there is no prospective evidence. Poly ADP-ribose polymerase(PARP) inhibitors have shown significant benefit over standard chemotherapy in patients with HER2-neg metastatic breast cancer and gBRCA1/2 pathogenic mutation in two Phase 3 trials. Since preclinical data suggested that PARP inhibitors play a role in anti-tumor immune modulation, immunotherapy combined with PARP inhibitors were explored and showed promising antitumor efficacy in several single arm trials. In this trial, we investigate talazoparib and atezolizumab combination compared with talazoparib monotherapy in premenopausal women with HR+/HER2- metastatic breast cancer with HRD-scar after failure with 1st line palbociclib and endocrine treatment combination. Methods This study is a multicenter, randomized, open-label phase II trial comparing talazoparib versus talazoparib with atezolizumab in premenopausal women with HR+/HER2- metastatic breast cancer harboring HRD scar whose disease have progressed with endocrine and palbociclib combination as the 1st-line endocrine treatment. Prior one line of cytotoxic chemotherapy other than platinum for metastatic setting is allowed, but prior palliative endocrine treatment is not allowed. Eligible patients will be pre-screened with tumor tissue biopsy and peripheral blood sampling before endocrine and palbociclib treatment commencement. HRD status is determined through targeted sequencing(SOLIDaccuTestTM by NGeneBio) of tumor tissue and germline HRD genes including BRCA1/2 variant test. Whole genome sequencing and RNA sequencing are performed for biomarker analyses. Patients harboring HRD scar will receive first line endocrine treatment with palbociclib plus aromatase inhibitor with ovarian suppression. After progression with 1L endocrine treatment, patients will be randomized to either talazoparib alone or talazoparib plus atezolizumab combination. Germline BRCA1/2 pathogenic mutation is a stratification factor. Primary endpoint is a progression free survival after randomization(PFS2). Secondary objectives are a composite of PFS1 and PFS2, PFS1, overall survival, patient reported outcome, and biomarkers for treatment response. A total of 178 subjects are required to detect hazard ratio of 0.62 (median PFS2 of at least 10.5 months with talazoparib and atezolizumab combination vs 6.5 months with talazoparib alone), to achieve 80% power at a two-sided a significance level at 10%, considering drop-out rate of 5%. The study period is expected to be 72 months overall(36 months for accrual and randomization and 24 months of follow-up for primary endpoint PFS2). Citation Format: Hee Kyung Ahn, Jieun Lee, Jee Hung Kim, Kyung-Hun Lee, Jee Hyun Kim, Min Hwan Kim, Minsuk Kwon, Han Jo Kim, Kyung Hae Jung, Yeon Hee Park. Randomized phase II study of talazoparib vs talazoparib plus atezolizumab for patients with premenopausal HR+/HER2- metastatic breast cancer harboring homologous recombination deficiency scar (Young-PALETTA, KCSG BR21-09) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-08.

HER2-low and Overexpression in Mucinous Ovarian Cancer: Analysis of ASCO/CAP and ToGA Immunohistochemical Scoring.

Mucinous ovarian carcinoma is an uncommon malignancy characterized by resistance to chemotherapy and poor survival in the metastatic setting. HER2 amplification is a frequent late event in carcinogenesis, yet the incidence of HER2-low in mucinous ovarian carcinoma is unknown. Further, the optimal method for determining overexpression in these tumors is not established. We sought to assess the ASCO/CAP and ToGA trial scoring methods for HER2 IHC with correlation to FISH, p53, and mismatch repair protein status and to determine the incidence of HER2-low in mucinous ovarian carcinoma. A total of 29 tumors from 23 patients were included. Immunohistochemistry for HER2, p53, MLH1, PMS2, MSH2, and MSH6 was performed. Scoring was performed according to the ASCO/CAP and ToGA trial criteria. HER2 FISH was performed and scored according to the ASCO/CAP criteria. The proportion of HER2-low, defined as 1+ or 2+ staining with negative FISH, was determined. Using ASCO/CAP, 26% demonstrated 3+ while 35% demonstrated 2+ staining. Using ToGA, 30% demonstrated 3+ while 57% demonstrated 2+ staining. By FISH, 26% were positive for HER2 amplification. Both systems captured all FISH-positive cases; the use of ASCO/CAP resulted in fewer equivocal and false-positive cases. Among HER2-negative cases, 88% were HER2-low. Aberrant p53 expression was detected in 55% of cases; mismatch repair deficiency was not identified in any cases. ASCO/CAP guidelines are accurate and resource-effective in determining HER2 overexpression in mucinous ovarian carcinoma. HER2-low is common in these tumors; further studies to determine the role of HER2-targeted therapy including antibody-drug conjugates are indicated.