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Background: For HR+/HER2- metastatic breast cancer (MBC) patients, after resistance to endocrine therapy (ET), treatment options are mostly limited to traditional chemotherapies (CT) that offer poor survival and quality of life (QoL), creating an area of unmet need. The antibody-drug conjugate sacituzumab govitecan (SG) comprises an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker. In the phase 3 TROPiCS-02 trial, heavily pretreated patients with relapsed/refractory HR+/HER2- MBC received SG vs single-agent chemotherapy treatment of physician’s choice (TPC). The study met its primary endpoint of improved progression-free survival with SG vs TPC. Here, we report the effect of SG vs TPC on patient-reported outcomes (PROs) from TROPiCS-02. Patients and Methods: Patients who had received ≥1 CDK 4/6 inhibitor, ≥1 ET, and 2-4 prior lines of CT were randomized to receive SG (10 mg/kg intravenous on days 1 and 8 of a 21-day treatment cycle) or TPC (capecitabine, eribulin, gemcitabine, or vinorelbine). In the PRO-evaluable population (all randomized patients with an evaluable assessment at baseline (BL) and ≥1 post-BL visit) SG and TPC were compared regarding time to first clinically meaningful worsening (TTD) or death from BL on the EORTC QLQ-C30 domains (≥10 points), EQ-5D-5L health utility index (≥0.08 points), and EQ-VAS (≥7 points). For the EORTC QLQ-C30 function and global health status/QoL domains, patients with a BL score ≥10 and for symptom scales, patients with a BL score ≤90 were included. In the safety population (all randomized patients who received ≥1 dose of study drug), SG and TPC were compared regarding worst level of toxicities during treatment for the PRO-CTCAE items. For TTD, a stratified Cox proportional hazards regression analysis was conducted and the PRO-CTCAE items were summarized descriptively (numbers and percentages). Results: Of 543 randomized patients, 446 (82%), 445 (82%), and 517 (95%) were included in the PRO-evaluable population (EORTC QLQ-C30: SG vs TPC n=236 vs 210 and EQ-5D-5L: n=238 vs 207) and in the safety population for PRO-CTCAE (SG vs TPC n=268 vs 249), respectively. TTD of EORTC QLQ-C30 global health status/QoL, physical functioning, emotional functioning, fatigue, dyspnea, insomnia, and financial difficulties and EQ-VAS were significantly longer in the SG vs the TPC arm (Table). TTD of EORTC QLQ-C30 diarrhea was significantly shorter for SG vs TPC. For PRO-CTCAE items, decreased appetite, nausea, vomiting, constipation, abdominal pain, shortness of breath, and fatigue were similar between SG and TPC arms, whereas frequency of diarrhea and amount of hair loss were higher in the SG vs TPC arm. Conclusions: In this trial, SG significantly delayed worsening of overall QoL, physical and emotional functioning, and symptoms like fatigue, dyspnea, and insomnia. Overall, our findings suggest that SG has more favorable effects on PROs compared with TPC in pts with HR+/HER2- MBC. Table: Time to First Clinically Meaningful Deterioration PRO Scores Citation Format: Frederik Marmé, Aditya Bardia, Hope Rugo, Peter Schmid, Sara M. Tolaney, Mafalda Oliveira, Andreas Schneeweiss, Ling Shi, Wendy Verret, Mahdi Gharaibeh, Anju Shah, Javier Cortés. Effect of sacituzumab govitecan vs chemotherapy in HR+/HER2- metastatic breast cancer: patient-reported outcomes from the TROPiCS-02 trial [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 P4-07-65.

Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2-negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Methods: PROMETEO (NCT03802604) is a single-arm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 ≥ 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter ≥ 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Results: Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (≥10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 – 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusions: Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the pre-surgical radiological imaging and the actual surgical pathological report. Pre-operative window-of-opportunity trials in this context might provide important clues regarding the activity of novel treatment strategies. Citation Format: Tomás Pascual, Maria Vidal, Juan Miguel Cejalvo, Estela Vega, Esther Sanfeliu, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz-Merino, Manel Juan, Patricia Galván, Xavier Gonzalez-Farré, Juan Manuel Ferrero-Cafiero, Patricia Villagrasa, Mafalda Oliveira, Aleix Prat. PD11-04 Primary results of SOLTI-1503 PROMETEO phase 2 trial of Combination of Talimogene Laherparepvec (T-VEC) with Atezolizumab in patients with residual breast cancer after standard neoadjuvant multi-agent chemotherapy [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 PD11-04.

Background Within HR+/HER2- disease, patients with non-luminal subtypes of breast cancer (HER2-enriched [HER2-E] and Basal-like) have poorer prognosis than those with luminal subtypes, may be more sensitive to chemotherapy, and have higher expression of immune-related genes and tumor infiltrating lymphocytes (TILs). Here, we report the interim efficacy and safety data of the TATEN trial (NCT04251169), the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, metastatic breast cancer (MBC). Methods TATEN is a single-arm, multicenter phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal, MBC. Key inclusion criteria include progression to prior CDK4/6 inhibitors, presence of measurable disease by RECIST V1.1, no prior chemotherapy for MBC, and ECOG 0-1. Patients receive pembrolizumab at 200 mg every 3 weeks (on D1 of each 21-day cycle, beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2, beginning at cycle 2. The primary endpoint is to evaluate overall response rate (ORR), defined as the rate of complete (CR) and partial response (PR) according to RECIST V1.1. Secondary endpoints include clinical benefit rate (CBR; CR + PR + stable disease >24 weeks), progression free survival, overall survival, safety, and predictive biomarkers. Tumor samples collected during advanced/metastatic disease are mandatory to assess PAM50 and other translational endpoints. This study had a planned interim analysis after 15 patients were evaluable for ORR based on a Simon’s two stage design with 80% power and a type I error rate of 0.05. Stage I of the trial would be considered successful if at least 6 patients achieved a PR and/or CR. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41. Here we report results from the patients who received at least one dose of combination treatment and had a first, post-baseline, tumor assessment according to RECIST v1.1 (evaluable population). Results From July 2020 to December 2021, 119 patients were screened, and 25 PAM50 non-luminal tumors were identified (21%). From these, 17 (68%) patients were recruited, and 15 were evaluable for primary endpoint. Two patients discontinued the trial before the first dose of pembrolizumab and paclitaxel, because of clinical progressive disease (PD). Baseline patient characteristics were as follows: median age 53 years (range: 40-77), ECOG 0 52.9%, de novo MBC at diagnosis 29.4%, and visceral disease 64.7% (including 53.3% with liver metastasis). Ten patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 intrinsic subtype, two patients had basal-like and 13 HER2-E tumors. At the time of data cut-off (May 17,2022), 8 patients (53.3%) had stopped their treatment because of PD and 2 (13.3%) due to toxicity. Five patients (33.3%) were still on treatment. The ORR was 53.3 % (8 of 15, 95% CI 26.6-78.7), meeting the pre-specified ORR for the first stage of the trial. The CBR was 86.6% (13 of 15, 95%CI 59.5-98.34), and median PFS was 7.5 months (95% CI: 5.6 – 10.2). Overall, all patients experienced treatment-related adverse events (TRAEs) of any grade, while 53.3% of patients experienced grade 3 TRAEs. No grade 4 or 5 TRAEs were reported in the evaluable population. Correlative analysis including gene expression analysis and centralized TILs scoring and PD-L1 IHC will be presented. Conclusions The first stage of TATEN combining pembrolizumab with paclitaxel after progression to CDK4/6 inhibitors in patients with HR+/HER2-negative, PAM50 non-luminal MBC met its pre-specified endpoint. Completion of the stage II part of the trial with the inclusion of up to 46 patients is warranted to assess the activity of this combination in this group of patients. Correlative studies to find predictive biomarkers of response to this regimen are ongoing and will be presented at the meeting. This study was funded by MSD. Citation Format: Aleix Prat, Tomás Pascual, Montserrat Muñoz, Cristina Hernando, Silvia Vazquez, Salvador Blanch, Manuel Alva, Mafalda Oliveira, Esther Sanfeliu, Lorea Villanueva, Fara Brasó-Maristany, Nuria Chic, Eva Ciruelos. TATEN TRIAL (SOLTI-1716) Targeting non-Luminal disease by PAM50 with pembrolizumab + paclitaxel in Hormone Receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC): interim analysis [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 P3-06-02.

Background Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death protein 1 (anti–PD-1) agents with chemotherapy have shown promise in mTNBC. Ladiratuzumab vedotin (LV) is an investigational antibody-drug conjugate directed to LIV-1, a protein highly expressed on breast cancer cells, via a humanized IgG1 monoclonal antibody conjugated to approximately 4 molecules of monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1–mediated delivery of MMAE disrupts microtubules and induces cell cycle arrest and apoptosis. LV has also been shown to drive immunogenic cell death (ICD) to elicit an immune response. LV + pembrolizumab may result in synergistic activity through LV-induced ICD, creating a microenvironment favorable for enhanced anti–PD-1 activity. Interim results from an ongoing, multi-part, open-label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (SGNLVA-001, NCT01969643), showed weekly LV monotherapy at doses up to 1.5 mg/kg were clinically active and generally well tolerated (Tsai 2021). Based on pharmacokinetic and pharmacodynamic modeling and simulation analysis, an intermittent LV + pembrolizumab dosing regimen is being evaluated to further enhance efficacy and improve the tolerability profile. Due to an unmet medical need for patients with unresectable locally advanced (LA)/mTNBC who are programmed death ligand 1 (PD-L1) low or negative, Part D will focus on this patient population. Trial Design SGNLVA-002 (NCT03310957) is an ongoing global single-arm, open-label phase 1b/2 study of LV + pembrolizumab as 1L therapy for patients with unresectable LA/mTNBC. Part D is currently enrolling ~40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-1 treatment, PD-L1 combined positive score < 10, measurable disease per RECIST v1.1, and an ECOG performance status ≤1. Patients with Grade ≥2 pre-existing neuropathy or active central nervous system metastases are not permitted. Patients will receive LV at 1.5 mg/kg on Days 1 and 8 every 21 days plus pembrolizumab 200 mg on Day 1 q3w. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab. Secondary objectives include duration of response, disease control rate, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized with descriptive statistics. Global enrollment is ongoing in the US, EU, and Asia. Citation Format: Patrick Dillon, Reva Basho, Hyo S. Han, Hans-Christian Kolberg, Katherine Tkaczuk, George Zahrah, Maria Gion, Herman Voss, Jane Meisel, Timothy Pluard, Jenny Fox, Mafalda Oliveira, Ursa Brown-Glaberman, Erica Stringer-Reasor, Luis Manso, Sherko Küemmel, Lin Chi Chen, Sheng Wu, Brandon Croft, Valentina Boni. Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress) [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 OT1-03-06.

Supplementary Table S1. IC50 values of ipatasertib on cell viability in cell lines with or without alterations in PTEN or PIK3CA. Supplementary Table S2. Percent tumor growth inhibition (%TGI) in xenograft models with or without alterations in PTEN or PIK3CA. Supplementary Table S3. PI3K/Akt pathway status in archival tumors. Supplementary Table S4. Reasons for discontinuation of study. Supplementary Table S5. Common adverse events for ipatasertib in {greater than or equal to} 10% of patients in any presented group. Supplementary Table S6. All Grade {greater than or equal to} 3 adverse events related to ipatasertib. Supplementary Table S7. Hemoglobin A1C (HgbA1C) values for patients who had both pre-treatment and post-treatment values in Stages 1 and 2. Supplementary Table S8. Summary data for patients with best radiographic stable disease (SD) by RECIST version 1.0 criteria. Supplementary Figure S1. Exposure plots confirm that exposures achieved in patients in the dose-escalation stage (right side) correlated with exposures in preclinical models at TGI90 (left side). Supplementary Figure S2. Relationship between exposure of ipatasertib to the most common ipatasertib-related AEs of fatigue, diarrhea, nausea, and rash. Supplementary Figure S3. Suppression of pGSK3β in platelet-rich plasma versus ipatasertib concentrations. Supplementary Figure S4. Pharmacodynamic (PD) dose-dependent elevations in glucose and insulin following treatment with ipatasertib.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2− cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC.Significance:The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659

File with the supplementary material & methods, supplementary tables and supplementary figure.

Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.

Background The combination of HP and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2+ ABC. PIK3CA mut can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mut had a shorter PFS. The AKT inhibitor IPAT blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. Patients and Methods IPATHER (NCT04253561) is an open-label, single-arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP in patients with HER2+ ABC with a PIK3CA-mut (detected in tissue or plasma ctDNA in a Central Laboratory) who are candidates to receive maintenance HP after taxane discontinuation in the first line setting for a reason different to progressive disease. The primary objective is to characterize the safety and tolerability of IPAT in combination with HP, and to identify a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The study has two phases: a dose safety phase and a dose expansion phase. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose-limiting toxicity (DLT) during the first 28 days of treatment. DLT during first 28 days of therapy is defined as grade ≥3 diarrhea lasting more than 72 hours, grade ≥2 diarrhea lasting more than 5 days, and other non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy. Given the low risk for overlapping toxicities, the first cohort of the dose safety phase tested IPAT at 400 mg orally once daily D1-21 q28d and standard dose HP. Dose level -1 and -2 of IPAT were 300 mg and 200 mg in case dose de-escalation was needed. Loperamide was given as prophylaxis for diarrhea. In HR-positive tumors, endocrine therapy could be started after the DLT period. Here, we present the results of the dose safety phase of IPATHER. Results A total of 6 female patients with PI3KCA-mut/HER2+ ABC were included in the first dose safety cohort. Median age was 52 (41-78), most patients had ECOG 0 (66.6%), and 50% were postmenopausal. Five out of six patients (83.3%) had HR-negative tumors and visceral metastases. Patients received a median of 6 treatment cycles (range 4-7) with taxane plus HP. At the time of the data cut-off (28/02/2021), all the patients remained on treatment. Median follow up is 4 months (range 2-12). Treatment was well tolerated with no DLTs or grade 3/4 adverse events (AEs) observed during the DLT period or the rest of treatment period (Table 1). The most common treatment-related AEs were diarrhea (N=5, [83.3%]) and nausea (N=2,[33.3%]), mostly grade 1. There was no dose reduction and diarrhea was controlled with prophylactic loperamide. A partial response (PR) was observed in one patient, and 5 had stable disease. Of note, the addition of IPAT to HP in the patient with a PR deepened the response achieved during the induction phase with chemotherapy plus HP. Conclusion IPAT 400 mg orally once daily D1-21 q28d in combination with HP is well tolerated and has shown preliminary signs of efficacy. Given the favourable safety profile, the dose expansion phase testing IPAT 400 mg in combination with HP has started and will include 19 additional patients. Table 1.Adverse Events during treatment period related with study treatment (IPAT and/or HP).Adverse EventN AEsN patientsGrade 1Grade 2% (N=6)Diarrhea55 (83%)5083%Nausea32 (33%)2033Vomiting21 (17%)1017Anemia11 (17%)1033Lymphopenia11 (17%)1033Gastroesophageal reflux11 (17%)0117Dyspepsia11 (17%)1017Hyporexia11 (17%)1017 Citation Format: Mafalda Oliveira, Eva Ciruelos, Serafín Morales, Joaquín Gavilá, Vanesa Quiroga, Estela Vega, Javier Salvador Bofill, Alexandra Cortegoso, Fernando Henao, Pablo Tolosa, Jordi Canes, Patricia Villagrasa, Xavier Gonzalez Farré, Tomás Pascual, Cristina Saura. Solti-1507 IPATHER - A phase Ib study of ipatasertib (IPAT) and dual anti-HER2 therapy with pertuzumab and trastuzumab (HP) in patients with HER2-positive (HER2+) advanced breast cancer (ABC) and a PIK3CA mutation (mut): Results from the first safety cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-34.

BACKGROUND: Metastatic breast cancer (mBC) remains an incurable disease and is the cause of nearly all deaths related to BC. Next-generation sequencing technologies are allowing the application of personalized targeted molecular therapies, thereby improving outcomes in breast cancer patients. However, they are not routinely used in the clinic and their cost could be a cause of disparity. One strategy to overcome the barriers of implementing NGS in the clinic is to promote the active participation of patients with mBC in the management of their disease and offering free access to these tests. With this in mind, we designed HOPE (SOLTI-1903), a Spanish real-world study where patients lead their inclusion, participation, and follow-up through a digital tool (DT) that guides them in every step of the journey. The ultimate objective of HOPE is to gather real-world data on the utilization of molecular information in the management of mBC and to empower these patients. TRIAL DESIGN: Patients diagnosed with locally advanced or mBC can be included. Basic demographic data, disease characteristics, treatment history and quality of life data are collected by patients through a DT. The study is complemented by a patient empowerment program including informative workshops and precision medicine video-tutorials. Patients are encouraged to involve their physicians in HOPE. A total of 600 patients will be included in Spain. PATIENT JOURNEY: Once patients request participation through the DT, a dedicated team in SOLTI assists them in the subsequent steps while validating that eligibility criteria are met according to patient-provided data. Then, patients receive instructions from SOLTI’s team to attend the nearest partner local laboratory, where they sign the study informed consent form. A metastatic (preferably) or primary archival tumor sample is requested from the patient’s reference hospital and analyzed by FoundationOne®CDx. Patients that are in progression or not receiving active systemic chemo- or radiotherapy undergo a blood draw to receive a Guardant360 analysis. These two NGS tests are offered to all patients, and the blood test is performed even if no tissue is available. The results from the molecular analyses are regularly reviewed by a Molecular Advisory Board (MAB). The MAB, based on its joint experience in clinical oncology, genomics, bioethics, and pathology, may add some advice to these reports via DT, making comments about detected molecular alterations and adding further recommendations for specific treatment options or available CT with targeted therapies and/or additional genetic tests such as germline validation of potentially significant findings. From that moment, patients are requested to record their disease evolution in the DT every 3 months for 2 years. The primary objective is to assess the real-world clinical practice integrating molecular profiling in the Standard of Care management of patients with mBC connected through a DT. Secondary objectives include to i) describe the genetic mutational profile of mBC, ii) estimate the enrollment rate in CT of patients engaged in a patient-centered strategy for molecular tumor assessment, iii) assessing Progression Free Survival, Overall Survival and Quality of Life status among patients enrolled in CT according to the tumor’s genomic profile and iv) evaluate the logistic feasibility of the study. Recruitment started on October 2020. By June 2021, 362 patients had been enrolled. ACKNOWLEDGEMENTS: This study is sponsored by SOLTI and financially supported by Novartis and three non-profit organizations: Asociación Cáncer de Mama Metastásico, Asociación Saray and Fundación Actitud frente al Cáncer. Roche and Guardant Health provide their tests for all patients. Citation Format: Ana Casas, Eva Ciruelos, Mafalda Oliveira, Cristina Saura, Meritxell Bellet, Sonia Pernas, Joaquín Gavilá, Montserrat Muñoz, Maria Vidal, Blanca González-Farré, Juan M. Cejalvo, Rafael López, Ana Vivancos, Marcos Malumbres, Javier Salvador Bofill, Isabel Blancas, Emilio Alba, Valentina Boni, Susana De la Cruz, Elena Galve, Antonia Perelló, Mireia Margelí, Meritxell Soler, Rubén Olivera-Salguero, Helena Masanas, Rosa Olmos, Marga Forns, Pilar Fernández Pascual, Elia Seguí, Tomas Pascual, Aleix Prat. Solti-1903 HOPE: Real-world clinical practice study to assess the impact of using genomic data on the next treatment decision making-choice in patients with locally advanced or metastatic breast cancer in Spain [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-06-01.

Background.Patients with metastatic hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) are usually treated with CDK4/6 inhibitors combined with endocrine therapy (ET) as first line treatment. The addition of CDK4/6 inhibitors to endocrine therapy has demonstrated improved progression free survival (PFS), overall response rate (ORR) and, more recently, overall survival (OS). However, there is a 20% of patients who do not benefit from these drugs and those who respond eventually progress to the treatment, for whom no standard treatment exists. The information provided by the intrinsic subtypes (PAM50) highlight the potential value of BC molecular classification as a prognosis and predictive marker. Within HR+/HER2- disease, patients with non-luminal subtypes (HER2-enriched and Basal-like) present poorer prognosis than those with luminal subtypes, may be more sensitive to chemotherapy, and have higher expression of immune-related genes and tumor infiltrating lymphocytes (TILs). Recently, immunotherapy has been approved for treating metastatic triple negative (TN) BC and several trials evaluating the action of immune checkpoint inhibitors are ongoing both in TN and in HR+/HER2- BC. TATEN study aims to evaluate the combination of pembrolizumab and chemotherapy in metastatic HR+/HER2-negative, PAM50 non-luminal BC.Study design. TATEN is an open-label, single arm, multicenter phase II study evaluating pembrolizumab in combination with paclitaxel in patients with locally advanced or metastatic PAM50 non-luminal HR+/HER2- BC who had recurrence or progression after therapy with a CDK4/6 inhibitor plus endocrine therapy. Tumor samples collected during advanced/metastatic disease are mandatory. No prior chemotherapy for inoperable locally advanced or metastatic BC is permitted. Eligible patients will receive pembrolizumab 200 mg every 3 weeks (on day 1 of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 80 mg/m2 administered at days 1, 8, 15 of each 21-day cycle beginning at cycle 2. The primary endpoint of the study is to evaluate ORR according to RECIST V1.1. The study will use a Simon’s 2-stage design and will include up to 46 evaluable patients. If 6 or more responses are observed in up to 15 patients in the first stage, the trial will continue to the second stage and 31 additional patients may be evaluated for a total of 46 evaluable patients. The null hypothesis will be rejected if 19 or more responses are observed. Tumor assessments will be performed every 9 weeks. Secondary endpoints include clinical benefit rate (CBR), PFS, duration of response (DoR), time to response (TtR), OS, as well as the correlation of clinical benefit (ORR, PFS) with PD1 mRNA expression and early dynamic changes in ctDNA after 1 cycle of pembrolizumab (collection of blood samples at Cycle 1 Day 1, Cycle 2 Day 1 and end of treatment are mandatory). Safety and tolerability of the combination will also be assessed. Exploratory objectives include to determine ORR, PFS, DoR and TtR based on iRECIST and to identify predictive biomarkers of response to pembrolizumab plus paclitaxel. As of July 2021, 10 patients have been enrolled in 7 sites in Spain. Clinical trial identification: NCT04251169. Acknowledgements:This study is financially supported by MSD Citation Format: Eva Ciruelos, Montserrat Muñoz, Mafalda Oliveira, Nuria Chic, Cristina Hernando, Juan Antonio Viruzuela, Silvia Vázquez, Salvador Blanch, Laia Paré, Fernando Salvador, Patricia Villagrasa, Tomás Pascual, Aleix Prat. Solti-1716. Targeting with pembrolizumab + paclitaxel non-luminal by PAM50 hormone receptor-positive/HER2-negative advanced/metastatic breast cancer patients who have progressed on or after CDK4/6 inhibitor treatment (TATEN trial) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-17-01.

Background: HER3 is overexpressed in 30-50% of breast cancers and has been associated with poor prognosis. Patritumab deruxtecan (HER3-DXd; U3-1402) is a HER3-directed ADC with a potent topoisomerase I (TOP1) inhibitor payload. A phase 1/2 study of HER3-DXd (NCT02980341) demonstrated promising antitumor activity in hormone receptor positive (HR+) metastatic BC patients with clinical activity observed across baseline levels of HER3 protein or mRNA expression. A window of opportunity clinical trial is currently ongoing to evaluate the biological activity of HER3-DXd in patients with treatment naïve BC according to HER3 mRNA/protein expression levels (NCT04610528). Here, we aimed to describe the activity of HER3-DXd in PDX models to identify robust biomarkers of response. Methods: The antitumor activity of HER3-DXd was assessed in 21 BC PDX models (14 HR+ and 7 triple negative). HER3-DXd sensitivity was established as a complete response that lasted longer than 120 days, following 4 weekly doses of 10 mg/kg. HER3-DXd antitumor activity was compared to the antitumor activity of irinotecan (50 mg/kg dosed once weekly), which was evaluated according to modified RECIST criteria in a subset of 14 BC PDX models. PDX models of acquired resistance to HER3-DXd were generated by repeated treatment cycles. Pharmacodynamic (PD) experiments were conducted by collecting tumor samples from PDXs after a single dose of HER3-DXd or irinotecan. Baseline HER3 expression was assessed by immunohistochemistry (IHC) and Western blot. mRNA expression of 72 genes including ERBB3 and genes from the PAM50 signature were measured using the nCounter platform. Two-class unpaired significance analysis of microarrays (SAM), using a false-discovery rate Citation Format: Andreu Òdena, Laia Monserrat, Fara Brasó-Maristany, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maurizio Scaltriti, Sarat Chandarlapaty, Yang Qiu, Kumiko Koyama, Mafalda Oliveira, Aleix Prat, Violeta Serra. Antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3-directed antibody drug conjugate (ADC) across a diverse panel of breast cancer (BC) patient-derived xenografts (PDXs) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-14.

Background: In ASCENT, patients with mTNBC refractory to or relapsing after ≥2 prior chemotherapies (at least one in the metastatic setting) were randomized 1:1 to receive sacituzumab govitecan (SG) or single-agent treatment of physician’s choice (TPC) (capecitabine, eribulin, vinorelbine, or gemcitabine). Primary endpoint was progression free survival. Secondary endpoints included overall survival, objective response rate, clinical benefit rate, and safety. Here we examined whether health-related quality of life (HRQoL) differed by clinical response. Methods: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQC30) version 3 was used to assess HRQoL at baseline and on day 1 of each treatment cycle. This analysis included intention-to-treat patients who had a completed at least one of the 15 domains/scales at baseline and at least one evaluable assessment at post-baseline visits based on EORTC QLQ-C30. Patients were classified as responders (partial or complete disease response) or non-responders (stable or progressive disease or not evaluable) based on best overall response (RECIST). A mixed-effect model for repeated measures (MMRM) was used to estimate leastsquare (LS) mean EORTC QLQC30 score changes from baseline using all HRQoL data assessed during Cycle 2 Day 1 (C2D1) to C6D1 (where n was ≥25 in both treatment arms) for responders and nonresponders within each treatment group. Results: Mean QLQ-C30 subscale scores at baseline were similar between treatment arms. The analysis included 236 patients in the SG arm of the full trial population, of whom 82 (35%) were clinical responders; and 183 in the TPC arm, of whom 11 (6%) were clinical responders. Due to the small number of TPC responders, inferential statistical testing to compare between-group difference was not performed.Irrespective of their clinical response status, patients treated with SG showed more favorable LS mean changes than patients who received TPC in all EORTC QLQ-C30 domains, except for nausea/vomiting and diarrhea (Table). Overall, LS mean changes in EORTC QLQ-C30 scores in SG nonresponders were less favorable than those in SG responders, but more favorable than those in TPC responders and TPC nonresponders for most EORTC QLQ-C30 domains. Conclusions: The analysis demonstrates that regardless of response status, SG responders and non-responders showed a better trend in HRQoL changes than TPC. Patients who achieved a tumor response to SG may benefit most in HRQoL. Although patients treated with SG reported higher rates of diarrhea, this did not generate a negative impact on their overall quality of life or functioning. Table: Mixed effects model least-square mean EORTC QLQ-C30 score changes from baselineLeast-square mean change from baseline (95% confidence interval)SG responders(N=82)SG nonresponders(N=154)TPC responders(N=11)TPC non-responders(N=172)Global health status/QoL2.46 (-1.52, 6.43)-0.57 (-3.68, 2.54)-1.64 (-10.22, 6.95)-2.29 (-5.63, 1.05)FunctioningPhysical2.93 (-0.92, 6.79)0.22 (-2.71, 3.15)-3.47 (-11.93, 4.99)-3.75 (-6.87, -0.63)Role-0.35 (-5.74, 5.04)-3.23 (-7.45, 0.99)-8.40 (-19.93, 3.13)-7.33 (-11.88, -2.78)Emotional6.20 (2.23, 10.18)1.97 (-1.12, 5.06)4.87 (-3.70, 13.44)0.08 (-3.24, 3.40)Cognitive0.90 (-2.99, 4.79)-2.25 (-5.26, 0.76)-4.46 (-12.87, 3.95)-1.26 (-4.49, 1.98)Social2.06 (-3.50, 7.61)-3.35 (-7.65, 0.95)-5.79 (-18.29, 6.72)-4.36 (-8.99, 0.27)SymptomsFatigue0.90 (-3.49, 5.28)2.84 (-0.60, 6.29)4.15 (-5.34, 13.65)6.65 (2.93, 10.38)Nausea/vomiting4.68 (1.42, 7.95)4.03 (1.42, 6.64)1.38 (-5.53, 8.29)2.62 (-0.21, 5.45)Pain-11.40 (-16.43, -6.36)-8.57 (-12.48, -4.66)-11.99 (-22.85, -1.13)-0.24 (-4.47, 3.99)Dyspnea-7.88 (-13.09, -2.67)-1.90 (-5.93, 2.13)1.97 (-9.33, 13.27)3.86 (-0.47, 8.18)Insomnia-6.12 (-11.99, -0.26)-3.51 (-8.04, 1.02)4.83 (-7.85, 17.51)-0.98 (-5.86, 3.90)Appetite loss0.22 (-5.25, 5.70)5.45 (1.15, 9.75)8.67 (-3.05, 20.40)4.60 (-0.05, 9.26)Constipation0.93 (-4.57, 6.43)2.20 (-2.09, 6.49)3.87 (-7.96, 15.70)3.52 (-1.12, 8.16)Diarrhea16.03 (10.32, 21.74)13.65 (9.19, 18.11)2.46 (-9.88, 14.80)-1.53 (-6.34, 3.29)Financial difficulties-3.57 (-8.54, 1.39)-2.44 (-6.21, 1.34)-4.41 (-15.27, 6.46)0.61 (-3.42, 4.64)A higher score for a functional domain represents a higher or healthier level of functioning; a higher score for the global health status/QoL represents a higher overall HRQoL; but a higher score for a symptom domain represents a higher level of symptomatology or problems Citation Format: Sibylle Loibl, Sara M. Tolaney, Kevin Punie, Mafalda Oliveira, Hope S. Rugo, Aditya Bardia, Sara A. Hurvitz, Adam Brufsky, Kevin M Kalinsky, Javier Cortes, Joyce O’Shaughnessy, Lisa A. Carey, Luca Gianni, Véronique Diéras, Ling Shi, Mahdi Gharaibeh, Luciana Preger, Lee Moore, See Phan, Martine Piccart. Assessment of health-related quality of life by clinical response from the phase 3 ASCENT study in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-01.

Background: Ipat is a potent oral AKT inhibitor that has been studied in multiple clinical trials, primarily in breast and prostate cancers. Combining fulv and AKT inhibition demonstrated efficacy in pts with HR+ aBC regardless of PI3K/AKT pathway alterations [Jones, Lancet Oncol 2020]. IPATunity150 (NCT04060862) was designed as a phase III trial with an open-label phase Ib portion adding ipat to palbo plus fulv in biomarker-unselected HR+ HER2-negative aBC. The biological rationale was to prevent or delay resistance to CDK4/6 inhibition plus endocrine therapy (ET). AKT1 alterations and PTEN loss have been implicated in resistance to CDK4/6 inhibitors [Wander, Cancer Discov 2020; Costa, Cancer Discov 2020]. We report results from the open-label phase Ib portion. Patients and Methods: The primary objective was to assess safety and pharmacokinetics (PK) of ipat in combination with palbo and fulv; several efficacy parameters were also analyzed. Pts with measurable disease who had not previously received a CDK4/6 inhibitor and had experienced relapse during adjuvant ET were treated with ipat at a dose of 300 mg/d, d1-21 q28d, plus standard-of-care doses of palbo (125 mg/d, d1-21 q28d) plus fulv (500 mg q28d with a loading dose in cycle 1). The selected ipat dose was lower than the 400 mg typically used in other studies because of the anticipated drug-drug interaction (DDI) when combining ipat (a sensitive CYP3A4 substrate and mild-to-moderate CYP3A inhibitor) with palbo (a weak time-dependent CYP3A4 inhibitor and CYP3A substrate). Results: Of the 20 pts treated, 20% were Asian, 65% had primary endocrine resistance (relapse ≤2 years after starting adjuvant ET), 80% had received prior (neo)adjuvant chemotherapy, and 60% had liver and/or lung metastases. At the data cutoff (19 Mar 2021; median follow-up 6.1 months), median treatment duration was 5.1, 5.9, and 5.3 months for ipat, palbo, and fulv, respectively. Treatment was ongoing in 13 pts. Grade 3/4 adverse events (AEs) occurred in 80% of pts (no grade 5). The most common AEs were diarrhea (80% any grade, 10% grade 3, no grade 4) and neutropenia (75% any grade, 45% grade 3, 20% grade 4). Other notable grade ≥3 AEs were grade 3 liver function test elevations in 10%. There were no cases of febrile neutropenia and only 1 case of pneumonitis (grade 1). AEs led to at least one dose reduction of ipat in 6 pts (30%; diarrhea n=3 [with vomiting in 1 pt], neutropenia n=3 [with fatigue in 1 pt]) and of palbo in 9 pts (45%; all for neutropenia). One pt (5%) discontinued ipat and palbo permanently due to ongoing neutropenia after protocol-defined dose reductions. As expected, a DDI led to increased ipat exposure (AUC0-24,ss ~60% and Cmax ~40%) when ipat and palbo were combined. Based on population PK analysis, palbo AUC0-24,ss was ~30% higher than reported from the PALOMA 1 and 2 trials, which was expected and consistent with previously reported physiologically based PK modeling of palbo exposure when administered with moderate CYP3A inhibitors [Yu, J Clin Pharmacol 2017]. All 20 pts had at least one post-baseline tumor assessment. Best overall response rate was 45% (95% CI: 23-68%), including confirmed responses in 7 pts (35%; 5% complete response, 30% partial response) at the clinical cutoff date. Median duration of response was 9.6 months (95% CI: 7.1-not estimable). An additional 10 pts (50%) had stable disease. Progression-free survival results were immature (events in 7 pts). There was no obvious association between efficacy and mutations in PIK3CA/AKT1 as tested in ctDNA. Conclusion: The triplet combination of ipat, fulv, and palbo had an acceptable safety profile generally consistent with that of the individual study drugs; ipat exposure was increased through a predicted DDI. Updated results will be presented. Citation Format: Mafalda Oliveira, Aditya Bardia, Sung-Bae Kim, Naoki Niikura, Cristina Hernando, Gustavo Werutsky, Yoland Antill, Pedro Liedke, Catherine Oakman, Eriko Tokunaga, Seth Wander, Vanessa Krause, Toshinari Yamashita, Frauke Schimmoller, Jacob Rotmensch, Heidi Savage, Rucha Sane, Nicholas Turner. Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-11.

Background Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2 negative breast cancer (BC) remains an unmet medical need. We hypothesized that combining T-VEC with Atezolizumab may offer clinical benefit in terms of residual cancer burden (RCB) rate in the pre-operative setting for patients with early BC with intermediate to high risk of recurrence who present RD after standard NAC. Methods SOLTI-1503 PROMETEO is an open-label, multicenter trial of T-VEC + Atezolizumab in patients with RD after completing standard NAC. Overall, 30 women with triple-negative BC (TNBC) or Luminal B-like/HER2-negative BC are planned to be included in the trial. RD must be confirmed by core-biopsy and tumor should have a diameter ≥ 10 mm measured by magnetic resonance imaging (MRI). Adequate organ function and ECOG PS 0-1 are required. T-VEC is administered intratumorally on week 1 (106 plaque-forming units/mL [pfu/mL]), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) is administered intravenously every 2 weeks for 4 infusions, starting at week 4. BC surgery is performed 1 to 3 weeks after completing the treatment. The primary objective is to evaluate the efficacy of the combination, measured by the rate of RCB class 0/1 at surgery. Secondary endpoints include rate of pCR, objective response rate (ORR; rate of complete response + partial response) assessed by MRI, safety, and the increase of mean expression of a gene signature tracking activated CD8+ T-cells. Here we present the safety and efficacy results of the interim analysis including the first 10 enrolled patients. Results: As of April 2021, 10 patients received the study treatment and were evaluable for primary endpoint and safety. Main patient characteristics were: median age 48 (37-71), ECOG PS 0 (70%) and post-menopausal (60%). Four patients had TNBC and 6 Luminal B-like BC; 5 patients had stage II BC and 4 stage III; 7 tumors were grade II and 3 were grade III; median Ki-67 was 44% (20-75). Mean tumor size by MRI after NAC was 30.5 mm (11-75). At surgery, one patient achieved RCB0. Two patients achieved an objective response, five patients a stable disease and disease progression was observed in three patients (2 TNBC and 1 Luminal-like tumor). Nine patients reported AEs. Only grade 1-2 adverse events were reported, being the most common Fever (n=6) Arthralgia ((n=4) AST increased (n=3) and ALT increased (n=3). Conclusion: The treatment of T-VEC and atezolizumab was feasible at the approved doses and the safety profile was consistent with that previously reported. One patient achieved RCB0. After the efficacy and safety analysis of the first 10 patients, it was decided to continue with the inclusion of up to 30 patients. Correlative analysis including gene expression analysis and centralized Tumor-infiltrating lymphocytes (TILs), PD-L1 (SP142) IHC will be presented. Citation Format: Tomás Pascual, Maria Vidal, Mafalda Oliveira, Juan M Cejalvo, Estela Vega, Esther Sanfeliu, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz, Claudette Falato, Manel Juan, Juan M Ferrero-Cafiero, Xavier González-Farré, Patricia Villagrasa, Aleix Prat. Talimogene laherparepvec (T-VEC) + atezolizumab combination in early breast cancer (SOLTI-1503 PROMETEO): Safety and efficacy interim analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-13.

Background: SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG is FDA approved for pts with mTNBC who received ≥2 prior chemotherapies (≥1 in the metastatic setting). The confirmatory phase 3 ASCENT study (NCT02574455) in pts treated in second line or greater (2L+) mTNBC demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit of SG over single-agent chemotherapy treatment of physician’s choice (median PFS: 4.8 vs 1.7 months, HR 0.43, P Citation Format: Javier Cortés, Aditya Bardia, Delphine Loirat, Sara M. Tolaney, Kevin Punie, Mafalda Oliveira, Sara A. Hurvitz, Adam Brufsky, Sagar Sardesai, Kevin M Kalinsky, Tiffany Traina, Erika Hamilton, Joyce O’Shaughnessy, Véronique Diéras, Lisa A. Carey, Martine Piccart, Sibylle Loibl, Hope S. Rugo, Yanni Zhu, See Phan, Luca Gianni. Post-progression therapy outcomes in patients (pts) from the phase 3 ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-15.

Purpose:FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.Experimental Design:Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.Results:High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.Conclusions:Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.

Response to AZD5363 in PDX models recapitulates patients' response

Supplementary Figure 1. FGFR1-4 DNA CN, mRNA levels and ROC curves analysis. A) Waterfall plot representing the best antitumor response of FGFRi in 24 patients from 8 different cancer types treated at VHIO. FGFR1/2 amplification status and high FGFR1-4 mRNA levels are indicated in the underneath panel. B) Copy number (CN) values of FGFR1-4 by MSK-IMPACT in the FGFR/FGFamp PDX collection and categorized analysis in PDXs harboring CN amplification (CN>4), according to the response to rogaratinib (responders (SD and PR) and non-responders (PD)). C) Evaluation of FGFR1/4 CN ratio by FISH ratio (the dashed line indicates the CN ratio>2.2 that is considered amplified) and categorized analysis according to the response to rogaratinib. D) Correlation analysis between the CN values (X-axis) and mRNA levels (Y-axis) of FGFR1-4 obtained from MSK-IMPACT or nCounter, respectively. Pearson correlation coefficient (r2) is shown. E) Categorized analysis of FGFR1-4 mRNA composite biomarker according to the response to rogaratinib, obtained from HTG or qPCR data. Statistical test: Mann-Whitney U test. ROC curve analysis the FGFR1-4 mRNA composite biomarker, obtained from HTG or qPCR (AUC=0.89, both).

Exposure to taselisib

Purpose:Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial.Experimental Design:In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points.Results:Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment.Conclusions:We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.

PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies.Significance:This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.

RPPA data analysis

Purpose:FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.Experimental Design:Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.Results:High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.Conclusions:Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.

Purpose:AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor–positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.Experimental Design:Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.Results:Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K.Conclusions:This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.

Purpose:Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).Patients and Methods:Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.Results:Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.Conclusions:Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.

Supplementary Table from Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification