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Background Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in treating solid tumors with Homologous Recombination Deficiency (HRD), the inability to repair DNA double-stranded breaks through the Homologous Recombination Repair (HRR) pathway. Specific genetic and epigenetic alterations result in defective HRR function. Bi-allelic loss of BRCA1 or BRCA2 principally drives HRR deficiency. While BRCA1/2 are instrumental to HRR, multiple genes, including PALB2, impact the HRR pathway. PALB2 mutations occur in an estimated 0.97% to 3.66% of solid tumors [AACR GENIE PALB2] and are associated with susceptibility to various cancers. No clinically approved therapies specifically targeting PALB2 currently exist. Emerging evidence suggests that patients with germline or somatic PALB2 mutations may benefit from PARPi treatment, which has potential to be a new tumor agnostic therapy option across a wide range of solid tumors. Methods PAVO is a pan-tumor, single-arm, multicenter Phase-II study assessing the safety and efficacy of niraparib (a PARPi) in patients who harbor a confirmed PALB2 mutation. The study plans to enroll up to 110 adult subjects. Eligible participants must have: locally advanced or metastatic solid tumor(s); confirmed pathogenic or likely pathogenic somatic or germline PALB2 mutation; received all standard of care (SOC) therapy for their tumor type, or are unlikely to derive benefit from SOC therapy in the opinion of the treating physician; ECOG performance status of 0 or 1; life expectancy of ≥ 12 weeks with adequate organ/bone marrow function. Exclusion criteria include a confirmed somatic or germline BRCA1/2 mutation, prior treatment with any PARPi, ovarian or prostate cancer, or rapid progression while on platinum-based therapy in the metastatic setting. Niraparib will be administered in 28 day cycles with daily dosing, as outlined in the protocol. Participants will continue study treatment until documented radiographic progression, unacceptable toxicity, death, or consent withdrawal. The primary study endpoint is objective response rate (ORR), defined as the proportion of participants who have partial or complete response to therapy as assessed by Independent Central Review. Secondary endpoints include DOR, PFS, and CBR. PAVO is sponsored by Tempus with support from GSK (GlaxoSmithKline). The trial opened in March 2022. Tempus molecular data tracking (integrated NGS and EMR data) and the TIME Trial program (rapid match of patients to Just in TIME sites for clinical trials), enable patient identification and prescreening. Enrollment occurs through a combination of TIME and prospective clinical sites, where individualized prescreening models are in development. New site identification and referral of molecularly eligible patients to enrolling centers are ongoing. Clinical Trial Registry: NCT05169437 Citation Format: Tian Zhang, Thomas Weart, Matthias Weiss, Drew Murray, Minaxi Jhawer, Edward Huynh, Shumei Kato, Amy Cummings, Lydia Usha, Arvinder Bhinder, Rajiv Desai, Brad Johnson, Anjali Avadhani, Cecile Rose T. Vibat, Lauren Lopez, Brynna Driscoll, Annajane Ward, Christie K. Rice, Blathnaid Donovan, Scott Sherrin, Mykel Robble, Stephanie O'Leary, Kimberly Blackwell, Amine Aziez, Stephanie Petrone, Kathleen Harnden, Kimberly Strickland, Sonya Reid, Mark Robson, Andrew S. Paulson, Afshin Dowlati. PAVO: A phase-II, open label, single arm study of niraparib in patients with locally advanced/metastatic PALB2 mutated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT055.

CDK4/6 inhibitors (CDK4/6i) in combination with antiestrogens have revolutionized the treatment of ER+ metastatic breast cancer (MBC), significantly prolonging survival. However, this combination is not curative, and tumors eventually acquire resistance. Following progression on this combination, patients are left with limited treatment options. A diverse array of mechanisms of resistance to CDK4/6i + antiestrogens have been described. However, laboratory models that capture this heterogeneity of resistance mechanisms are lacking. Patient-derived organoids (PDOs) provide a rapid, robust and reliable platform that recapitulates intra-tumor heterogeneity, partially mimics the cancer microenvironment, and accurately predicts drug response. We aspired to generate a platform of CDK4/6i-resistant breast cancer PDOs to serve as models for understanding acquired resistance to CDK4/6i + antiestrogens and identifying therapies to overcome resistance. We successfully established 16 PDOs out of 32 biopsies (50% efficiency) of metastates from patients with ER+ MBC progressing on CDK4/6i (palbociclib or abemaciclib) + antiestrogens (letrozole or fulvestrant; median response to combination = 9 months). Our collection includes PDOs derived from lobular (n=3) and inflammatory (n=2) breast cancers and reflects racial/ethnic diversity (50% white/not Hispanic; 18.8% Hispanic; 12.5% Black; 12.5% other/unknown). Next-gen sequencing reports were available for 10 patients from which organoids were established, revealing alterations associated with CDK4/6i and/or antiestrogen resistance, including ESR1 (n=2), HER2/ERBB2 (n=2), PTEN (n=2), CCNE1 (n=1), NF1 (n=1), and ARID1A (n=1). Furthermore, one biopsy and its derived organoid lost ER expression, and 5 harbored PIK3CA activating mutations. Thus far, we have performed targeted DNA-sequencing on 7 PDOs and found 13/15 (86.7%) concordance with driver mutations from tumor NGS reports. PDOs established from CDK4/6i-resistant biopsies maintained resistance to palbociclib or abemaciclib ± fulvestrant (500 nM each) in 3D cell viability assays (6 days of treatment). In contrast, control PDOs established from primary ER+ breast cancer surgical samples (n=2) were sensitive to each CDK4/6i ± fulvestrant (median viability for combination=25.6-31.5% for control vs 65.2-80.5% for resistant). GSEA analysis of RNA-seq data from control (n=2) and CDK4/6i-resistant (n=6) PDOs cultured in estrogen-depleted media ± 200 nM palbociclib revealed that palbociclib treatment resulted in downregulation of E2F target and G2M checkpoint signatures in control but not resistant PDOs. Next, we performed a high-throughput screen of 1,000 compounds in 3 resistant PDOs. One PDO showed exquisite sensitivity to G2/M cell cycle checkpoint components, including CDK1, PLK1, Aurora kinase, ATR, Chk1, and Wee1 inhibitors. Finally, treatment of 10 resistant PDOs with the CDK2/4/6 inhibitor PF-06873600 revealed that the CCNE1 (cyclin E1)-amplified PDO was highly sensitive (IC50=130 nM vs >1000 nM), supporting that CCNE1-amplified tumors are vulnerable to CDK2 inhibition. Conclusions: PDOs can be successfully established from ER+ MBC biopsies, maintain the resistant phenotype in culture, retain driver alterations found in tumors from which they were derived, and fail to suppress E2F targets following treatment with CDK4/6i. Therefore, these PDOs represent valuable models to understand and explore diverse mechanisms of CDK4/6i resistance and therapeutic vulnerabilities. Citation Format: Ariella B. Hanker, Sumanta Chatterjee, Yunguan Wang, Dan Ye, Dhivya R. Sudhan, Brian M. Larsen, Lauren C. Smith, Yilin Zhang, Vishal Kandagatla, Kuntal Majmudar, Ezequiel Renzulli, Saurabh Mendiratta, Kimberly Blackwell, Alana L. Welm, Sunati Sahoo, Nisha Unni, Cheryl M. Lewis, Tao Wang, Ameen A. Salahudeen, Carlos L. Arteaga. A platform of CDK4/6 inhibitor-resistant patient-derived breast cancer organoids illuminates mechanisms of resistance and therapeutic vulnerabilities [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 PD2-01.

Premenopausal women treated for early stage breast cancer (ESBC) are at risk for chemotherapy-related amenorrhea (CRA). Prospectively-validated, predictive markers of CRA are needed.Premenopausal women with ESBC and planned chemotherapy (/= 25% risk of amenorrhea) were evaluated. Follicle stimulating hormone (FSH), estradiol, Inhibin A and B, anti-Müllerian hormone (AMH), and quality of life (QOL) were prospectively evaluated pre-, post-, 6 months and 1 year post-chemotherapy and correlated with age and menstrual status. CRA was defined as absence of menses 1 year post-chemotherapy.Forty-four women were evaluated at the time of analysis. Median age at diagnosis and FSH 1 year post-chemotherapy were higher among women with CRA (44 yrs [33-51] vs. 40 yrs [31-43]; p = 0.03; 39.8 vs. 5.0 mLU/mL, p = 0.0058, respectively). Median estradiol 1 year post-chemotherapy was higher among women who resumed menses (108.3 vs. 41.3 pg/mL, p = 0.01). Pre-chemotherapy median Inhibin B and AMH were lower among women with CRA (33.2 vs. 108.8 pg/mL; p = 0.03; 0.16 vs. 1.09 ng/mL, p = 0.02, respectively). The risk of CRA was increased among women with lower pre-chemotherapy Inhibin B (RR = 1.67, p = 0.15) and AMH (RR = 1.83, p = 0.05). Amongst women whose pre-chemotherapy Inhibin B and AMH values were below the median, the incidence of CRA was 87.5%.RESULTS indicate that pre-chemotherapy Inhibin B and AMH are lower among women experiencing CRA and may be predictive of CRA among premenopausal women facing chemotherapy for ESBC.

Background: The heterogeneity of TNBC includes a subtype that is androgen dependent and whose growth is inhibited by antiandrogen therapy. We conducted a multicenter phase II trial which established the activity of bicalutamide for the treatment of patients (pts) with metastatic ER/PR-negative breast cancer TBCRC011 (Gucalp CCR 2013). We now report results of whole genome, next generation sequencing of the 26 evaluable pts to molecularly classify the study population and to identify potential biomarkers of response to bicalutamide. We hypothesized that those pts whose tumors express increased AR output are most likely to benefit from anti-androgen therapy. Methods: Archival formalin-fixed, paraffin-embedded (FFPE) samples were collected from either primary or metastatic site and RNA was isolated using standard techniques. Whole transcriptome sequencing was performed using the Illumina HiSeq 2000 platform. This data set was compared to that of TCGA, the PAM50 and the Lehmann TN subtypes for molecular classification. Bioinformatic analysis defined a model of AR transcriptional output based on androgen stimulated AR+ ER/PR- breast cancer cell lines (HCC202, SUM185, MDA453) that was applied to the TBCRC011 data set as a predictor of response. Gene set analysis was performed to test secondary hypotheses. Results: 21/26 pts provided adequate gene expression estimates for further analysis. Principal component analysis in comparison to whole transcriptomes from breast cancers in the TCGA show that TBCRC011 tumors associate with the basal like (BL) intrinsic subtype, and this was confirmed by PAM50 classification. Relative AR expression of TBCRC011 cases was similar to that of BLBC in the TCGA. There is a weak but statistically significant positive correlation between AR expression by IHC and transcriptome (r=0.395, p=0.034). An expression-based model of AR activity was derived from AR+ ER/PR- cell lines exposed to androgen. TBCRC011 samples segregate with the TCGA samples predicted to be AR responsive by this model. However, the AR output signature did not predict clinical benefit (CR+PR+SD>24 weeks) as defined in TBCRC011. Unexpectedly, by the Lehmann TNBC subtype criteria TBCRC011 tumors were not consistently molecularly classified as luminal AR (BL1-1, BL2-1, Immunomodulatory-5, Luminal AR-4, Mesenchymal-2, Mesenchymal Stem Like-2, Unclassified-6). None of the 4 pts with clinical benefit were classified as BL by the Lehmann model. Gene set analysis revealed that estrogen signal pathways were associated with the number weeks on therapy, and that samples with high scoring AR by IHC exhibited expression patterns of medullary breast cancer. Conclusions: The majority of samples demonstrated expression variation consistent with TCGA basal like breast cancer. Although cell line models predict enrichment of AR activity in both the TCGA basal like and TBCRC011 cohorts, this AR output signature did not predict clinical benefit of bicalutamide. Molecular classification found clinical benefit beyond the luminal AR subtype but exclusive of basal like 1 and 2. Whether IHC or molecular subtype is the optimal biomarker for pt selection for antiandrogen therapy remains uncertain. Citation Format: Tiffany A Traina, Ayca Gucalp, William Polkinghorn, Steven Isakoff, Sara Tolaney, Lisa Carey, James Ingle, Lisle Nabell, Andres Forero, Hope Rugo, Kimberly Blackwell, Minetta Liu, Matthew Soloway, Lisle Mose, Dilip Giri, Agnes Viale, Clifford Hudis, Charles Sawyers, Joel Parker. Whole transcriptome analysis of AR+ ER/PR- metastatic breast cancers treated with bicalutamide on TBCRC011 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-04-01.

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2-positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response.

Introduction Neoadjuvant chemotherapy has become the standard of care for the diverse population of women diagnosed with locally advanced breast cancer. Serum biomarker levels are increasingly being investigated for their ability to predict therapy response and aid in the development of individualized treatment regimens. Multianalyte profiles may offer greater predictive power for neoadjuvant treatment response than the individual biomarkers currently in use. Methods Serum samples were collected from 44 patients enrolled in a phase I–II, open-label study of liposomal doxorubicin and paclitaxel in combination with whole breast hyperthermia for the neoadjuvant treatment of locally advanced breast cancer (stage IIB or stage III). Samples were collected prior to each of four rounds of treatment and prior to definitive surgery. Samples were assayed by Luminex assay for 55 serum biomarkers, including cancer antigens, growth/angiogenic factors, apoptosis-related molecules, metastasis-related molecules, adhesion molecules, adipokines, cytokines, chemokines, hormones, and other proteins. Results Biomarker levels were compared retrospectively with clinical and pathologic treatment responses. Univariate analysis of the data identified several groups of biomarkers that differed significantly among treatment outcome groups early in the course of neoadjuvant chemotherapy. Multivariate statistical analysis revealed multibiomarker panels that could differentiate between treatment response groups with high sensitivity and specificity. Conclusion We demonstrate here that serum biomarker profiles may offer predictive power concerning treatment response and outcome in the neoadjuvant setting. The continued development of these findings will be of considerable clinical utility in the design of treatment regimens for individual breast cancer patients. Trial registration #NCT00346229.