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Background: We previously demonstrated that intrinsic subtypes were associated with prognosis for early recurrence risk in patients (pts) with early-stage HER2-positive (HER2+) BC treated with trastuzumab (H) in the N9831 trial. Here, we evaluated the prognostic value of Intrinsic subtypes and 21-gene assay and the risk of early and late recurrence in the N9831 trial. Methods: NanoString custom code set, which included PAM50 and housekeeping genes, was used to quantify mRNA and generated intrinsic subtypes and risk of recurrence (ROR) score from the N9831 trial in Arms A and C: Arm A chemotherapy alone and arm C concurrent H. Quantitative RT-PCR of 21 genes, calculation of the axis, including estrogen axis (ER, PGR, BCL2, SCUBE2), HER2 axis (GRB7, HER2), proliferation axis (Ki67, STK15, Survivin, CCNB1, MYBL2), invasion axis (MMP11, CTSL2), and recurrence score (RS) risk group assignment (RS group 1 and 2: RS < 31 and RS group 3: RS ≥ 31) were performed using Oncotype DX assay. Cox regression models for RFS were used for analysis. Early recurrence was defined as a recurrence that occurred at ≤ 5 years, and late recurrence was defined as recurrence at > 5 years. Results: A total of 783 patients (Arm A 409 and Arm C 374) were included in this analysis. Using multivariate Cox regression analysis to evaluate the risk of early recurrence in patients who received chemotherapy alone in arm A, both invasion genes (MMP11 HR 1.23, 95%CI 1.05-1.44, p 0.01 and CTSL2 HR 1.36, 95%CI 1.1-1.69, p 0.005) and invasion axis (HR 1.64, 95%CI 1.26-2.13, p < 0.001) were associated with a higher rate of early recurrence. CD68 was associated with improved outcomes (HR 0.56, 95%CI 0.38-0.83, p 0.004). For the risk of early recurrence in patients treated with trastuzumab in arm C, ER (HR 0.85, 95%CI 0.74-0.97, p 0.02), PR (HR 0.78, 95%CI 0.64-0.94, p 0.008), and estrogen axis (HR 0.7, 95%CI 0.57-0.87, p 0.001) were associated with improved outcomes. Invasion axis (HR 1.61, 95%CI 1.08-2.41, p 0.02), Oncotype Dx risk group (3 vs. 1 and 2, HR 8.89, 95%CI 1.27-1124, p 0.02), and basal subtype (HR 2.77, 95%CI 1.1-5.95, p 0.03) were also significantly associated with worse outcomes. For risk of late recurrence, in arm A, ER (HR 1.22, 95%CI 1.04-1.44, p 0.02), PR (1.26, 95%CI 1.05-1.5, p 0.01), and estrogen axis (1.39, 95%CI 1.09-1.77, p 0.008) were associated with worse outcomes. Oncotype Dx risk group (3 vs. 1 and 2, HR 0.4, 95%CI 0.16-0.98, p 0.05) was associated with improved outcomes. However, neither individual gene, axis, nor intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Conclusions: For risks of early recurrence, the invasion genes/axis were associated with increased risks of recurrence in patients with early-stage HER2+ BC regardless of trastuzumab treatment. Among patients treated with trastuzumab, ER genes/axis, Oncotype Dx risk group, and intrinsic subtype were prognostic for risks of recurrence in the first five years. For risks of late recurrence, ER genes/axis and Oncotype Dx risk group were prognostic but only in patients treated with chemotherapy alone. The ER genes/axis were associated with less recurrence in the first five years but worse after five years, reflecting a higher risk of late recurrence in ER/PR+ HER2+ BC patients treated with chemotherapy alone. However, none of the individual gene, axis, or intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Therefore, future studies are needed to identify biomarkers for the risk of late recurrence in HER2+ BC patients treated with adjuvant trastuzumab. Support: BCRF-19-161; U10CA180821, U10CA180882, Genentech. https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT00005970 Citation Format: Saranya Chumsri, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Keith L. Knutson, Antonio C. Wolff, Edith A. Perez, E. A. Thompson. Effects of Intrinsic Subtypes and 21-gene Assay on the Early and Late Recurrence Risks in Patients with Early Stage HER2+ Breast Cancer: An Analysis of the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) 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 P2-11-05.

Background: SG was approved in 2020 for the treatment of metastatic triple negative breast cancer (TNBC). The most common grade 3/4 adverse event in the ASCENT trial was neutropenia (51.2%) with a 6% incidence of febrile neutropenia. 1 Package insert recommendations do not endorse primary prophylactic growth factor support, rather only initiating if severe neutropenia occurs on treatment.2 Objective: This study retrospectively reviewed the utilization of growth factor support in patients (pts) with metastatic TNBC initiated on SG at each Mayo Clinic Enterprise site. Methods: We performed a multi-center, retrospective review of all pts with TNBC who received SG from January 2021 to December 2021 at Mayo Clinic sites in Minnesota, Florida, Arizona, and its community-based health system network. Data collected included history of neutropenia with previous cycles of SG resulting in a treatment delay, number of cycles, grade of neutropenia and cycle/day of treatment plan when growth factor added. Pts who received only one dose of SG were excluded. The Fisher’s exact test was utilized to compare the difference in the use of primary prophylaxis between sites. Results: 67 pts received at least two doses of SG. Within this cohort, 42 pts (63%) received growth factor support during treatment with SG. Growth factor support was most often added during the first two cycles (59.5%). A total of 12 patients initiated growth factor with no history of delays related to neutropenia and without neutropenia at the time of administration. Eleven of these pts had growth factor support added on Cycle 1 as primary prophylaxis. Primary prophylaxis was most common at Mayo Clinic – Rochester compared to the other sites (Table 1), however there was not a statistically significant difference (p=0.27). There were 26 pts (39%) with a treatment delay due to neutropenia while receiving SG, of which 21 (81%) were managed with the addition of growth factor (13 pegfilgrastim, 8 filgrastim). The median number of cycles for all pts was 5 (range: 1-25). Pts who received growth factor were treated with a median of 5 cycles (range: 1-25) and pts who did not receive growth factor were treated with a median of 4 cycles (range: 1-19) (p=0.10). Conclusions: We observed wide variability in the use of prophylactic growth factor between Mayo Clinic sites with SG. The optimal practice of growth factor use with SG warrants further exploration. References: 1. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541 2. Immunomedics, Inc. Trodelvy (sacituzumab govitecan-hziy) [package insert]. Foster City, CA: Gilead Sciences; 2020. Table 1: Grade of neutropenia for patients receiving SG when growth factor initiated Citation Format: Kaylee Clark, Jamie L. Carroll, Alvaro Moreno-Aspitia, Brenda Ernst, Farah Raheem, Ashley Heil, Beth Boyer, Kristin Mara, Matthew P. Goetz, Roberto A. Leon-Ferre, Karthik V. Giridhar, Jodi Taraba. Mayo Clinic Enterprise patterns of growth-factor utilization for sacituzumab govitecan (SG)-induced neutropenia among patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-56.

To determine if the COVID-19 pandemic has further exacerbated racial disparities in late-stage presentation of breast, colorectal, lung, and prostate cancers.We conducted a registry-based retrospective study of patients with newly reported diagnoses of breast, colorectal, lung, and prostate cancers between March 2019-June 2019 (pre-COVID-19) and March 2020-June 2020 (early-COVID-19). We compared the volume of new diagnoses and stage at presentation according to race between both periods.During the study period, a total of 3528 patients had newly diagnosed cancer; 3304 of which had known disease stages and were included in the formal analyses. 467 (14.1%) were Blacks, and 2743 were (83%) Whites. 1216 (36.8%) had breast, 415 (12.6%) had colorectal, 827 (25%) had lung, and 846 (25.6%) had prostate cancers, respectively. The pre-COVID-19 period included 2120 (64.2%), and the early-COVID-19 period included 1184 (35.8%), representing a proportional 44.2% decline in the volume of new cases of breast, colorectal, lung, and prostate cancers, p 0.0001. Pre-COVID-19, 16.8% were diagnosed with metastatic disease, versus 20.4% early-COVID-19, representing a proportional increase of 21.4% in the numbers of new cases with metastatic disease, p = 0.01. There was a non-significant proportional decline of 1.9% in Black patients diagnosed with non-metastatic breast, colorectal, lung, and prostate cancers early-COVID-19 (p = 0.71) and a non-significant proportional increase of 7% in Black patients diagnosed with metastatic disease (p = 0.71). Difference-in-difference analyses showed no statistically significant differences in metastatic presentation comparing Black to White patients.While we identified substantial reductions in the volume of new cancer diagnoses and increases in metastatic presentations due to the COVID-19 pandemic, the impact was similar for White and Black patients.

Background Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). The response to NAC is prognostic, with reductions in overall survival and disease-free survival rates in those patients who do not achieve a pathological complete response (pCR). Based on this premise, we hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence. Methods and results We investigated 24 samples from 12 non-LAR TNBC patients with paired pre- and post-NAC data, including four patients with recurrence shortly after surgery ( 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and nonrecurrent TNBC tumors; however, post-NAC samples demonstrated significant alterations in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the 9 paired non-LAR samples available in the NAC I-SPY1 trial confirmed 56 gene sets. Within these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n = 392) breast cancer dataset with relapse-free survival (RFS) data was used to refine our gene list to a 17-gene signature. A threefold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine-learning models. Due to the limited number of studies with pre- and post-NAC TNBC tumor data, further validation of the signature is needed. Conclusion Analysis of multiomics data from post-NAC TNBC chemoresistant tumors showed down regulation of mismatch repair and tubulin pathways. Additionally, we identified a 17-gene signature in TNBC associated with post-NAC recurrence enriched with down-regulated immune genes.

Background: Although major advances have been made in the treatment of HER2+ metastatic breast cancer (MBC), the goal of care remains largely palliative, therefore better treatments are needed. Given encouraging preclinical and clinical data, the combination of cyclin dependent 4/6 kinase inhibitors and HER2-directed therapy is further being evaluated in this trial. Trial Design: In this phase I/II multicenter trial, we will determine the maximum tolerated dose (MTD) of abemaciclib (Abem) combined with T-DM1. Three Abem dose levels will be examined, 50 mg, 100 mg and 150 mg. The phase 2 portion of this trial will examine whether PFS is increased with addition of Abem to T-DM1 in two pt cohorts - those with ER+ HER2+ MBC and those with ER-HER2+ MBC. For phase 2, a pre-registration biopsy is required to confirm ER and HER2-status and to determine levels of tumor infiltrating lymphocytes; vimentin (an epithelial-mesenchymal transition marker); and CD8 and FOXP3 expression. Blood samples will be collected pretreatment , at 6 weeks, and at progression for all pts. Eligibility Criteria: Phase I&II: All pts must have HER2+ MBC per ASCO-CAP guidelines and prior treatment with a taxane, trastuzumab and pertuzumab. For the phase Iportion, pts can have measurable or non-measurable disease with no restriction on the number of prior lines of therapy. In the phase II portion, pts must have measurable disease with ≤1-2 prior lines of chemotherapy alone, ≤1 HER2-directed therapy alone, and/or chemotherapy with HER2-directed therapies. There is no limit on prior endocrine therapy. Specific Aims: The primary objective of the phase II trial is to assess whether addition of Abem to T-DM1 increases PFS in one or both patient cohorts. Secondary objectives include an assessment of toxicity, objective response rates and overall survival. Correlative studies will assess the association between baseline TIL levels, vimentin expression, and CD8/FOXP3 expression with PFS. Changes in peripheral blood mononuclear cells, CTCs, ctDNA and serum thymidine kinase 1 during the course of treatment will be examined to determine if there is a link with PFS outcomes overall and separately for each cohort. Pharmacogenomic studies will determine if pts with the FCGR3A-158 polymorphism derive less benefit from T-DM1 and have inferior PFS outcomes compared with pts who do not have this polymorphism. Statistical Methods:Phase I: Standard 3+3 design, with dose limiting toxicities as per protocol. Phase II: For each pt cohort, a stratified randomization scheme will be used to assign pts to treatment with liver mets as a stratification factor. For each pt cohort, a stratified log rank test will be used to assess whether PFS is increased with the addition of Abem to T-DM1. A non-binding futility analysis will be applied in each cohort after 58 events in the ER+ HER2+ MBC study cohort and 48 events in the ER- HER2+ MBC study cohort. Present Accrual: 0; target accrual: minimal 120 pts., maximal 140 pts CohortOne-sidedalphaPowerAccrual Period (accrual rate)Follow-up after close of enrollmentPFS with T-DM1PFS with abema and T-DM1Number of eligible patientsER+/HER2+0.100.912 months (5-6 pts per month)12 months12 weeks24 weeks64 (32 per arm)ER-/HER2+0.100.8512 months (3-4 pts per month)12 months6 weeks12 weeks50 (25 pts per arm) Citation Format: Ciara C O Sullivan, Jun He, Vera J Suman, Krishna R Kalari, Roberto A Leon-Ferre, Jose C Villasboas-Bisneto, Pratima Chalasani, Demet Gokalp Yasar, Daniel M Anderson, Philip J Stella, Anthony J Jaslowski, Susan H Tannenbaum, Angela Saverimuthu, Donald Northfelt, Alvaro Moreno-Aspitia, Jodi M Carter, Minetta C Liu, Liewei Wang, Zhenkun Lou, Matthew P Goetz. A phase I/II trial of abemaciclib and T-DM1 in women and men with HER2-positive advanced or metastatic breast cancer that has progressed on treatment with a taxane, trastuzumab and pertuzumab (THP) (ACCRU-BR-1801) [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 OT2-19-05.

Background: The erythropoietin (EPO) receptor activation can stimulate tumor proliferation and may be implicated in resistance to anti-HER2 therapies. EPO administration can be used for the management of chemotherapy-induced anemia. We aim to assess if EPO intake during the adjuvant anti-HER2 treatment impacts the outcomes of HER2-positive early breast cancer (EBC) patients. Methods: For this post hoc analysis of the ALTTO trial (NCT00490139), we categorized two cohorts according to the use of EPO during adjuvant anti-HER2 treatment: i) at least one EPO dose (EPO-cohort) vs ii) no EPO (non-EPO-cohort). We compared their baseline characteristics to identify potential confounders. The primary endpoint disease-free-survival (DFS), and the secondary endpoint overall survival (OS) were compared between these two cohorts, with subgroup analysis according to menopausal status, tumor characteristics, and anti-HER2 treatment. Kaplan Meier method, log-rank test, and Cox regression model adjusted for confounders were performed for DFS and OS (removal criterion p2 cm (56.9%), positive nodal status (58.5%), positive hormone receptor (HR) status (61.8%), and poorly differentiated or undifferentiated histologic grade (64.2%). Baseline characteristics were similar in both cohorts, except for the timing of chemotherapy, for which 93.5% of patients from the EPO-cohort were enrolled in the concurrent designs (2/2B) vs 44.2% in the non-EPO-cohort (p Citation Format: Diogo Martins-Branco, Marie Kassapian, Véronique Debien, Rafael Caparica, Daniel Eiger, Urania Dafni, Charitini Andriakopoulou, Sarra El-Abed, Miguel Izquierdo, Malou Vicente, Saranya Chumsri, Martine Piccart-Gebhart, Alvaro Moreno-Aspitia, Ann Søegaard Knop, Janine Lombard, Evandro de Azambuja. The impact of erythropoietin administration concomitantly with adjuvant anti-HER2 treatment on the patients’ outcome: Sub-analysis of the ALTTO study [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 P1-14-05.

Background: SARS-CoV-2 mRNA vaccines have been demonstrated to have robust and durable humoral immune response in healthy individuals. However, their effectiveness in immunocompromised patients, particularly cancer patients, remains less known. Newer data suggests that cancer patients may not mount adequate protective immune response after vaccination. Methods: A retrospective study of patients ≥ 18 years old who had SARS-CoV-2 spike antibody (anti-S Ab) testing after 2 doses of SARS-CoV-2 mRNA vaccines between 12-90 days at Mayo Clinic between January 1, 2021 and May 10, 2021 was performed. The Elecsys Anti-SARS-CoV-2 S electrochemiluminescence immunoassay (Roche Diagnostics, Switzerland) was used to measure the antibody response. Patients with prior COVID-19 infection and patients on immunosuppressive therapy for an indication other than cancer were excluded. Categorical variables were summarized as frequencies (percentages) and continuous variables were reported as median with range. Wilcoxon signed rank test was used to compare continuous variables between groups and Chi-squared or Fisher’s exact test was used to compare categorical variables. All tests were two-sided with p value < 0.05 considered statistically significant. The analysis was done using R program version 3.6.2. Results: Among 201 patients, 79 had breast cancer, 91 had a hematologic malignancy, 6 had other solid malignancies, and 25 had no history of cancer. All breast cancer patients on endocrine therapy or trastuzumab ± pertuzumab without chemotherapy (n=35) had anti-S Ab titer ≥ 500 U/mL. Patients on cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) appeared to have low level of anti-S Ab with 28.6% (n=4/14) had anti-S Ab titer ≤ 500 U/mL. Patients on chemotherapy also had low levels of anti-S Ab with 47% (n=14/30) having anti-S Ab titers ≤ 500 U/mL. When combining breast cancer patients on endocrine therapy alone or anti-HER2 therapy with patients without history of cancer as an immunocompetent group, there was significantly greater proportion of immunocompetent patients (97%) who had anti-S Ab titer ≥ 500 U/mL compared with only 8% of patients with hematologic malignancy and 55% of patients with solid malignancy on chemotherapy or CDK4/6i (p < 0.001). Using multivariate logistic regression analysis adjusted for age, gender, and vaccine type, patients with solid malignancies and treatment-related cytopenia, including chemotherapy and CDK4/6i, (OR 35.51 [95%CI 8.38-255.25, p < 0.001]) were more likely than immunocompetent patients to have a suboptimal anti-S Ab results ≤ 500 U/mL.Conclusion: A significant number of breast cancer patients on chemotherapies and CDK4/6i had poor humoral responses after SARS-CoV-2 mRNA vaccination. While CDK4/6i is not commonly considered as immunosuppressive therapy, breast cancer patients on CDK4/6i appeared to have suboptimal response to SARS-CoV-2 mRNA vaccine. Our study also highlights the significance of assessing antibody response after COVID-19 vaccines in these vulnerable patients. Citation Format: Saranya Chumsri, Pooja P. Advani, Tanmayi S Pai, Zhou Li, Marites Acampora, Gina A Reynolds, Alvaro Moreno-Aspitia, Christopher P Marquez, Keith L. Knutson. Antibody responses after SARS-CoV-2 mRNA vaccination in breast cancer patients [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 P3-23-01.

Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical 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 OT2-24-03.

Background: Cyclin dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in HR+ MBC, but progression of disease ultimately occurs. Apart from HR+ status, there are no clinically available biomarkers that enable oncologists to determine prognosis and predict response to CDK4/6i. An emerging biomarker is serum thymidine kinase 1 (TK1), a secreted marker of proliferation that is prognostic in pts with HR+ HER2- MBC. High levels of TKa are associated with inferior PFS, whereas pts with low TKa levels pretreatment, or TKa levels that decrease on ET and a CDK4/6i, have superior PFS. Notably, TKa levels rebound ≥ 5 days off Pb, with resumption of cell cycling. PROMISE (NCT0281902) is a prospective study that enrolled women with HR+ MBC starting Pb + letrozole (L) in the 1st line [FL] or Pb + fulvestrant in the 2nd line [SL] setting. The trial includes a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify novel genomic variants and pathways associated with an early decline in TKa (measured after 2 months or end of cycle [C]2) and PFS. Here, we report the association between i) pre-treatment TKa (pre-TKa) levels and PFS (i.e. from registration to the 1st disease event) and ii) TKa levels at the end of C2 (C2-TKa) and PFS-2 (i.e. from the start of C3 to the 1st disease event).Methods: TKa testing was performed using the DiviTum assay (Biovica). TKa+ disease was defined as ≥ 200 Du/L and TKa- disease as below limit of detection to 200 Du/L. Log-rank test and univariate Cox modeling were used to assess the association between pre-TKa levels and PFS and between end of C2-TKa levels and PFS-2. The database was locked on June 28, 2021. Results: Of 68 pts enrolled, 4 were ineligible and pre-TKa data was unavailable for 4. Of the remaining 60 pts (45 FL, 15 SL), the percentage of pts with pre-TKa+ disease was 33.3% in FL (15/45, 95% CI: 20.0-49.0%), and 46.7% (7/15, 95% CI: 21.4-71.9%) in the SL. The median follow-up time for pts on study was 24 months (range: 2-42 months). There were 22 disease events (13 in FL, 9 in SL). In the FL setting, PFS was significantly shorter for preTKa+ pts compared to preTKa- pts (HR: 4.15, 95% CI:1.35-12.74; p=0.007), but not for SL pts (HR: 1.11, 95% CI: 0.30-4.18, p=0.875). End of C2 TKa data was obtained for pts while on Pb (n=5), or after stopping Pb as follows: 1-4 days (n=9), 5-8 days (n=28) and 9-36 days (n=11). PFS-2 was not associated with C2-TKa in the FL (p=0.834) or SL (p=0.454) settings. An analysis of TKa levels by metastatic site will be presented at the meeting.Conclusions: A secreted biomarker of proliferation (TK1) obtained prior to initiating CDK4/6i and ET for the treatment of HR+ MBC is associated with PFS in pts receiving 1st line Pb + L, but not in those receiving 2nd line Pb + fulvestrant. While the end of C2 TKa levels were not associated with PFS, the interpretability of these data are limited, given treatment delays (0-36 days) prior to starting C3 that may result in TKa rebound. Future studies evaluating the predictive nature of TKa and Pb response should focus on earlier timepoints while on drug. Citation Format: Ciara C O'Sullivan, Jun He, Jason Sinnwell, Vera J Suman, Krishna R Kalari, Peter T Vedell, Ann M Moyer, Xiaojia Tang, Kevin J Thompson, Abe Eyman Casey, Alvaro Moreno-Aspitia, Donald W Northfelt, Minetta C Liu, Tufia C Haddad, Saranya Chumsri, Brendan McMenomy, Prema Peethambaram, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Mattias Bergqvist, Adrian Nordmark, Richard M Weinshilboum, Liewei Wang, Matthew P Goetz. Serum thymidine kinase 1 activity (TKa) levels and progression-free survival (PFS) in patients (pts) with hormone receptor positive (HR+) HER2-negative metastatic breast cancer (MBC) on palbociclib (Pb) and endocrine therapy (ET) [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 P5-13-22.

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Purpose:Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown.Experimental Design:A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated.Results:In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45–0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33–0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years.Conclusions:Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.

Purpose: To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central Cancer Treatment Group metastatic breast cancer (MBC) trials in which specimens were shipped (at 4°C) from community-based sites to a reference laboratory (Mayo Clinic, Rochester, MN).Experimental Design: Blood was collected at treating sites from MBC patients before (baseline), during, and at the end of treatment with erlotinib + gemcitabine (N0234), sorafenib (N0336), irinotecan + cetuximab (N0436), or paclitaxel-poliglumex + capecitabine (N0437). CTCs from 10 mL of EDTA blood were enriched with CD45 depletion, 24 to 30 hours postblood collection. Reverse transcription/quantitative PCR was used to determine cytokeratin-19 (CK19) and mammaglobin (MGB1) mRNA levels in CTCs from up to 13 (N0234), 16 (N0336), 18 (N0436), and 39 (N0437) patients. The gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2–ΔΔCq algorithm; positivity was defined as 2 or more.Results:CK19+mRNA cells were detected in 56% to 75% and MGB1+mRNA cells in 23% to 38% of 86 patients at baseline. CK19+mRNA cells were detected in 30% to 67% and MGB1+mRNA cells in 14% to 64% of 110 postbaseline serial samples. The presence of baseline CK19+mRNA cells (P = 0.01) but not MGB1+mRNA cells (P = 0.14) was significantly associated with shorter overall survival. A decrease in MGB1+mRNA levels (baseline-week 8) seemed to be associated with clinical response (P = 0.05).Conclusions: CTC gene expression analysis conducted by a reference laboratory is feasible when blood is collected from treating sites and processed 24 to 30 hours postcollection. The presence of baseline CK19+mRNA CTCs was associated with poor prognosis; a decrease in MGB1+mRNA CTCs may help predict response to therapy of MBC patients. Clin Cancer Res; 17(22); 7183–93. ©2011 AACR.

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). Response to NAC is prognostic, with reductions in low overall survival and disease-free survival rates in those patients who do not achieve pathological complete response (pCR). Based on this premise, we focused on patients with residual disease and hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence.Methods and Results: We investigated 24 TNBC tumors from 12 patients with pre- and post-NAC data, including four patients who recurred shortly after surgery( 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and non-recurrent TNBC tumors; however, post-NAC samples demonstrated a significant alteration in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the paired NAC I-SPY1 trial confirmed 56 genesets. Underlying these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n=392) breast cancer data set with relapse-free survival (RFS) data was used to refine our gene list to a 17 gene signature. A three-fold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine learning models. Due to the limited studies with pre-and post-NAC TNBC tumor data, further validation of the signature is needed.Conclusion: Analysis of multi-omics data from post-NAC TNBC chemoresistant tumors showed downregulation of mismatch repair, purin, and tubulin pathways. Additionally, we identified a 17 gene signature in TNBC associated with post-NAC recurrence enriched with down-regulation of immune genes.

Background: Cyclin dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in hormone-receptor (HR)-positive metastatic breast cancer (MBC), but progression of disease is inevitable. Serum thymidine kinase-1 (TK1) is a secreted marker of proliferation that is prognostic in patients (pts) with HR-positive, HER2-negative MBC and may be predictive of ET and CDK 4/6i response. PROMISE (NCT0281902) is a prospective study enrolling women with HR-positive MBC starting palbociclib (Pb) + letrozole (L) (1st line) or Pb + fulvestrant (2nd line). We undertook a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome in order to identify novel genomic variants and pathways associated with an early decline in TK1 (measured after 2 months) and PFS. Additionally, patient derived xenografts/organoids were generated at baseline and progression to test new therapeutic approaches to overcome resistance to CDK4/6i and ET. We report the initial association between the baseline genomic landscape and baseline TK1 levels. Methods: FFPE tumor biopsies were obtained for DNA/RNA sequencing (TempusTM) and blood samples for TK1 (Divitum® assay, Biovica) were collected pretreatment (pre-Pb) and after 2 cycles of Pb + ET (post-Pb2). Both whole-exome (exome capture) sequencing (WES) and RNA-Seq used the Integrated DNA Technologies xGen Exome Research Panel v1.0 capture kit. TK1+ disease was defined as > 200 Du/L and TK1- disease as below limit of detection up to 200 Du/L. We tested the association between genomic and transcriptomic characteristics with baseline TK1 data in pretreatment samples where both WES and RNA-seq and TK1 was available. The data were analyzed using bioinformatics pipelines for somatic and germline mutations and copy number alterations. The current analysis focuses on baseline 1st-line pre-Pb omics data in conjunction with baseline TK1 levels. The database was locked for analysis on 5/29/2020. Results: Thirty-three pts (median age: 59 yrs.) were evaluable, with paired samples for TK1 in 32. Six pts had TK1+ disease pre-Pb and post-Pb2. Twenty-two pts had TK1- disease pre-Pb and post-Pb2. Four pts had a decrease in TK1 after 2 cycles of treatment that altered the classification from TK1+ to TK1-. Both baseline RNA seq and serum TK1 (n=16) were available for 4 TK1+ and 12 TK1- pts. In this group, 476 genes were differentially regulated (398 upregulated; 78 downregulated). Pathway analysis demonstrated enrichment in complement and coagulation cascade pathway, PPAR signaling pathway, and metabolism-related pathways related to up-regulation of CYP and UGT gene families. Further testing for the association of WES data with baseline TK1+ (n=8) and TK1- (n=16) disease demonstrated somatic copy number variations on chromosomes 6, 11, 12 and 15. CDK4 copy number gains were observed in 3/8 TK1+ pts and 0/16 TK1- pts. We also observed that somatic mutations (LOH, copy number and/or SNV/INDELs) were more prevalent in the TK1+ compared to the TK1- pre-Pb group in several cancer-associated genes (FAS [p=0.06] PTEN, PIK3CB, NAB2, SOX9 and FAT1 [p=0.08], TP53, and MAP2K4 [p=0.22]). Conversely, we also noted that 6/7 pts with GATA3 mutations had TK1- disease (p=0.23). Conclusions: Using a comprehensive “omics” approach, our data suggest that a secreted biomarker of proliferation (TK1) obtained prior to initiating CDK4/6i and ET for the first line treatment of HR+ MBC is associated with established and novel genes and pathways associated with prognosis of pts receiving ET and CDK 4/6i. Analysis of on-treatment (after 2 cycles) tumor RNA seq and its association with change in TK1 as well as data from the 2nd-line cohort will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Abraham D Eyman Casey, Jason Sinnwell, Xiaojia Tang, Kevin Thompson, Alvaro Moreno-Aspitia, Donald W Northfelt, Minetta C Liu, Tufia C Haddad, Saranya Chumsri, Prema Peethambaram, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Adrian Nordmark, Mattias Bergqvist, Brendan P McMenomy, Richard M Weinshilboum, Liewei Wang, Matthew P Goetz. Novel genomic variants and pathways associated with baseline serum thymidine kinase 1 levels in HR-positive HER2-negative MBC patients commencing palbociclib and letrozole [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-24.

Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-09.

Background: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. Methods: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, 2; normal weight, 18.5 to 2; overweight, ≥25 to 2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. Results: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04–1.50) and OS (aHR, 1.27; 95% CI, 1.01–1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97–1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05–1.71), DDFS (aHR, 1.46; 95% CI, 1.07–1.98), and OS (aHR, 1.83; 95% CI, 1.18–2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. Conclusions: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

Background: Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. Methods: We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Findings: Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p Interpretation: Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics.

BACKGROUND: Beta-2 adrenergic receptor (ß2AR) modulates immune activation and may enhance trastuzumab activity. We assessed the impact of ß2AR gene (ADRB2) expression on the outcomes of patients with HER2-positive early-stage breast cancer enrolled on the NCCTG-N9831 trial. PATIENTS AND METHODS: This is a post-hoc analysis of the NCCTG-N9831 trial, which compared chemotherapy (arm A) versus chemotherapy plus trastuzumab (arms B&C) as adjuvant treatment of patients with HER2-positive early-stage breast cancer, with disease-free survival (DFS) as primary endpoint. Gene expression levels retrieved by DASL assay were used to classify patients as ADRB2-high or ADRB2-low. Hazard ratios (HRs) were calculated by a Cox proportional model adjusted for prognostic variables and ADRB2 expression. Correlations between ADRB2 expression and stromal tumor-infiltrating lymphocyte (TIL) levels were assessed with Pearson coefficient. A multivariable Cox regression model with interaction term was performed to assess the interaction between ADRB2 expression and treatment arm; and ADRB2 expression and a 8-gene signature previously shown to predict trastuzumab benefit. RESULTS: Overall, 1,282 patients were included (ADRB2-high [N = 944] / ADRB2-low [N = 338]). A high expression of ADRB2 was associated with a longer DFS (P = .01) in the overall population. The addition of trastuzumab to chemotherapy improved DFS only in patients with ADRB2-high tumors (P < .01). ADRB2 expression was correlated with TIL levels (r = 0.24, P < .001). No association between ADRB2 expression and the 8-gene trastuzumab benefit signature was observed (P = .32). CONCLUSION: Our findings suggest that a high ADRB2 expression is a favorable prognostic factor and may identify patients with HER2-positive early-stage breast cancer who benefit from adjuvant trastuzumab. TRIAL REGISTRATION: clinicaltrials.gov NCT00005970. ispartof: CLINICAL BREAST CANCER vol:22 issue:4 pages:308-318 ispartof: location:United States status: published

Triple negative breast cancer (TNBC) patients who fail to achieve a pathological complete response to neoadjuvant chemotherapy (NAC) will likely experience recurrence of the disease within 3-4 years. Prognostic assessment of early recurrence could facilitate clinical decisions and impact disease survival. This study investigated pre- and post-NAC multi-omics data from both an in-house and a public clinical study to identify biomarkers of NAC response. We observed significant transcriptional differences associated with response in the residual disease (post-NAC biopsies), which did not exist in the pre-NAC biopsies. We further refined the post-NAC transcriptional changes to a 17-gene signature and machine learning models were applied to evaluate the signature’s diagnostic potential (area under the curve ≥ 0.8). Interestingly, the signature was enriched with down-regulated immune genes and several of these genes demonstrated prognostic potential in basal TNBC tumors. Our 17-gene signature provides additional insight into TNBC recurrence, which warrants further investigation.

Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours.The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis.A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%).With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial.Clinicaltrials.gov identifier NCT00490139.

Background There are few treatment options for patients with leptomeningeal metastases (LM). Methods We report a case series of patients with breast cancer and LM treated with intra‐CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4‐5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment. Results Thirty‐one women [median age, 58 (37‐81); median KPS 60 (40‐100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3‐71); median duration of treatment, 11 weeks (1‐176); and median OS, 6.9 months (range, 0.9‐48.8). Patients remaining progression‐free during 4‐6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8‐48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4‐34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts). Conclusions Intra‐CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS., In this case series, intra‐CSF topotecan treatment of women with leptomeningeal metastases and breast cancer was associated with durable CSF clearing of malignant cells in 48% of patients, median OS of 6.9 months, and 11.5 months in those completing 4‐6 weeks induction. Thirty‐two percentage of patients remained free of neurologic progression at 12 months. A method for treatment of patients with VP shunts and programmable valves is also described.

PURPOSE Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900 ) are reported. PATIENTS AND METHODS Eligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

BACKGROUND: The addition of lapatinib (L) to trastuzumab (T) was previously found to be synergistic in preclinical models and in the neoadjuvant setting. Prior to the results of the ALTTO trial, this study assessed the safety and feasibility of adding L to the standard adjuvant docetaxel, carboplatin and trastuzumab (TCH) regimen in early stage HER2-positive breast cancer (HER2+ BC). METHODS: In this single-arm, 2-stage, phase II study, patients with stages I–III HER2+ BC received TCH plus L at 1000 mg daily for a total of 12 months. The primary endpoint was the safety and tolerability, including the rate of diarrhea. Secondary endpoints included adverse event (AE) profile using the NCI CTCAE v3.0 and cardiac safety. RESULTS: Thirty eligible patients were enrolled. Median follow-up is 5.3 years. Diarrhea was the most common AE with 50% Grade (G)1/2 and 43% G3 diarrhea. However, it was responsive to dose reduction of L (750 mg) and institution of anti-diarrheal medications. Cardiovascular AE were infrequent and no patients experienced congestive heart failure while on treatment. CONCLUSION: TCHL was a tolerable regimen at a starting L dose of 750 mg PO daily when given concurrently with chemotherapy.

Background: The combination of cyclin dependent 4/6 kinase inhibitors (CDK4/6i) with endocrine therapy (ET) has resulted in clinically significant improvements in progression-free survival (PFS) and overall survival (OS) in hormone-receptor (HR)-positive metastatic breast cancer (MBC). However, most patients’ disease ultimately progresses on CDK4/6i and ET. Therefore, further research is necessary to understand the mechanisms driving primary and secondary resistance. PROMISE is a multicenter prospective cohort study enrolling women with HR-positive MBC commencing treatment with palbociclib + letrozole (1st line) or palbociclib + fulvestrant (2nd Line). The study provides a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify molecular or cellular features associated with primary endocrine resistance (e.g. disease progression ≤ 12 months on treatment) and acquired resistance to CDK 4/6i. Additionally, patient derived xenografts and organoids are created to test new drug strategies designed to overcome resistance to CDK 4/6i and ET. Here, we present initial sequencing results from pretreatment biospecimens collected from PROMISE study participants. Methods: On-study tumor biopsies and blood samples were collected for DNA/RNA sequencing (TempusTM). The analyzed biospecimens were all obtained prior to initiation of palbociclib and ET. We correlated patient clinical characteristics (phenotypes) with molecular data and responses to protocol treatment. The data were analyzed using a series of cutting-edge bioinformatics pipelines for somatic and germline mutations in addition to copy number alterations (CNAs). The study database was locked for analysis on 06/20/2019. Results: We analyzed the somatic single nucleotide variants/INDELs (sSNV/INDEL) profiles across the tumor samples to determine the genes that were least likely to occur as a result of background mutation processes. Twenty-six patients had somatic copy number alterations (sCNA) and/or sSNV/INDEL in at least one of 18 genes with the most significant sSNV/INDEL profiles (p < 0.03) which included clinically and biologically relevant genes. The genes with the most statistically significant sSNV/INDEL mutation profiles were GATA3, PIK3CA, CDH1, and ESR1 (p < 0.0009). We observed a high percentage of tumors with somatic alterations in GATA3 (23% sSNV/INDEL, 15% sCNA), PIK3CA (38%, 12%), CDH1 (19%, 50%) and ESR1 (19%, 58%). ESR1 mutations were more frequent in patients receiving 2nd line treatment. Other frequently altered genes included TP53 (15%, 46%), MAP2K4 (8%, 50%), DNAAF1 (8%, 50%), and CDKN1B (8%, 35%). Further, ZNF317 and F3 were altered in 9 and 7 patients, respectively. Twenty-four samples had alterations in at least one of the CDK4/6 pathway genes (RB1, CCNE2, CCND1, CDK6, ESR1, CDKN2A, CCND3, CDK4, CDK2 and CCNE1). Four patients progressed on therapy; three of the four patients had mutations in PIK3CA, and one had a mutation in ESR1. Results of the RNA sequencing data (N=26) will be presented at the SABCS meeting. Conclusions: This is the first report of a prospective study designed to characterize the genomic landscape of ER+/HER2- MBC prior to palbociclib treatment. We observed high frequencies of known targetable alterations in PIK3CA and ESR1, including in patients that progress, which is consistent with previous reports. RNA sequencing data will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Erin Carlson, Jason Sinnwell, Tejaswi Alaparthi, Xiaojia Tang, Kevin Thompson, Jaeyun Sung, Alvaro Moreno-Aspitia, Donald Northfelt, Minetta C Liu, Tufia C Haddad, Prema Peethambaram, Saranya Chumsri, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Paula Gill, Mohammad Ranginwala, Asad Javed, Sameer Batoo, Brendan P. McMenomy, Richard Weinshilboum, Liewei Wang, Matthew P Goetz. Comprehensive tumor sequencing to identify biomarkers of palbociclib response: First report of the PROMISE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-07.

Background: Cardiac toxicity (CT) in the form of left ventricular systolic dysfunction is a well-known complication of anti-HER2 therapy. Prior clinical trial data has suggested potential factors associated with increased risk for CT. We sought to develop a clinical risk prediction model from real world patients to better identify patients who may be at higher risk for CT. Methods: Patients treated with anti-HER2 agents at all Mayo Clinic sites from Jan 2008 to July 2015 were reviewed. Patient data including age, race, body mass index, comorbidities, smoking history, baseline ejection fraction (EF), presence of left ventricular hypertrophy (LVH), prior cancer treatments, number of anti-HER2 agents used, and cardiac medication use were recorded. Factors were compared in patients with and without development of CT. Cox regression models were used to identify univariate and multivariate predictors of CT. A risk score was then assigned based on the final multivariable model. Results: 604 patients were included in final analysis. Median follow-up 2.9 yrs; median age: 57 yr; baseline EF: 64%. One yr CT rate was 7%. Independent predictors of CT were age, baseline EF, LVH, and anthracycline use (C index=0.74). Based on model coefficient, scores of 1, 1, 2 and 3 were assigned to age>55, EF Table 1. Multivariable Cox regression model predicting cardiac dysfunctionParameterParameter EstimateHR (95%CI)p valueScoreAge >550.909552.48(1.27, 4.84)0.00751EF Citation Format: Pooja P Advani, Lauren Cornell, Zhuo Li, Jordan Ray, Catalina Sanchez, Armando Villanueva, Taryn Smith, Alvaro Moreno-Aspitia. A validated clinical risk prediction model for cardiac toxicity in patients treated with antiHER2 agents [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-14.

Background: Previous studies demonstrated that activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Further in vivo study showed that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors (ICIs). Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were treated with pembrolizumab 200 mg every 3 weeks plus an oral MEK inhibitor binimetinib. Treatment was started with a 2-week run-in period with single-agent binimetinib. There were 2 dose levels in phase I, including dose level 0 (DL 0) with binimetinib at 45 mg orally twice daily continuously and dose level -1 (DL -1) at 30 mg twice daily. A standard 3+3 design was used in phase I to identify the recommended phase II dose (RP2D) and Simon’s two-stage Optimal design was used in phase II. Results: A total of 22 patients were enrolled. The median age was 58 years old (range 37-77). 14 (63.6%) patients had no prior systemic therapy in the metastatic setting and 8 (36.4%) patients had 1-2 prior lines of therapy. There were 4 patients treated in DL 0. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0 with grade 3 ALT abnormality in one patient and grade 3 flank pain together with grade 3 nausea and vomiting > 48 hours despite anti-emetic therapy in the other patient. Binimetinib dose was reduced to DL -1. In the next 6 patients, there was 1 DLT observed with grade 3 AST/ALT abnormality. Thus, DL -1 was the RP2D, and an additional 12 patients were treated with DL -1 in phase II. Overall, 18 patients were treated in DL -1 and were included in phase II efficacy evaluation. 17 patients were evaluable for response. Objective responses were observed in 5 patients (29.41% 55.96) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR) was 35.29% (95% CI: 14.21 - 61.67) with 6 out of 17 having had CR, PR, or stable disease >= 24 weeks. Since previous studies showed poor responses to ICIs in patients with liver metastases due to macrophage-mediated T cell elimination, we further conduct exploratory analysis to evaluate responses among patients with and without liver metastases. Among all 5 patients with liver metastases, no response was observed. The objective response rate (ORR) in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51), when excluding 3 patients who discontinued treatment due to adverse events prior to follow-up scans. Median progression-free survival in DL 0 was 2.4 (95%CI: 0.5-NE) and in DL -1 was 8.3 (95% CI: 3.9-NE) months. Median overall survival in DL 0 was 7 (95%CI: 0.5-NE) and in DL -1 was 33.2 (95% CI: 10.3-NE) months. Among patients who responded, 3 out of 5 (60%) had a duration of response greater than 12 months and ongoing even after stopping treatment (range: 5.4 - 32.0 months). Adverse events (AEs) were mostly grade 1-2 including anemia, CPK increase, fatigue, diarrhea, nausea, peripheral neuropathy, acneiform rash, AST increase, cardiac troponin increase, and constipation. Additional correlative studies are ongoing and will be presented at the meeting. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe with manageable toxicities. Promising activity with durable responses was observed with this combination without chemotherapy, particularly in patients without liver metastases. Future studies are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Kathleen S. Tenner, Jun He, Mei-Yin Polley, Morgan T. weidner, Amanda N. Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith A. Perez, Keith L. Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-17.

Alpelisib is a PIK3a inhibitor approved for the treatment of metastatic ER+ breast cancer in combination with fulvestrant. Although rash is a common side effect of this medication, we present the first case of drug reaction with eosinophilia and systemic symptoms (DRESS) upon initial exposure to alpelisib. Here we describe the clinical-pathological findings and management of our patient with alpelisib-induced life-threatening DRESS syndrome. The goal of this case report is to highlight association of alpelisib with DRESS syndrome, in clinical practice, so that alpelisib can be immediately stopped and treatment for this serious condition promptly initiated.

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.

OBJECTIVE. The purpose of this study is to prospectively compare the size of invasive breast cancer before and after neoadjuvant chemotherapy (NAC) at breast MRI and molecular breast imaging (MBI) and to assess the accuracy of post-NAC MBI and MRI relative to pathologic analysis. SUBJECTS AND METHODS. Women with invasive breast cancer greater than or equal to 1.5 cm were enrolled to compare the longest dimension before and after NAC at MRI and MBI. MBI was performed on a dual-detector cadmium zinc telluride system after administration of 6.5 mCi (240 MBq) 99mTc-sestamibi. The accuracy of MRI and MBI in assessing residual disease (invasive disease or ductal carcinoma in situ) was determined relative to pathologic examination. RESULTS. The longest dimension at MRI was within 1.0 cm of that at MBI in 72.3% of cases before NAC and 70.1% of cases after NAC. The difference between the longest dimension at imaging after NAC and pathologic tumor size was within 1 cm for 58.7% of breast MRI cases and 59.6% of MBI cases. Ninety patients underwent both MRI and MBI after NAC. In the 56 patients with invasive residual disease, 10 (17.9%) cases were negative at MRI and 23 (41.1%) cases were negative at MBI. In the 34 patients with breast pathologic complete response, there was enhancement in 10 cases (29.4%) at MRI and uptake in six cases (17.6%) at MBI. Sensitivity, specificity, positive predictive value, and negative predictive value after NAC were 82.8%, 69.4%, 81.4%, and 71.4%, respectively, for MRI and 58.9%, 82.4%, 84.6%, and 54.9%, respectively, for MBI. CONCLUSION. Breast MRI and MBI showed similar disease extent before NAC. MBI may be an alternative to breast MRI in patients with a contraindication to breast MRI. Neither modality showed sufficient accuracy after NAC in predicting breast pathologic complete response to obviate tissue diagnosis to assess for residual invasive disease. Defining the extent of residual disease compared with pathologic evaluation was also limited after NAC for both breast MRI and MBI.