Citations

Abstract Background: Retrospective studies suggest that breast cancer survivors report treatment-associated hair loss or thinning years after their initial diagnosis. This study investigates patient perceptions of alopecia persisting 6 years after the diagnosis of breast cancer. Methods: Breast cancer survivors who had signed informed consent for participation in a prospective longitudinal cohort study, the Mayo Clinic Breast Disease Registry (MCBDR), after diagnosis of breast cancer approximately six years prior, were mailed a survey. This survey asked about degree of bother from hair thinning and hair loss on a scale from 0 “not at all” to 4 “extremely” and about use of hair thickening/regrowth products. PROMIS-10 project scales assessed global mental health (5: worst mental health, 20: best mental health). Data were analyzed using descriptive statistics. Results: 969/1476 participants responded (response rate 65.7%); 819 participants were available for analysis. Participant median age was 65.7 years (range 34 -100 years). 604 (73%) had been diagnosed with stage I-II breast cancer, 248 (30%) had received chemotherapy (+/- endocrine therapy), 365 (45%) had received only endocrine therapy, and 206 (25%) had received neither. Nearly half (381, 47%) reported hair loss and over half (468, 57%) reported hair thinning. 155 (19%) used hair regrowth products. Amongst the 526 who were 55 years and older, 270 (51%) reported hair loss and 323 (61%) hair thinning; 111 (38%) of the 291 women under 55 years reported hair loss and 145 (50%) hair thinning. Twenty-eight percent of chemotherapy recipients, 18% of patients who did not receive chemotherapy but received endocrine therapy, and 14% of patients who had received neither reported continued difficulty with moderate to extreme hair loss. Moderate to extreme bother from hair thinning was reported by 34% of chemotherapy recipients, 22% of endocrine therapy-only recipients, and 18% of those who had received neither. See the table for associations between mental health scores and hair loss/thinning. Use of hair growth products was reported by 29% of chemotherapy recipients, 14% of endocrine therapy-only recipients, and 15% of those who had received neither oncologic therapy. Conclusions: Hair loss and thinning are frequently reported as persistently bothersome symptoms from breast cancer survivors. Future investigations into the incidence, predictors, and treatment of chemotherapy and endocrine therapy-associated alopecia are needed. Global mental health scores on PROMIS scale for hair loss and hair thinning Citation Format: Sarah Premji, Kathryn Ruddy, Nicole Larson, Charles Loprinzi, Brittany Dulmage, Maryam Lustberg, Fergus Couch, Janet Olson, Elizabeth Cathcart-Rake. Delayed alopecia among breast cancer survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-09.

Abstract Artificial intelligence (AI) models applied to mammography have been shown to improve breast cancer (BC) detection and risk estimation. The Transpara AI detection system has been associated with short and longer-term risk of invasive BC. Whether Transpara can identify changes in the breast associated with tamoxifen (TAM) and aromatase inhibitor (AIs) treatment is unknown. We compare changes in the Transpara malignancy score in the unaffected breast of BC cases using TAM or AIs to those of untreated women without cancer. Cases and controls were sampled from the Mayo Clinic Rochester Breast Screening Practice. Eligible cases were women with breast cancer treated with TAM and/or AIs for at least 8 months who had full field digital (FFDM) mammograms within two years prior to start of treatment (pretreatment mammogram). Controls did not have BC, were not using TAM, AIs, or postmenopausal hormones, and had at least two FFDM screening mammograms. Transpara scores (1-10) were calculated for the contralateral breast in cases and a randomly selected side for controls. Two controls were matched to each case on menopausal status at both mammograms, time between mammograms (< 6 months) and baseline Transpara score (±2 units). Conditional logistic regression was used to assess the association of treatment (case (TAM/AIs) vs. control) with change in Transpara score between the pretreatment mammogram and the mammogram taken closest to 13 months later. Change was classified as having a decrease in Transpara score between the two mammograms vs. no change or an increase. Models were adjusted for age and Transpara score at pretreatment mammogram, and time between the two mammograms. We performed analyses on all women combined and stratified by time on treatment, menopausal status, and treatment type (TAM vs. AIs). A total of 134 cases were identified, with 53 on TAM (21 premenopausal and 32 postmenopausal) and 81 on AIs (postmenopausal); 268 controls were matched to the cases. Characteristics of the study population are summarized (Table). Most case mammograms were obtained within six months prior to treatment start [median 2.63 months (interquartile range (IQR), 1.62, 5.72)] and median time on TAM/AIs was 10.9 months (IQR, 8.03, 16.6) at time of second mammogram. The median absolute change in Transpara score between the two mammograms was similar in cases [0 (IQR, -2, 1)] vs. controls [0 (IQR, -1.25, 1)]; 40.3% of cases and 39.2% of controls had any decrease. Conditional logistic models found no evidence for an association between TAM/AIs and decrease in Transpara score [odds ratio (OR) = 1.07; 95% confidence interval (CI), 0.65, 1.78]. When stratified by median time on treatment (10.9 months), there was suggestion of a stronger association for those on treatment for a longer duration (OR = 1.21; 95% CI, 0.61, 2.40 for >10.9 months vs. OR = 0.96; 95% CI, 0.43, 2.13 for < 10.9 months) but these results were not statistically significant. Similarly, odds ratios were stronger in postmenopausal (OR = 1.18; 95% CI, 0.67, 2.07) compared to premenopausal (OR = 0.91; 95% CI, 0.24, 3.45) women, and for AIs (OR = 1.21, 95% CI, 0.64, 2.29) vs. TAM (OR = 0.93; 95% CI, 0.39, 2.22) but none of these results reached statistical significance. In summary, we found no association between treatment with TAM/AIs and change in Transpara score. However, our study had limited power. Also, longer time on treatment as well as investigation of AI-based scores trained directly to assess BC risk may be necessary to identify relevant changes. Citation Format: Yvonne Wang, Christopher Scott, Matthew Jensen, Dan Hursh, Kathleen Brandt, Aaron Norman, Fang Fang Wu, Stacey Winham, Karla Kerlikowske, Celine Vachon. Changes in an artificial intelligence model score for breast cancer detection (Transpara) with tamoxifen and aromatase inhibitor treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-09-04.

Abstract BACKGROUND: The amplification of genes PDL-1, PDL-2, and JAK2 on chromosome 9p24, known as the PDJ amplicon, has been identified in 15% of triple negative breast cancer (TNBC) and is associated with tumor infiltrating lymphocytes and elevated JAK2 mRNA, suggesting a coordinated inflammatory response in TNBC. Adding pembrolizumab to chemotherapy in KEYNOTE trials 355 and 522 has validated the use of PD-1 blockade in TNBC and redefined the standard of care. Despite preclinical data suggesting a role for targeting the IL- 6/JAK2/STAT3 pathway, the JAK1/JAK2 inhibitor ruxolitinib has not shown efficacy as a single Agent in breast cancer. This is the first phase I clinical trial evaluating the combination of pembrolizumab and ruxolitinib in the treatment of metastatic TNBC. METHODS: We conducted a phase I clinical trial with accrual from 2018 to 2023 at Mayo Clinic Arizona. Patients (n=12) received 200 mg of IV pembrolizumab per cycle (every 3 weeks) with 3+3 dose escalation of oral ruxolitinib twice a day (dose level 0: 10 mg PO BID, level 1: 15 mg PO BID, level 2: 20 mg PO BID). The primary endpoint was to determine the maximum tolerated dose (MTD) of ruxolitinib and secondary endpoints were treatment safety and efficacy. Clinical response was assessed by computed tomography of the chest, abdomen, and pelvis every 3 cycles. PD-L1 expression in tumor was measured by immunohistochemistry (IHC). The effect of the combined therapies on T and B cell populations were assessed by flow cytometry and antibody profiling of 695 tumor antigens and 8 viral antigens by nucleic acid protein programmable array. RESULTS: Twelve female patients with chemotherapy refractory metastatic TNBC were treated on study. All received 200 mg IV pembrolizumab every cycle. Due to rapid disease progression of three patients early after treatment initiation, eligibility was restricted to prohibit patients with extensive pulmonary disease or elevated LDH. Those patients were excluded from efficacy or correlative analysis. The most common toxicities were transaminitis (n=12), anemia/leukopenia (n=12), and fatigue (n=9). The majority of adverse events were grade 1 and occurred at dose level 2. There were 5 adverse events grade 3 or higher: respiratory or thoracic complications (n=3), hypertension (n=1), and abdominal pain (n=1), but MTD was not established. The median number of cycles was 4 for each dose level (range n=2.0-9.0) and the median time to progression was 3 months (range n=1.4-6.3). No patient had tumor response by RECIST v1.1 criteria and there was no association of disease stability with PD-L1 tumor expression by IHC. Circulating antibodies to tumor antigens remained stable, and viral-specific antibodies mildly decreased by month 2 in all patients at dose levels 0 and 1. Of the 7 patients reactive to TRIM21 autoantibodies, 2 patients had a transient increase at 2 months. CONCLUSIONS: The combination of pembrolizumab with ruxolitinib was well tolerated at all dose levels, and the number but not the severity of adverse events increased with higher ruxolitinib dose. Two of six patients in dose level 0 and 1 had stable disease for six months on treatment, suggesting that the lower dose levels of ruxolitinib (i.e. 10 mg PO BID) may have more activity in combination with pembrolizumab. Citation Format: Anelia Kassi, Jacqueline Carmona, Sarah M. Green, Heidi Kosiorek, Michael T. Barrett, Barbara A. Pockaj, Donald Northfelt, Karen S. Anderson. Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-07.

Abstract Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (BC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene, an oral, next-generation ET and ER breast antagonist, had potent activity in mBC xenograft models expressing ESR1 mutations, either as a single agent or combined with a CDK4/6i. Subsequently, two phase 2 studies evaluated lasofoxifene in women with ER+/HER2- metastatic BC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 months; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with lasofoxifene monotherapy versus the ER degrader fulvestrant, with a favorable safety profile (Goetz MP, et al. Ann Oncol. 2022;33:S1387). The single-arm, ELAINE 2 trial demonstrated that lasofoxifene combined with abemaciclib was well tolerated with a median PFS of ~13 months, ORR of 56%, and CBR of 66% (Damodaran S, et al. J Clin Oncol. 2023;41:suppl 16; abstr 1057). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive lasofoxifene 5 mg/day plus abemaciclib 150 mg BID, or fulvestrant 500 mg IM on days 1, 15, and 29, then 4 weekly plus abemaciclib 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit for genomic analyses. Outcomes with lasofoxifene/abemaciclib and fulvestrant/abemaciclib will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites. Citation Format: Matthew Goetz, Seth Wander, Thomas Bachelot, Gerald Batist, Javier Cortés, Massimo Cristofanilli, Giuseppe Curigliano, Alexandre de Nonneville, Einav Nili-Gal Yam, Komal Jhaveri, Cynthia Ma, Heather Parsons, Hope Rugo, Sarah Sammons, Daniel Stover, Chris Twelves, Aditya Bardia, Paul V. Plourde, David J Portman, Senthil Damodaran. Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-12.

Abstract Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (< 11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to < 70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (07-07-2023) is 555 screened and 488 randomized (~96% of predicted accrual). Support: U10CA180868, -180822, UG1CA189867, UG1CA189867; Susan G. Komen Foundation (JRW). NCT: 04852887. Citation Format: Julia White, Reena Cecchini, Eleanor Harris, Eleftherios Mamounas, Daniel Stover, Patricia Ganz, Reshma Jagsi, Stewart Anderson, Carmen Bergom, Valérie Théberge, Mahmoud El-Tamer, Richard Zellars, Dean Shumway, Guang-Pei Chen, Thomas Julian, Norman Wolmark. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-02.

Abstract Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available for BRCA1/2 mutation carriers, and irreversible prophylactic mastectomy is the primary option. Designing chemo-preventive strategies requires an in-depth understanding of the physiological processes underlying tumor initiation. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells differs from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. These results reveal alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients. Citation Format: Mihriban Karaayvaz, Anthony Caputo, Kavya Vipparthi, Peter Bazeley, Erinn Downs-Kelly, Patrick McIntire, Ying Ni, Bo Hu, Ruth Keri. Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-04.

Abstract Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 (BRCA1/2) pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline PALB2 PV have not previously been described. This is of particular relevance as PALB2 BC has demonstrated biologic features similar to BRCA1/2 BC such as poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) sensitivity. Methods: Patients with early-stage, HR+, HER2-, invasive breast cancer and a germline PALB2 PV were ascertained from academic cancer center databases and the Prospective Registry of MultiPlex Testing (PROMPT), an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. Study participants (pts) were categorized by age < 50 and ≥50. Oncotype DX RS were retrospectively reviewed and categorized as those that would and would not warrant consideration of chemotherapy (≥16 and < 16, respectively, for pts < 50; ≥26 and < 26, respectively, for pts ≥50). Yates corrected Chi-square tests were used to compare RS distributions between carriers and a previously published genetically unselected reference population. Results: Oncotype DX reports were reviewed for 20 pts with BC and germline PALB2 PV. Median RS was 19 (range 6-41) overall. Four patients were diagnosed under the age of 50 (range 33-48); median RS for these individuals was 19 (range 12-41). Sixteen patients were diagnosed at age 50 or greater (median 59, range 50-70); median RS for these individuals was also 19 (range 6-31). Compared to the genetically unselected reference population, Oncotype DX RS in pts with PALB2-associated BC demonstrated a numerical but not statistically significant shift in distribution towards categories in which chemotherapy would be considered. Among pts under the age of 50, 75% had Oncotype DX RS for which chemotherapy would be considered and 25% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.726 compared to reference). Among pts aged 50 and older, 25% had Oncotype DX RS for which chemotherapy would be considered and 75% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.579 compared to reference). Conclusions: Compared to data from the published genetically unselected commercial database, BC associated with PALB2 PV may have higher Oncotype DX RS reflective of intrinsically less favorable biology and greater therapeutic sensitivity. Larger datasets are forthcoming to confirm presence of significant differences in Oncotype DX RS distributions between BC with and without PALB2 PV. Table 1. Oncotype DX RS distribution by age among pts with gPALB2 PV and genetically unselected reference *Jakubowski et al., J Surg Oncol 2020. PMID 3249731 Citation Format: Payal Shah, Siddhartha Yadav, Jamie Brower, Jada Hamilton, Erica Simmons, Judy Garber, Kenneth Offit, Mark Robson, Fergus Couch, Susan Domchek. Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-09-03.

Abstract Background The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. NEJM 2020, Curigliano et al. Ann Oncol 2022). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS, time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a two-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in Austria, Chile, Greece, Italy, Japan, Poland, Portugal, Spain, the US, and several other European, APAC, and LATAM countries. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara O'Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-11.

Abstract Rapid developments in cancer genetics and hereditary cancer risk assessments have enabled the identification of individuals at elevated risk for hereditary malignancies to guide enhanced cancer screening and prevention efforts. Multigene panel testing has emerged as the standard approach as emphasized in the National Comprehensive Cancer Network (NCCN) guidelines. The purpose of this study was to investigate the frequency of other pathogenic mutations identified through multigene panel testing in individuals who previously tested negative for germline BRCA1/2 and assess the clinical impact of panel testing. Patients either previously diagnosed with breast cancer or with a family history of breast or ovarian cancer that had also been seen by Oncology Genetics at a single institution and tested negative for BRCA1/2 genes but had not undergone prior multigene panel testing were invited via a letter to return for an additional genetic counseling visit to discuss multigene panel testing. Patients were also able to opt-in to a survey component of the study and received an email to fill out the Multidimensional Impact of Cancer Risk Assessment (MICRA) and Cancer Worry Scale (CWS). Surveys were completed prior to the initial genetic counseling appointment and repeated after discussion of the multigene panel test results. A total 24 women met with a genetic counselor of which 22 (92%) had a personal history of breast cancer, 1 (4%) had a family history of breast cancer, and 1 (4%) had a family history of ovarian cancer. The mean age was 52.6 years (range, 42-68) and 100% of women were Caucasian. Of the 24 women, 17 (71%) completed multigene panel testing. Of the women that underwent testing, 7 (41%) had negative results, 6 (35%) had variants of unknown significance (VUS), and 4 (24%) had a pathogenic mutation identified in another gene (CDKN2A, CHEK2, and CFTR). There was no significant change in MICRA or CWS scores after multigene panel results were reviewed in the 9 patients that completed both pre- and post-genetic testing surveys. The mean/median summary MICRA scores pre- and post-counselling were 30 (SD 12.4), median 26 (min 18, max 56), and 21.2 (SD 15.4), median 21 (min 3, max 43), respectively (p=0.19, Wilcoxon signed ranks test). The mean/median summary CWS scores pre- and post-counselling were 14.3 (SD 5), median 15 (min 7, max 24), and 13.6 (SD 2.59), median 14 (min 10, max 17), respectively (p=0.53, Wilcoxon signed ranks test). Of the 4 patients with newly identified pathogenic mutations, 2 started new screening protocols and 1 underwent a prophylactic mastectomy. In conclusion, multigene panel testing identified pathogenic mutations in a subset of individuals who previously tested negative for BRCA1/2 genes leading to changes in clinical management. The completion of multigene panel testing did not lead to a significant increase in MICRA or CWS scores. Key limitations of this study include a small sample size and an all Caucasian population. Citation Format: Devon Miller, Stephanie Pritzl, Angela Tess, Jessica Gooding, Lisa Barroilhet, Lori Dubenske, Kari Wisinski. Clinical Impact of Multigene Panel Testing in Patients with a Personal or Family History of Breast or Ovarian Cancer Previously Negative for BRCA1/2 Genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-03.

Abstract Background: Low levels of HER2 expression (HER2-low) have recently emerged as a therapeutic target in patients (pts) with breast cancer (BC). The aim of this study was to evaluate clinical and demographic variables associated with HER2 expression, as well as the value of HER2-low as a prognostic and predictive biomarker for palbociclib benefit in pts enrolled in the PALLAS trial. Methods: The phase III PALLAS trial investigated the addition of palbociclib to adjuvant endocrine therapy (ET) in pts with stage II-III hormone receptor-positive BC. The aims of this analysis are (1) to assess the association between the presence of low levels of HER2 expression with demographic and clinicopathological parameters, (2) to test the prognostic value of HER2-low status on invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) to assess the value of HER2 expression as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization; all pathologic evaluation was performed locally. Pts with HER2-0 and Her2-low BC were included in this analysis; those with HER2-positive BC or missing HER2 status were excluded. Association of HER2 with other baseline covariates were tested with Chi-squared tests. Prognostic and predictive power of HER2 were assessed with Cox Models. Multivariable models included age, T-stage, N-stage, grade and progesterone receptor (PR) expression. Hazard ratios (HR) and 95% Confidence intervals (CI) are reported. Results: From the original PALLAS intention-to-treat population (N = 5,753), 5304 pts (92.2%) were included in this analysis. Among these, 2,254 pts (42.5%) were classified as HER2 IHC 0 (HER2-0) and 3,050 (57.5%) as HER2-low (1,838 with IHC 1+ and 1,212 with IHC 2+). For this analysis, median follow-up was 59.8 months. Compared to HER2-0, pts with HER2-low tumors had statistically higher estrogen receptor expression levels (mean expression 89.2% vs 88.2%, p = 0.019), lower PR expression levels (65.9% vs 68.2%, p = 0.007). Importantly, HER2-low status varied significantly across 21 participating countries (range 16.7% to 75.6%; p< 0.001) and was more frequent in pts enrolled in North America (63.1%) than in Europe (53.4%) and other regions (53.4%) (p < 0.001). No differences in HER2 expression were observed according to anatomic stage, T-stage, N-stage, histological grade, age, menopausal status, primary surgery type, prior radiation, prior chemotherapy, or baseline performance status. There were no statistically significant differences in IDFS, DRFS or OS according to HER2 status in univariate or multivariable Cox models (prognostic value, HR provided in the Table). There was no significant interaction between the HER2 status and the benefit to palbociclib in IDFS, DRFS or OS (Table). Similar results were obtained when HER2-0 was compared to HER2 1+ and HER2 2+ separately. Conclusions: In this large, prospective and international cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib (predictive value) between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes. Support: AFT, Abbvie Pfizer; Clinicaltrials.gov: NCT02513394 https://acknowledgments.alliancefound.org Citation Format: Guilherme Nader-Marta, Christian F. Singer, Dominik Hlauschek, Angela DeMichele, Paolo Tarantino, Georg Pfeiler, Miguel Martín, Justin Balko, Zbigniew Nowecki, Marija Balic, Adam Brufsky, Arlene Chan, Patrick G. Morris, Tufia Haddad, Sibylle Loibl, Yuan Liu, Lidija Sölkner, Christian Fesl, Erica Mayer, Michael Gnant. Clinical characterization, prognostic and predictive values of HER2-low in early breast cancer in the PALLAS trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-13.