High-risk Early Breast Cancer Research Articles

Abstract P3-07-23: Defendor Special: Primary empegfilgrastim prophylaxis (prolonged G-CSF) for optimal treatment outcomes in high risk early breast cancer cohort. The interim analysis

Abstract BACKGROUND Relative dose intensity (RDI) of chemotherapy (CT) < 85% significantly decrease therapy efficiency (including overall survival) in early breast cancer (BC) patients (pts). Pathological complete response (pCR) reflects better outcomes and correlates with the RDI of neoadjuvant CT (NAC). Neutropenia is the most common AE leading to RDI drop. Recent studies are demonstrate that G-CSF could switch immunosuppressive tumor microenvironment via neutrophils plasticity. In early BC neutrophils, can mediated antitumor responses by direct killing of tumor cells and by participating in cellular networks that mediate antitumor resistance. Primary G-CSF prophylaxis (PP) with prolonged G-CSF may be an option for optimal therapy results. This multicenter prospective study was designed to evaluate the RDI and treatment outcomes of cytotoxic therapy under PP by empegfilgrastim (E) in pts with high-risk early BC. METHODS High-risk BC pts (n=195) with II-III stages are getting NAC of the following regimens: 4 dose dense doxorubucin/cyclophosphamide with E followed by 12 weekly paclitaxel/carboplatin (4ddAC+E/12P+carbo) for triple negative (TN) pts or 4 dose dense doxorubucin/cyclophosphamide with E followed by 4 dose dense paclitaxel with E (4ddAC+E/4ddP+E) for HR+HER2- pts and 6 docetaxel/carboplatin trastuzumab/pertuzumab (TCHP+E) for HER2+ pts. RDI of therapy course was primary endpoint and presented here for pts who completed the planned regimen. For each agent, the planned and actual dose intensity were calculated by dividing the total cumulative dose by treatment duration in days. RDI was calculated for each single agent in CT regimen and for CT regimen in total. These descriptive analyses were performed for the whole CT regimen. The secondary endpoint: pCR (ypT0/is, ypN0) is also presented here. ClinicalTrials.gov No NCT04905329. RESULTS At the data cut-off (April’2022) 111 pts with BC (HER2+ (n=56); HR+ HER2- (n=17); TN (n=38)) underwent ≥ 1 cycle of NAC with E. The planned CT course completed in 67 (60%) BC pts. RDI≥85% were fixed in 56 (84%) pts: 93% RDI for 4ddAC+E/4ddP+E regimen; 90,3% RDI for 6TCHP+E; 94,1% RDI for 4ddAC+E/12P+carbo. Preliminary, in HER2+ BC pts pCR rate exceeds KRISTINE trial data despite a more enriched pts’ population with poor prognosis (36% pts with IIIB - III C and 65% pts with IIA-IIIA stages per TNM v.8): 93,3% (15 pts HR-) and 70,4% (34 pts HR+). In TNBC pts pCR rate is 56% (9 pts) according to historical control. In HR+ HER2- BC – pCR rate is 20% (10/17 pts under surgery). Neutropenia as a reason of RDI drop was in 1 (0,9%) case in HER2+BC pt. The mature data are awaited. CONCLUSION PP with E allows to maintain RDI efficiently and safely in high-risk recurrence pts populations. High pCR rate under E in HER2+ BC pts focused on further confirmation with translational research. KEY WORDS: empegfilgrastim, neutropenia, pCR, dose intensity, G-CSF, breast carcinoma, neoadjuvant therapy Citation Format: Irina Sorokina, Inna Ganshina, Tansuly Ibragimova, Irina Bondareva, Lyudmila Zhukova. Defendor Special: Primary empegfilgrastim prophylaxis (prolonged G-CSF) for optimal treatment outcomes in high risk early breast cancer cohort. The interim analysis. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-23.

Abstract OT2-18-02: OlympiaN: a phase 2, multicenter, open-label study to assess the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in patients with BRCA mutations and early-stage HER2-negative breast cancer

Abstract Background: In early breast cancer (BC), neoadjuvant therapy can promote de-escalation of surgery or treat micrometastases. Pathological complete response (pCR) is a standard primary endpoint in neoadjuvant BC studies, and correlates with long-term outcomes such as event-free survival (EFS). The poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib are approved in the metastatic setting for patients with BC and a germline BRCA1 and/or BRCA2 pathogenic/likely pathogenic mutation (gBRCAm). Following the phase 3 OlympiA trial primary analysis (data cut-off [DCO] Mar 2020), the PARP inhibitor olaparib was FDA approved for the adjuvant treatment of patients with gBRCAm and HER2-negative, high-risk early BC who have been treated with neoadjuvant/adjuvant chemotherapy. At the second pre-specified OlympiA analysis (DCO Jul 2021), olaparib treatment sustained improvements in invasive disease-free survival (IDFS HR 0.63, 95% CI 0.50–0.78) and distant disease-free survival (DDFS HR 0.61, 95% CI 0.48–0.77), and also significantly reduced the risk of death (overall survival [OS] HR 0.68, 98.5% CI 0.47–0.97) vs placebo. PARP inhibitors have also shown efficacy in the neoadjuvant setting in smaller studies. Durvalumab, a programmed death-ligand 1 inhibitor, has been studied as neoadjuvant therapy in triple negative BC and showed improved IDFS, DDFS and OS vs placebo (GeparNuevo). For BRCAm carriers at low risk of recurrence, olaparib monotherapy may provide adequate neoadjuvant treatment, allowing de-escalation or omission of chemotherapy. For those at high risk of recurrence, it is hypothesized that addition of the immune checkpoint inhibitor durvalumab will enhance immunogenicity provided through cell death following PARP inhibition. Feasibility for a larger study will be assessed. Methods: OlympiaN is a phase 2, international, multicenter, open-label trial examining the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in adults with deleterious/suspected deleterious BRCAm and operable, early-stage, HER2-negative, ER-negative or ER-low BC (immunohistochemistry nuclear staining < 10%). Patients will be enrolled in two cohorts: (A) patients at lower risk of recurrence: tumor size >5 to < 20 mm and nodal status N0 will receive olaparib 300 mg orally twice daily continuously in 28-day cycles; (B) patients at higher risk of recurrence: tumor size >20 to ≤50 mm and N0, or T1 and N1 will receive olaparib 300 mg orally twice daily continuously in 28-day cycles plus durvalumab 1500 mg IV infusion every four weeks. After four to six cycles, patients will undergo definitive surgery, then systemic and radiation therapy in accordance with local standard of care. Patients who achieve pCR at surgery will be able to receive adjuvant olaparib monotherapy in lieu of standard adjuvant systemic therapy for a total of twelve 28-day cycles of neoadjuvant and adjuvant olaparib therapy. The primary endpoint is the pCR rate after completion of neoadjuvant systemic therapy, assessed by central pathology review. Secondary endpoints include the pCR rate assessed by local pathology review, residual cancer burden, tumor volumetric analysis, EFS, safety and tolerability. Tumor tissue will be collected pre-treatment and at surgery to evaluate the mechanism of action of therapy. Baseline and longitudinal assessment of ctDNA and its association with clinical outcomes will also be performed. The primary pCR analysis will occur ~6 months after last participant enrollment; the final DCO will be 3 years after last participant dosed or once all participants have had an EFS event. No formal statistical analyses are planned, data will be summarized descriptively. Enrollment is planned to commence by late 2022, across ~65 sites in 10 countries; the target accrual is ~25 patients per cohort to ensure adequate precision in the estimated pCR rate. Funding: This study is funded by AstraZeneca UK Plc. Citation Format: Judith Balmaña, Mike Dymond, Elizabeth S. Lowe, Natalia Lukashchuk, Maria Winter, Nadine Tung. OlympiaN: a phase 2, multicenter, open-label study to assess the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in patients with BRCA mutations and early-stage HER2-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 OT2-18-02.

Abstract P3-03-12: Risk of recurrence with adjuvant endocrine therapy in real world patients with hormone receptor positive/human epidermal growth factor receptor-negative early breast cancer: a US database analysis

Abstract Background The recommended 5-10 years of adjuvant endocrine therapy (ET) as standard of care has improved outcomes in patients with HR+/HER2− early breast cancer (EBC); however, risk of recurrence persists. The monarchE study demonstrated improvement in invasive disease-free survival (iDFS) with abemaciclib in node-positive, high-risk EBC, the majority of which were stage III (Johnston SRD, et al. J Clin Oncol. 2021;38:3987); however, monarchE’s relatively short follow-up time to date only allowed for observation of early recurrences—longer follow-up is needed to evaluate late recurrences. Risk of recurrence is a concern for patients with all stages of EBC (Pan H, et al. N Engl J Med. 2017;377:1836). We assessed the risk of recurrence in a real-world setting among patients with stage II-III HR+/HER2− EBC after initiation of adjuvant ET. Methods This was a retrospective analysis of ConcertAI’s deidentified electronic medical records data set among patients treated from January 1, 1995, to April 30, 2021. The cohort included stage II-III patients with HR+/HER2− EBC who underwent surgery and initiated adjuvant ET (if IIIB or IIIC, confirmation was required on residual tumor status). Patients were from academic and community oncology clinics across the US. Data were missing from the database for some variables; thus, percentages may not add up to 100%. iDFS was assessed to determine the risk of disease recurrence, death, or second primary tumor and was defined as the time interval between start of ET and first iDFS event. Kaplan-Meier methods were used to estimate cumulative probabilities of experiencing an iDFS event at 5 and 10 years from the start of ET. Results A total of 3133 patients (98.8% female) with stage II-III HR+/HER2− EBC were included in the analysis. The median follow-up time was 68.1 months. The median age was 59 years; 22.2% of female patients were pre/perimenopausal and 44.7% were postmenopausal; 80.9% of all patients had stage II disease, while 19.1% had stage III disease. In total, 42.1% and 3.7% of those with stage II and III disease had no nodal involvement, respectively. Overall, 51.2% of patients did not receive radiotherapy, and 59.5% of patients did not receive (neo)adjuvant chemotherapy. In the total sample, the 5- and 10-year risk of an iDFS event was 26.1% and 45.0%, respectively. In patients with stage II disease, the 5- and 10-year risks were 22.7% and 40.5%, respectively, and 40.4% and 62.9% among stage III. Conclusions These real-world data demonstrate that the risk of recurrence with adjuvant ET, particularly in those with stage II EBC, is higher than reported in many randomized controlled trials. Importantly, our data show that, in the real-world setting, the stage II population represents a significant proportion of patients (nearly 4 times more than stage III). These findings confirm and underscore the clear unmet need in this population and highlight the need for improved treatment options in this broader EBC population. The NATALEE study will investigate ribociclib + ET in a broad population of patients including stage II and stage III HR+/HER2− EBC with high-risk features, regardless of nodal status. Citation Format: Joyce O’Shaughnessy, Denise Yardley, Lowell Hart, Pedram Razavi, Stephanie L. Graff, Jenifer Wogen, Courtney McDermott, Pierre-Alexandre Dionne, Sina Haftchenary, Purnima Pathak, Sara Tolaney. Risk of recurrence with adjuvant endocrine therapy in real world patients with hormone receptor positive/human epidermal growth factor receptor-negative early breast cancer: a US database analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-12.

Impact of the 21-Gene Assay in Patients with High-Clinical Risk ER-Positive and HER2-Negative Early Breast Cancer: Results of the KARMA Dx Study

The 21-gene Oncotype DX Breast Recurrence Score® assay is prognostic and predictive of chemotherapy benefit for patients with estrogen receptor-positive, HER2- early breast cancer (EBC). The KARMA Dx study evaluated the impact of the Recurrence Score® results (RS) on the treatment decision for patients with EBC and high-risk clinicopathological characteristics for whom chemotherapy (CT) was considered. Eligible patients with EBC were candidates for the study if CT was considered standard recommendation by local guidelines. Three high-risk EBC cohorts were predefined: (A) pT1-2, pN0/N1mi, and grade 3; (B) pT1-2, pN1, and grades 1-2; and (C) neoadjuvant cT2-3, cN0, and Ki67 ≤ 30%. Treatment recommendations before and after 21-gene testing were registered, as well as treatment received and physicians' confidence levels in their final recommendations. A total of 219 consecutive patients were included from eight Spanish centers: 30 in cohort A, 158 in cohort B, and 31 in cohort C. Ten patients were excluded from the final analysis as CT was not initially recommended. After 21-gene testing, treatment decisions changed from CT + endocrine therapy (ET) to ET alone for 67% of the whole group. In total, 30% (95% confidence interval [CI] 15% to 49%), 73% (95% CI 65% to 80%), and 76% (95% CI 56% to 90%) of patients ultimately received ET alone in cohorts A, B, and C, respectively. Physicians' confidence in their final recommendations increased in 34% of cases. Use of the 21-gene test resulted in an overall 67% reduction in CT recommendation in patients considered candidates for CT. Our findings indicate the substantial potential of the 21-gene test to guide CT recommendations in patients with EBC considered to be at high risk of recurrence based on clinicopathological parameters, regardless of nodal status or treatment setting.

Cost-Effectiveness of Abemaciclib in Early Breast Cancer Patients: One Size Fits All or Tailoring to Patients' Needs?

The addition of two years of abemaciclib treatment to standard adjuvant endocrine therapy in all patients with high risk ER+, HER2- early breast cancer (EBC) has been approved by the US Food and Drug Administration (FDA). Pre-selection of patients with an immediate risk of recurrence within the group of clinically high risk patients using detection of minimal residual disease (MRD) using patient-informed circulating tumor DNA assays during follow-up could enhance efficacy. Here, we investigate the cost-effectiveness of the addition of two years abemaciclib in all high risk HR+, HER2- patients and in MRD-guided high risk patients only. Two semi-Markov models were developed to evaluate the cost-effectiveness of adding two years of abemaciclib compared to "standard treatment": 1) "abemaciclib all" and 2) "MRD-guided abemaciclib" using MRD-guidance. Data of the MonarchE trial were used to model the invasive disease-free survival (iDFS). Since iDFS and overall survival (OS) data of abemaciclib were currently limited, abemaciclib effects were extrapolated using a favorable, intermediate and unfavorable effect scenario. The addition of abemaciclib in all high-risk EBC patients prolonged iDFS slightly (0.04 additional quality adjusted life years (QALYs)) and led to higher costs compared to standard ET, leading to a high incremental cost effectiveness ratio (ICER) of €1,551,876/QALY. Neither the favorable effect scenario (additional 1.09 QALYs) was cost-effective (ICER €62,935/QALY), using a willingness-to-pay threshold of €50,000/QALY. The "MRD-guided abemaciclib" strategy resulted in lower costs and an increase in QALYs (1.27) compared to "standard treatment" in the unfavorable effect scenario. The addition of abemaciclib to adjuvant endocrine therapy in all high-risk ER+, HER2- EBC patients is not cost-effective. However, using MRD detection to justify the addition of abemaciclib treatment dominates standard treatment in this cost-effectiveness analysis. Further evaluation of MRD detection in EBC by means of prospective clinical trials assessing clinical utility is recommended and promising in terms of cost-effectiveness.

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study.

Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2years). DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.

Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients. We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE. Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial

Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up. In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing. Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37-47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578-0·762, nominal p<0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2-87·3] in the abemaciclib plus endocrine therapy group vs 79·4% [77·5-81·1] in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748-1·153; p=0·50). The most common grade 3-4 adverse events were neutropenia (in 548 [19·6%] of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of 2800 patients in the endocrine therapy alone group), leukopenia (318 [11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six [0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group. Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients. Eli Lilly.

COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy

COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer.

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be "salvaged" through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies.

3MO Patient-reported outcomes (PROs) of Chinese patients (pts) in monarchE: Abemaciclib plus endocrine therapy (ET) in adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (EBC)

Adjuvant abemaciclib (CDK4 & 6 inhibitor) plus ET demonstrated clinically meaningful improvement in invasive disease-free survival among Chinese pts with HR+, HER2-, node-positive, high-risk EBC in the monarchE phase III study. Here, we present data on PROs of Chinese pts at primary outcome analysis.

Highly accurate response prediction in high-risk early breast cancer patients using a biophysical simulation platform

PurposePathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) is largely dependent on breast cancer subtype, but no clinical-grade model exists to predict response and guide selection of treatment. A biophysical simulation of response to NAC has the potential to address this unmet need.MethodsWe conducted a retrospective evaluation of a biophysical simulation model as a predictor of pCR. Patients who received standard NAC at the University of Chicago for EBC between January 1st, 2010 and March 31st, 2020 were included. Response was predicted using baseline breast MRI, clinicopathologic features, and treatment regimen by investigators who were blinded to patient outcomes.ResultsA total of 144 tumors from 141 patients were included; 59 were triple-negative, 49 HER2-positive, and 36 hormone-receptor positive/HER2 negative. Lymph node disease was present in half of patients, and most were treated with an anthracycline-based regimen (58.3%). Sensitivity and specificity of the biophysical simulation for pCR were 88.0% (95% confidence interval [CI] 75.7 – 95.5) and 89.4% (95% CI 81.3 – 94.8), respectively, with robust results regardless of subtype. In patients with predicted pCR, 5-year event-free survival was 98%, versus 79% with predicted residual disease (log-rank p = 0.01, HR 4.57, 95% CI 1.36 – 15.34). At a median follow-up of 5.4 years, no patients with predicted pCR experienced disease recurrence.ConclusionA biophysical simulation model accurately predicts pCR and long-term outcomes from baseline MRI and clinical data, and is a promising tool to guide escalation/de-escalation of NAC.

A network survey and local cohort study of high-risk early breast cancer regional nodal irradiation (RNI)

A network survey and local cohort study of high-risk early breast cancer regional nodal irradiation (RNI)

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis-Results from the Adjuvant SUCCESS A Trial.

Simple SummaryDue to recent advances in breast cancer detection and treatment strategies, the number of breast cancer survivors has increased over the past decades. However, breast cancer follow-up guidelines have not changed for years. The presence of CTCs detected during follow-up has been shown to indicate poor prognosis in high-risk breast cancer patients. Here, we evaluated if the presence of CTCs also indicates the site of metastatic disease by analyzing CTC status and metastatic location in 206 patients with distant recurrence from the large adjuvant breast cancer trial SUCCESS A. Patients who were CTC-positive both before and after chemotherapy were more likely to show bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs. These data indicate that CTCs might serve as a liquid biopsy surveillance-marker enabling risk-stratification for deciding on further adjuvant add-on-treatment.The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1–827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1–124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.

Two Instrument Comparison of Reagents From a US FDA-Approved Assay for the Assessment of Ki-67 in High-Risk Early Breast Cancer.

The objective of this study was to measure concordance of results obtained from the US Food and Drug Administration–approved Ki-67 immunohistochemistry MIB-1 pharmDx assay performed on the Dako Omnis automated staining instrument (Omnis) versus results produced from the assay reagents applied using an optimized protocol on the more widely available Autostainer Link 48 (ASL48) platform. Tissue sections obtained from 40 formalin-fixed paraffin-embedded breast carcinoma samples, with available Oncotype DX Breast Recurrence Score (RS) results, were stained. Three certified pathologists scored slides at 3 timepoints, totaling 360 observations for each instrument (N=720 total) using the approved scoring approach. Using the ≥20% cutoff, agreement was calculated with corresponding 2-sided 95% percentile bootstrap confidence intervals (CIs). Pairwise comparisons (N=360) from the interinstrument evaluation, performed with all observers, resulted in 325 (90.3%) concordant outcomes (244 negative and 81 positive) and 35 (9.7%) discordant outcomes. The overall agreement was 90.3% (95% confidence interval, 85.6% to 94.4%). No significant systematic differences were observed between instruments. Specimens scored from the Omnis were on average <1% higher than ASL48, with high correlation and little bias between the continuous Ki-67 scores (concordance correlation coefficient=0.916). Most specimens with a Ki-67 score ≥20% had a RS >25. This study demonstrated that good concordance can be achieved with the reagents run on the ASL48 instrument when using an optimized protocol and standardized scoring.

New Adjuvant Treatment for High-Risk Early Breast Cancer.

Olaparib (Lynparza) is now approved for the adjuvant treatment of adult patients who have, or are suspected to have, the germline variation of BRCA-mutated human epidermal growth factor receptor 2-negative high-risk early breast cancer and who were previously treated with neoadjuvant or adjuvant chemotherapy.

EE183 Cost-Effectiveness Analysis of Early Versus Delayed Use of Abemaciclib Combination Treatment in Patients with HR+/HER2- High-Risk Early Breast Cancer: A US Payer Perspective

Clinical guidelines recommend use of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, in combination with endocrine therapy (ET) as adjuvant treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (EBC) at high risk of recurrence or in combination with fulvestrant if patients develop metastatic breast cancer (MBC). We evaluated the cost-effectiveness of early use of abemaciclib and ET combination as first-line adjuvant therapy and then use of fulvestrant after developing MBC (early use) versus ET treatment in EBC followed by delayed use of combination abemaciclib and fulvestrant in MBC (delayed use).

Adjuvant abemaciclib for high-risk early breast cancer (EBC): Factors increasing the rate of treatment discontinuations in monarchE.

527 Background: Adjuvant abemaciclib plus endocrine therapy (ET) demonstrated clinically meaningful improvement in reducing the risk of recurrence in patients (pts) with HR+, HER2– high risk EBC. In monarchE, 25.6% pts discontinued abemaciclib before completing the 2-year treatment period due to reasons other than recurrence. This exploratory analysis evaluates the impact of baseline factors on time to discontinuation for abemaciclib-treated patients with an aim to identify pts at higher risk of discontinuation. Methods: Time to discontinuation(TTD) was defined as time from first dose to the discontinuation of abemaciclib or all treatment due to reasons other than recurrence. These exploratory analyses evaluated the association between TTD and baseline demographics, disease characteristics, and the extent of pre-existing medical comorbidities. Factors with p-value &lt;0.05 in the univariate Cox model were considered as potentially associated with TTD and then fitted into a multivariate Cox model with stepwise variable selection, with entry and retaining p-value threshold of 0.05. Discontinuation rates at selected timepoints (6-month, 12-month, 18-month, 24-month) within each subgroup were estimated using the Kaplan-Meier method. Results: The following variables were significantly associated with higher risk of discontinuation in the multivariate model: Age ≥65 yr, enrolled in North America or EU, ECOG PS=1, post-menopausal, 1-3 positive nodes, or 4 or more pre-existing comorbidities. The majority of discontinuations occurred within the first 6 months of the treatment period; thus, this timepoint was selected to estimate discontinuation rates for factors independently associated with TTD (Table). Complete results on discontinuation rates at other timepoints will be reported in the presentation. Conclusions: This exploratory analysis identified several factors associated with a greater risk of discontinuation. These results illustrate the importance of close monitoring and dose adjustments early on, particularly for patients with an increased risk of discontinuation prior to completing the 2-yr treatment period of abemaciclib. Clinical trial information: NCT03155997. [Table: see text]

The ImPrint immune signature to identify patients with high-risk early breast cancer who may benefit from PD1 checkpoint inhibition in I-SPY2.

514 Background: The remarkable increase of novel Immuno-Oncology drugs in many malignancies has led to the need for biomarkers to identify who would benefit. Various predictive biomarkers have been developed (PD-1/PD-L1 expression, mutations in mismatch repair genes and microsatellite instability, tumor mutational burden and immune infiltration), none have consistently predicted efficacy. The I-SPY2 consortium qualified several expression-based immune biology related signatures that predict response to PD1 checkpoint inhibition. Here we assessed whole transcriptome data of high-risk early-breast cancer (EBC) patients who received Pembrolizumab within the neoadjuvant biomarker-rich I-SPY2 trial (NCT01042379), aiming to migrate the I-SPY2 research findings to a robust clinical grade platform signature to predict sensitivity to PD1 checkpoint inhibition. Methods: Whole transcriptome microarray data were available from pre-treatment biopsies of 69 HER2- patients enrolled in the Pembrolizumab (4 cycles) arm of the I-SPY2 trial. All patients had a High-Risk 70-gene MammaPrint profile. Pathologic complete response (pCR) was defined as no residual invasive cancer in breast or nodes at the time of surgery. Of the 69 patients, 31 had a pCR (12 HR (hormonal receptor)+HER2-, 19 Triple Negative (TN)), while 38 (28 HR+HER2-, 10 TN) had residual disease (RD). To identify the most predictive genes associated with pCR, gene selection was performed comparing pCR and RD groups by iteratively splitting the dataset in training and test, balancing for HR status. Due to limited sample size, leave one out cross validation was used for performance assessment. Genes with effect size &gt; 0.45 were considered significant. Results: A signature of 53 genes, named ImPrint, was identified with overall sensitivity and specificity &gt; 90% and &gt; 80% for predicting pCR to pembrolizumab in all patients. Sensitivity and specificity in TN were &gt; 95% and ≥70%, and in HR+HER2- &gt; 80% and &gt; 85%, respectively. The Positive Predictive Value (PPV) is 77% for the HR+HER2- subgroup. Biological annotation of the 53 genes showed that over 90% of the genes have known immune system related functions, of which 63% were previously known to be involved in immune response (including genes coding PD-L1 and PD-1, as well as those identified in I-SPY2). Conclusions: In the signature development phase, ImPrint predicts pCR to Pembrolizumab in a set of 69 high risk EBC with high sensitivity and specificity. The signature features genes with immune-related functions known to be involved in immune response indicating that it might aid identifying patients with an immune-active phenotype. Importantly, ImPrint appears effective in identifying a subset of HR+HER2- patients who could benefit from immunotherapy. External validation in independent dataset(s) is ongoing and will be presented at the time of the meeting.

Predictive value of ectopic HORMAD1 tumor expression for high-dose platinum-based chemotherapy benefit in patients with high-risk HER2-negative breast cancer.

541 Background: The meiotic DNA break regulator HORMAD1 is aberrantly expressed in many cancers and is associated with increased genomic instability. The susceptibility of HORMAD1 expressing tumors to agents targeting DNA damage repair (DDR) pathways is poorly understood since clinical data within the context of a randomized clinical trial (RCT) is lacking. Here, we retrospectively studied HORMAD1 expression as a putative predictive biomarker in an RCT for benefit of adjuvant high-dose platinum-based chemotherapy (HDCT) with autologous stem cell support in patients with high-risk HER2-negative early breast cancer (BC). Methods: Patients with stage III BC participated in an RCT comparing HDCT to conventional chemotherapy (CDCT; Rodenhuis et all, NEJM, 2003; Steenbruggen et all, JAMA Oncol, 2020). We studied the subgroup with HER2-negative BC for whom tumor BRCA1-like classification was previously determined using a validated DNA comparative genomic hybridization algorithm (Vollebergh et all, BCR, 2014). Tumor HORMAD1 expression was determined on FFPE samples using RNAscope, an RNA in situ hybridization method, and classified as negative (no expression) or positive (any expression detected). Results: For 195/246 (79.3%) HER2-negative patients treated according to protocol, HORMAD1 RNAscope status was available; dropout was due to absence or insufficient quality of tumor specimens. HORMAD1 positivity was enriched in triple-negative breast cancer (TNBC) (23/47; 48.9%). Furthermore, in all HER2-negative BCs, HORMAD1 positivity (45/195; 23.1%) was associated with age ≤40 years, histological grade III, &lt;10 positive lymph nodes, breast-conserving surgery, BRCA1-like profile, and tumor-infiltrating lymphocytes (TILs) &gt;10%. Such association, although not significant, was also observed within TNBC. During a median follow-up of 20.3 years, 124 (63.6%) recurrences and 115 deaths (59.0%) occurred. The prognostic effect of HORMAD1 positivity on overall survival (OS) varied with follow-up time and was borderline significant at 10 years and significant thereafter (10-year: adjusted (adj.) HR 0.47, 95% CI 0.21-1.04; 15-year: adj. HR 0.25, 95% CI 0.07-0.91). Benefit on RFS from HDCT over CDCT was stronger in patients with HORMAD1-positive tumors (adj. HR 0.18, 95% CI 0.06-0.54) than in patients with HORMAD1-negative tumors (adj. HR 0.69, 95% CI 0.46-1.02) (P-interaction = 0.02). Similar results were observed for OS. Conclusions: In this retrospective sub study of 195 patients with high-risk HER2-negative BC participating in an RCT, tumor HORMAD1 expression is predictive for benefit of high-dose platinum-based chemotherapy. Our observations are consistent with the prior observations that HORMAD1 expression is associated with genomic instability and impaired DDR pathways. Further research is warranted to validate our findings. Clinical trial information: NCT03087409.