High-risk Early Breast Cancer Research Articles

Abemaciclib as adjuvant treatment for high-risk early breast cancer

ObjectiveTo adapt the GHEMA report of abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6. European Medicines Agency authorization (April 2022) includes, in combination with endocrine therapy, the adjuvant treatment of adult patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive, early breast cancer at high risk of recurrence. MethodThe efficacy and safety of abemaciclib were evaluated in a randomized, open-label, and multicenter phase III study. A total of 5637 patients diagnosed with early breast cancer with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive, and high risk of recurrence were included. High risk was defined as patients with 4 or more positive axillary lymph nodes, or 1–3 positive axillary lymph nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or Ki-67≥20%. Patients were randomized (1:1) to receive adjuvant abemaciclib+endocrine therapy (n = 2808) or endocrine therapy alone (n = 2829) for 2 years, with endocrine therapy prescribed for at least 5 years. ResultsWith a median follow-up of 15.5 months, abemaciclib+endocrine therapy demonstrated a statistically significant improvement in invasive disease-free survival versus endocrine therapy alone [HR = 0.747 (95% CI 0.598–0.932), P = 0.0096]; achieving an absolute improvement of 3.5% invasive disease-free survival rate at 2-years. These results were maintained, with a median follow-up of 27.7 months: absolute improvement of 2.7% and 5.4% in invasive disease-free survival rate at 2 and 3 years, respectively. All-causality grade 3 or 4 adverse events were 45.9% for abemaciclib and 12.9% for endocrine therapy, and included neutropenia (19.6% vs. 0.8%), leukopenia (11.4% vs. 0.4%), and diarrhea (7.8% vs. 0.2%). ConclusionsThe results of the pivotal trial are sufficient to consider abemaciclib as adjuvant treatment for high-risk early breast cancer in highly selected patients. However, in order to the efficacy results present less uncertainty, we must wait for a evaluation later, in which we can have a mature determination at 3 years (with more patients at risk).

Assessment of nuclear grade-based recurrence risk classification in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive high-risk early breast cancer

BackgroundHistological grade (HG) has been used in the MonrachE trial to select patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive high-risk early breast cancer (EBC). Although nuclear grade (NG) is widely used in Japan, it is still unclear whether replacing HG with NG can appropriately select high-risk patients.MethodsWe retrospectively reviewed 647 patients with HR-positive, HER2-negative, node-positive EBC and classified them into the following four groups: group 1: ≥ 4 positive axillary lymph nodes (pALNs) or 1–3 pALNs and either grade 3 of both grading systems or tumors ≥ 5 cm; group 2: 1–3 pALNs, grade < 3, tumor < 5 cm, and Ki-67 ≥ 20%; group 3: 1–3 pALNs, grade < 3, tumor < 5 cm, and Ki-67 < 20%; and group 4: group 2 or 3 by HG classification but group 1 by NG classification. We compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) among the four groups using the Kaplan–Meier method with the log-rank test.ResultsGroup 1 had a significantly worse 5-year IDFS and DRFS than groups 2 and 3 (IDFS 80.8% vs. 89.5%, P = 0.0319, 80.8% vs. 95.5%, P = 0.002; DRFS 85.2% vs. 95.3%, P = 0.0025, 85.2% vs. 98.4%, P < 0.001, respectively). Group 4 also had a significantly worse 5-year IDFS (78.0%) and DRFS (83.6%) than groups 2 and 3.ConclusionsNG was useful for stratifying the risk of recurrence in patients with HR-positive, HER2-negative, node-positive EBC and was the appropriate risk assessment for patient groups not considered high-risk by HG classification.

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases.

Bisphosphonates (BPs) are bone-protecting osteoclast inhibitors, typically used in the treatment of osteoporosis and skeletal complications of malignancies. When given in the adjuvant setting, these drugs may also prevent relapses and prolong overall survival in early breast cancer (EBC), specifically among postmenopausal patients. Because of these findings, adjuvant nitrogen-containing BPs (N-BPs), such as zoledronate (ZOL), are now the standard of care for high-risk EBC patients, but there are no benefit-associated biomarkers, and the efficacy remains low. BPs have been demonstrated to possess anti-tumor activities, but the mechanisms by which they provide the beneficial effects in EBC are not known. We used stably transfected 4T1 breast cancer cells together with suppression of CD73 (sh-CD73) or control cells (sh-NT). We compared ZOL effects on tumor growth and infiltrating lymphocytes (TILs) into tumors and lung metastases using two mouse models. B cell depletion was performed using anti-CD20 antibody. Sh-CD73 4T1 cells were significantly more sensitive to the growth inhibitory effects of n-BPs in vitro. However, while ZOL-induced growth inhibition was similar between the tumor groups in vivo, ZOL enhanced B and T lymphocyte infiltration into the orthotopic tumors with down-regulated CD73. A similar trend was detected in lung metastases. ZOL-induced tumor growth inhibition was found to be augmented with B cell depletion in sh-NT tumors, but not in sh-CD73 tumors. As an internal control, ZOL effects on bone were similar in mice bearing both tumor groups. Taken together, these results indicate that ZOL modifies TILs in breast cancer, both in primary tumors and metastases. Our results further demonstrate that B cells may counteract the growth inhibitory effects of ZOL. However, all ZOL-induced TIL effects may be influenced by immunomodulatory characteristics of the tumor.

Efficacy and safety results by age in monarchE: Adjuvant abemaciclib combined with endocrine therapy (ET) in patients with HR+, HER2-, node-positive, high-risk early breast cancer (EBC).

501 Background: Adjuvant abemaciclib (a CDK4 &amp; 6 inhibitor) combined with ET demonstrated a sustained benefit in invasive disease-free survival (IDFS) and a tolerable safety profile in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Almost half of the newly diagnosed breast cancers occur in women older than 65 years. Older pts often have a higher incidence of comorbidities and increased risk for toxicities. Here, we report efficacy and safety by age subgroups in monarchE to help guide management of older pts receiving adjuvant abemaciclib. Methods: Pts were randomized (1:1) to receive ET for up to 10 years +/- abemaciclib for 2 years (study treatment period). Efficacy in IDFS and distant relapse-free survival (DRFS) was assessed in the intent-to-treat population by the pre-specified age groups of &lt;65 and ≥65 years, with hazard ratios (HR) estimated using unstratified Cox proportional hazard model within each subgroup. Safety was evaluated among older pts (≥65 years) in two subgroups; 65-74 and ≥75 years. Results: In monarchE (NCT03155997), 4787 pts (84.9%) were aged &lt;65 years and 850 pts (15.1%) were ≥65 years. At median follow-up of 42 months, a numerically favorable IDFS effect was observed in both the &lt;65 (270 vs 414 events; HR = 0.646, 95% CI: 0.554, 0.753) and ≥65 (66 vs 85 events; HR = 0.767, 95% CI: 0.556, 1.059) groups for abemaciclib + ET vs ET alone. Similar findings were observed in DRFS. Older pts (≥65 years) had ~5% higher incidence of grade ≥3 adverse events (AEs) than younger pts, mainly diarrhea and fatigue. Neutropenia was not increased among older pts and similarly, venous thromboembolic events occurred at similar rates (≥65 years, 3.0%; &lt;65 years, 2.5%). Serious AEs (SAEs) and treatment discontinuations due to AEs were more common in older pts. Older pts required more dose reductions to manage AEs. Conclusions: In pts with high-risk EBC, adjuvant abemaciclib + ET showed treatment benefit across age subgroups with a manageable safety profile. Older pts did have higher rates of AEs and discontinuations, especially those older than 75 years, suggesting that more frequent surveillance with early intervention may be key to the management of these pts. Clinical trial information: NCT03155997 . [Table: see text]

Influence of hormone therapy timing intake on disease free survival (DFS) for patients with high-risk early breast cancer: Results of the UCBG-UNIRAD phase III randomized trial.

546 Background: Circadian rhythms regulate the cellular and molecular processes that determine treatment effects. Scarce data suggest that daily timing could influence endocrine therapy (ET) pharmacology. We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271) in patients (pts) with hormone receptors positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC). Methods: Between June 2013 and March 2020, 1,278 pts with high-risk HR+/HER2- primary BC were randomly assigned to adjuvant ET combined with EVE or placebo. Pts were stratified according to lymph node involvement, progesterone receptor status, ET (tamoxifen or aromatase inhibitors (AI)), prior neoadjuvant or adjuvant chemotherapy, and duration of ET before randomization. Throughout their participation in the trial, patients were asked to declare prospectively in a daily diary the timing of ET intake within four 6-h slots (06:00 to11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The prognostic impact of the timing of ET and EVE/placebo on DFS was a prespecified secondary endpoint. Results: A total of 855 patients (67%) recorded ET intake daily timings (n = 401 in the EVE arm, n = 454 in the placebo arm). Morning intake was preferred by 465 pts (54%), whilst 344 pts (40%) chose evening intake, and minor proportions took ET in the afternoon (49 patients, 5%) or at night (5 patients, 1%). Pts choosing morning or afternoon intake were significantly older than those preferring evening or night intakes (mean age: morning: 56.4 y.o.; afternoon: 58.4 y.o; evening: 53.1 y.o ; night : 50.8 y.o.; p &lt; 0.001). Only 10 patients (1.1%) reported changing ET timing during the study. With a median follow-up of 72.5 months, 118 patients relapsed (locally n = 30, metastases n = 84), and 41 patients died. In the whole population, ET intake timing was not associated with DFS (HR 0.77 [95%CI, 0.53-1.12], p = 0.17). ET intake timing effects according to the stratification factors revealed a significant interaction between its prognostic impact and ET agent (tamoxifen versus AI, p for interaction = 0.01). DFS was prolonged in those pts taking tamoxifen in the evening/night rather than in the morning/afternoon (HR = 0.43 [0.22 - 0.85], p = 0.015), while no such effect was found for those on AI (HR = 1.07 [0.68 - 1.7], p = 0.761). Such interaction remained statistically significant at multivariate analysis (HR 0.38, p = 0.003). Conclusions: Tamoxifen intake in the evening was associated with an improved DFS in high-risk HR+/HER2- breast cancer pts and could be recommended at no cost in the adjuvant setting. Clinical trial information: NCT01805271 .

Use of adjuvant bisphosphonate therapy in breast cancer by Indian oncologists: An implementation science study.

e13667 Background: Several clinical trials, expert consensus and guidelines have recommended the use of bisphosphonates (BP) in reducing the breast cancer recurrence risk in postmenopausal women. The 2019 St. Gallen Panel voted 83.7% in favour of the routine use of bisphosphonates in postmenopausal women. Similarly, the 2022 ASCO-Ontario Health guidelines for breast cancer supports the recommendation. However, the uptake of these recommendations in routine clinical practice is poorly studied. We aimed to investigate the use of adjuvant BP therapy by Indian oncologists (implementation science study). Methods: A cross sectional survey study design was used to investigate our research question. Physicians in India who treat patients with breast cancer were presented with a clinical vignette of a young woman with postmenopausal (induced) non-metastatic high risk hormone receptor-positive breast cancer. A snowball sampling strategy was employed to avoid sampling bias. Participants were requested to state their gender, primary qualification, practice setting, number of years of practice as an oncologist and proportion of patients with breast cancer in their practice. Instead of providing the option of BP therapy, we asked an open-ended question whether they would recommend any additional therapy other than surgery, radiation, chemotherapy and anti-estrogen therapy. We asked them to write in the name or class of drug if they would prescribe an additional therapy to the patient. Results: The survey was completed by 74 Oncologists. The response rate is unknown as a snowball sampling strategy was employed. Majority of the respondents were male (74%), were non-teaching private practitioners (42%), medical oncologists (62%) with up to 10 years of experience (65%), and breast cancer patients make up to 50% of their patients (84%). Most of the oncologists responded no to our question on additional therapy (76%). Of those who responded yes, only 8 suggested BP therapy (11%). Conclusions: Despite strong evidence and guidelines, adjuvant BP therapy in high-risk early breast cancer was only recommended by very few oncologists in our survey study. Steps to bridge this gap between academic research and clinical application is urgently warranted. Implementation of clinical guidelines has to be monitored routinely which may be facilitated by provider and patient surveys. This can also assist in identifying and addressing the concerns with newer recommendations.

Clinical and pathological description of patients with triple negative breast cancer undergoing neoadjuvant chemotherapy and pembrolizumab in a Brazilian cancer center.

e14632 Background: High-risk early triple-negative breast cancer (TNBC) is frequently associated with early recurrence and high mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). In TNBC, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials, in this last scenario the addition of pembrolizumab to platinum containing NACT resulted in a significant increase of pathological complete response. Methods: We performed a retrospective observational cohort study of patients with early TNBC, stage I-III who received neoadjuvant treatment with chemotherapy based on doxorubicin, cyclophosphamide, paclitaxel and carboplatin associated with pembrolizumab treaties from January 2022 to January 2023, in AC Camargo Cancer Center, São Paulo, Brazil, to evaluate their clinical-pathological characteristics. Results: All 52 patients were women, 60,4% premenopausal, with a median age of 42 years old when diagnosed, 59.6% had comorbidities, most commonly hypertension, and 1.9% had an autoimmune disease. About 16.7% germline mutation in the BRCA 1 and 8.3% in the BRCA 2 gene. Regarding pathological characteristics of the tumor, 98% were invasive ductal carcinoma, 78% with histological grade III, 89.8% had nuclear grade III, 51.1% with score 3 mitoses. There were 56,3% with weak, 35,4% with moderate, and 8,3% with intense Tumor Infiltrating Lymphocytes Stromal (TILS). In 47.1% of cases, the ki67 was greater than 80%. The expression of HER 2 was low in 23,8%. About the clinical stage of the tumor 65.4% were cT2 and 17.3% cT3, being cN0, cN1 and cN2a was 40.4%, 36.5% and 13.5%, respectively and grouped clinical stage 40.45 IIA, 25% IIB and 19.2% IIIA. Treatment-related toxicities 20% patients had immune related toxicities, being the main one 30% endocrinologic and 20% hepatic, being that 36.4% occurring after the second cycle. Due to the toxicities, 22.2% of the patients had their treatment delayed. In terms of treatment, 68.6% had begun with platinum and taxane, and 7.8% received dense dose AC (ACdd). Now, only 42.6% of the patients have completed all NACT and 53.2% are still on treatment. From these, 56.8% had complete clinical response, 2.3% stable disease and and those who have already finished and operated 66.7% complete pathological response. Conclusions: Our cohort is mostly pre-menopausal cT2, cN0, stage IIA. Twenty percent of them had IRT, the most common being endocrine and hepatic, which occurred early after the second cycle, leading to treatment delay in 22.2%. About 8% received ACdd, of the patients who completed the treatment and underwent surgery, 66.7% had a complete pathological response.

Real world treatment patterns and survival by germline BRCA (gBRCA) mutation status in patients with HER2-negative early breast cancer (eBC) in the US community oncology setting: A retrospective observational study.

e12535 Background: Germline BRCA mutations (gBRCAm) are associated with a higher risk of breast cancer at a younger age. Generally, gBRCA gene testing is performed in patients perceived as high risk for gBRCAm. Olaparib, a targeted poly (ADP-ribose) polymerase inhibitor (PARPi), has significantly improved overall survival (OS) in the randomized, double-blind OlympiA trial of patients with HER2-negative gBRCAm and was subsequently approved for the adjuvant treatment of patients with gBRCAm HER2-negative high-risk early breast cancer (eBC) treated with neoadjuvant or adjuvant chemotherapy. This study examines the real-world patient characteristics, treatment patterns and OS by gBRCA status among patients with HER2-negative eBC in a US community oncology setting prior to olaparib US approval for treatment of eBC. Methods: This retrospective observational study used structured data from The US Oncology Network's iKnowMed database. Adult patients were included if diagnosed with HER2-negative eBC (stage I-III) and if they initiated systemic neoadjuvant or adjuvant therapy between January 1, 2012-December 31, 2018 (followed through December 31, 2021). Patients were excluded if they progressed to stage IV within 6 months after neoadjuvant treatment or were diagnosed with another primary cancer. Descriptive analyses assessed patient characteristics, early-stage systemic treatments and OS among patients by gBRCA status. Results: Among 19,258 patients with BC meeting initial criteria, 1436 (7.5%) had a documented gBRCA test result. Among them, 10% had gBRCAm (n = 141, 43% hormone receptor positive [HR+], 57% triple-negative BC [TNBC]), 90% BRCAwt (n = 1294, 70% HR+, 30% TNBC), and 1 had a variant of uncertain significance. Median age at surgery was numerically lower in gBRCAm (43 years) than gBRCAwt (48 years) patients. Treatments included neoadjuvant-only therapy (gBRCAm 58%; gBRCAwt 34%), adjuvant-only therapy (gBRCAm 42%; gBRCAwt 66%) and both neoadjuvant and adjuvant therapy (gBRCAwt 0.1%). Median OS in both study cohorts was not reached. Median follow-up from surgery was less than 4 years (gBRCAm 47 months; gBRCAwt 46 months). At 48 months, estimated survival was 95% in gBRCAm and 94% in gBRCAwt patients. Conclusions: In this cohort of patients with HER2-negative eBC, among the 7.5% with a documented gBRCA result, 10% were identified with gBRCAm, reinforcing the need for gBRCA testing. Using structured real-world data through 2021 (prior to PARPi approval for eBC) with limited follow-up of &lt; 4 years, our study found that OS by gBRCA status was similar among patients with HER2-negative eBC. Our further research with chart review data containing granular clinical information looking at intermediate endpoints such as recurrence in eBC is under way.

Olaparib (Lynparza)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses Olaparib (Lynparza) 100 mg and 150 mg, oral tablets.&#x0D; Indication: For the adjuvant treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated human epidermal growth factor receptor 2-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Patients must have confirmation of a germline BRCA mutation before olaparib treatment is initiated.&#x0D;

107P Results in Chinese patients from pre-planned overall survival interim analysis in monarchE: Abemaciclib plus adjuvant endocrine therapy for high risk HR+, HER2- early breast cancer

Abemaciclib (oral CDK4 and 6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in Chinese patients (pts) with Hormone Receptor (HR+)-positive and human epidermal growth factor 2 (HER2)-negative high risk early breast cancer (EBC). This combination therapy provided sustained clinical benefits at the pre-planned overall survival interim analysis (OS IA2). Here we present the results of the subset of Chinese patients from monarchE at OS IA2. The overall study design was previously reported. Pts were randomized 1:1 to receive Abemaciclib + ET or ET alone. Eligible pts with ≥4 positive nodes, or 1-3 nodes and Grade 3 disease and/or tumor size ≥5 cm were included in Cohort 1 (C1); pts with 1-3 nodes and central Ki-67 ≥20% who did not meet entry criteria for C1 were included in Cohort 2 (C2). Analyses were conducted in Chinese pts enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population (501 pts), consisting of C1 (440 pts) and C2 (61 pts). At the time of data cutoff (July 1, 2022), all Chinese pts were off treatment with median follow-up of around 41 months. Sustained benefits of IDFS (HR=0.563, 95%CI: 0.343-0.923) and DRFS (HR=0.586, 95%CI: 0.341-1.006) were observed in Chinese pts in the ITT, with clinically meaningful improvement in the 4-year IDFS rates (88.5% vs 79.6%) and DRFS rates (90.0% vs 82.4%). In C1, the HR for IDFS was 0.582 (95%CI: 0.351-0.965) and DRFS was 0.610 (95%CI: 0.350-1.063), and a consistent benefit of abemaciclib was observed regardless of Ki-67 index. There were limited events of deaths in Chinese pts (abemaciclib plus ET vs ET: 6 [2.3%] vs 5 [2.1%]). No new safety signals were observed in Chinese pts. Consistent with reported results for the overall ITT population, abemaciclib combined with ET demonstrated clinically meaningful and sustained IDFS and DRFS benefits among Chinese pts with HR+, HER2-, high risk EBC and continued separation of the IDFS and DRFS curves. The OS data remain immature and follow-up is ongoing.

57P Clinicopathologic landscape of high-risk early stage HER2-low breast cancer

57P Clinicopathologic landscape of high-risk early stage HER2-low breast cancer

109P Updated long-term overall survival of older adjuvant ibandronate-treated patients with intermediate- or high-risk early breast cancer compared with additional adjuvant capecitabine treatment: The ICE randomized clinical trial

The majority of breast cancers occur in women over the age of 65, but older breast cancer patients are largely underrepresented in clinical trials. We investigated the effect of adding capecitabine to adjuvant treatment with ibandronate in elderly breast cancer patients. The multicenter phase III ICE trial enrolled women ≥65 years with early node-positive/high-risk node-negative breast cancer and a Charlson Comorbidity Index (CCI) ≤2. Patients were randomized to capecitabine 2000 mg/m2 day 1-14 q3w for 6 cycles plus ibandronate (50 mg p.o. daily or alternatively 6 mg i.v. q4w) or ibandronate alone for 2 years. We present here an update on long-term follow-up for the secondary endpoint of overall survival (OS). 1358 (96.4%) from 1409 randomized patients started treatment. 564 (83.4%) completed 6 cycles of capecitabine. 513 (77.7%) and 516 (78.8%) completed ibandronate in the capecitabine/ibandronate and ibandronate arm, respectively. Median age was 71 (range 64-88) years, 1099 (81%) were hormone receptor (HR)-positive, 705 (51.9%) node-negative, 794 (58.5%) had a CCI of 0. HR-positive patients received additional adjuvant endocrine treatment. After an updated median follow-up time of 74 (IQR 56-126) months for OS in the entire cohort, 7-year OS was 83.5% for capecitabine/ibandronate versus 80.9% for ibandronate, and 10-year OS was 73.1% for capecitabine/ibandronate versus 70.8% for ibandronate (P=0.413). Lack of effect was independent from age, nodal and HR status. Addition of capecitabine caused significantly higher skin and gastrointestinal toxicities. The adjuvant combination of capecitabine and ibandronate did not show significantly better OS than ibandronate alone in elderly breast cancer patients.

Association of baseline ROR1 and ROR2 gene expression with clinical outcomes in the I-SPY2 neoadjuvant breast cancer trial

PurposeROR1 and ROR2 are Type 1 tyrosine kinase-like orphan receptors for Wnt5a that are associated with breast cancer progression. Experimental agents targeting ROR1 and ROR2 are in clinical trials. This study evaluated whether expression levels of ROR1 or ROR2 correlated with one another or with clinical outcomes.MethodsWe interrogated the clinical significance of high-level gene expression of ROR1 and/or ROR2 in the annotated transcriptome dataset from 989 patients with high-risk early breast cancer enrolled in one of nine completed/graduated/experimental and control arms in the neoadjuvant I-SPY2 clinical trial (NCT01042379).ResultsHigh ROR1 or high ROR2 was associated with breast cancer subtypes. High ROR1 was more prevalent among hormone receptor-negative and human epidermal growth factor receptor 2-negative (HR-HER2-) tumors and high ROR2 was less prevalent in this subtype. Although not associated with pathologic complete response, high ROR1 or high ROR2 each was associated with event-free survival (EFS) in distinct subtypes. High ROR1 associated with a worse EFS in HR + HER2- patients with high post-treatment residual cancer burden (RCB-II/III) (HR 1.41, 95% CI = 1.11–1.80) but not in patients with minimal post-treatment disease (RCB-0/I) (HR 1.85, 95% CI = 0.74–4.61). High ROR2 associated with an increased risk of relapse in patients with HER2 + disease and RCB-0/I (HR 3.46, 95% CI = 1.33–9.020) but not RCB-II/III (HR 1.07, 95% CI = 0.69–1.64).ConclusionHigh ROR1 or high ROR2 distinctly identified subsets of breast cancer patients with adverse outcomes. Further studies are warranted to determine if high ROR1 or high ROR2 may identify high-risk populations for studies of targeted therapies.

Abstract 4364: Cost-effectiveness analysis of abemaciclib and endocrine therapy combination for the adjuvant treatment of HR+/HER2-, node-positive, high-risk, early breast cancer

Abstract Background: Abemaciclib is the only approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for adjuvant treatment of hormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2-), node-positive, high-risk early breast cancer (EBC) patients. However, the addition of abemaciclib to the standard of care endocrine therapy (ET, such as tamoxifen or aromatase inhibitors) results in a drastic increase to the overall healthcare costs. Objective: In this study, we aimed to evaluate the cost-effectiveness of abemaciclib and ET combination versus ET monotherapy for the adjuvant treatment of HR+/HER2-, EBC from the U.S. third-party payer perspective. Methods: A Markov-based decision analytic model using TreeAge Software was developed. The model simulated lifetime costs and health outcomes over a lifetime. The model incorporated the disease course of the progression-free disease, progressive disease, death due to disease, and mortality due to other causes. All clinical data and utilities were derived from the literature and clinical trial: monarchE. Notable adverse events such as neutropenia, leucopenia, anemia, and diarrhea were included. Age-specific mortality risk was calculated from the U.S. life tables. The outcomes were measured by costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The willingness-to-pay threshold was set at $100,000 per QALY gained. Results: We simulated our analysis on patients assigned to either abemaciclib + ET or ET alone groups as per the monarchE trial. The median age of the patients was 51 years. In base case analysis, the total costs for abemaciclib plus ET and ET alone treatment, were USD 122,052.11 and USD 40,344.87, respectively. Abemaciclib plus ET treatment produced 4.5 QALYs, while the ET treatment alone produced 4.31 QALYs. Overall, abemaciclib plus ET was marginally more effective than ET with an additional 0.20 QALYs but much costlier with an ICER of $417,780.18/QALY. For utilities ranging from 0.41 to 0.69, the ICERs ranged from USD 36,5950 to USD 4,463,866.59 per QALY, which exceeded the WTP threshold. Using probabilistic sensitivity analysis, we estimated that the combination of abemaciclib plus ET was a cost-effective strategy at the willingness-to-pay threshold of $500,000 per QALY or higher for the base case population. Conclusion: At current costs, abemaciclib plus ET is not cost-effective as compared to ET monotherapy for patients with node-positive, high-risk, HR+/HER2- EBC in the US healthcare system from the third-party payer perspective. Citation Format: Ashna Talwar, Ashish Deshmukh, Meghana Trivedi, Rajender R. Aparasu. Cost-effectiveness analysis of abemaciclib and endocrine therapy combination for the adjuvant treatment of HR+/HER2-, node-positive, high-risk, early breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4364.

Adjuvant olaparib in the subset of patients from Japan with BRCA1- or BRCA2-mutated high-risk early breast cancer from the phase 3 OlympiA trial

BackgroundThe efficacy and safety of olaparib compared with placebo in the subset of patients from Japan in the phase 3 OlympiA trial (NCT02032823) are reported here and contextualized with reference to the global OlympiA population.MethodsPatients with germline BRCA1 and/or BRCA2 pathogenic variants and HER2-negative, high-risk early breast cancer who had received neoadjuvant or adjuvant chemotherapy and completed local treatment were eligible. Patients were randomized 1:1 to receive olaparib or placebo for 1 year. Primary endpoint: invasive disease-free survival (IDFS). Secondary endpoints: distant disease-free survival (DDFS), overall survival (OS), and safety. Data are reported from the first pre-specified interim analysis (data cut-off [DCO] March 27, 2020) and the second, event driven, pre-specified interim analysis of OS (DCO July 12, 2021) in patients from Japan.Results140 patients were randomized in Japan (olaparib, n = 64; placebo, n = 76). At the first pre-specified interim analysis (median follow-up: 2.9 years), hazard ratios (HRs) for adjuvant olaparib compared with placebo were 0.5 for IDFS (95% confidence interval [CI] 0.18–1.24) and 0.41 for DDFS (95% CI 0.11–1.16). At the second pre-specified interim analysis of OS, three deaths occurred in the olaparib group versus six deaths in the placebo group (HR, 0.62 [95% CI 0.13–2.36]). Findings were consistent with those for the global population. No new safety signals were observed.ConclusionsWhile this analysis in a Japanese subset of patients was not powered to detect population-related treatment differences, efficacy and safety analysis results were consistent with the global OlympiA population, suggesting the findings from the global study are generalizable to clinical practice in Japan.

Olaparib (Lynparza)

&#x0D; CADTH recommends that Lynparza be reimbursed by public drug plans for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy if certain conditions are met.&#x0D; Lynparza should only be covered in patients with a confirmed type of inherited (germline) abnormal BRCA gene, whose early-stage breast cancer tests negative for the HER2 protein, who are at high risk for breast cancer recurrence, and who have received chemotherapy before or after surgery.&#x0D; Lynparza should only be reimbursed if prescribed by clinicians with expertise and experience in treating breast cancer, and if the cost is reduced.&#x0D;

Therapy-related Myeloid Neoplasms Following PARP Inhibitors—Letter

Marmouset and colleagues describe an association between certain clinical and laboratory parameters and previous exposure to PARP inhibitors (PARPi; ref. 1). There are however important confounders, perhaps inappropriately correlating therapy-related myeloid neoplasms (t-MN) to PARPi, that are important to highlight.The authors report a cumulative incidence of t-MN of 3.5% and a 66% increase in t-MN but it was not reported whether the number of patients seen for ovarian cancer have remained the same. Also, patients with ovarian cancer are exposed to platinum agents and taxanes, thus the attribution of t-MN to PARPi is unclear. Because chemotherapies are also associated with secondary malignancies, the evaluation of prior agents is critical for the correct attribution of t-MN to PARPi.The authors compare features of PARPi-exposed patients with t-MN referred to hematology consultation for cytopenia with those who did not develop t-MN. Patients with t-MN had a longer exposure to PARPi, lower platelet levels, and more cytopenias. While the discussion includes the fact that the longer time observed can explain the higher event rate, it can be artificial that thrombocytopenia and cytopenias were associated with t-MN, because these are laboratory manifestations of the disease itself. From a prospective perspective, all cytopenias should be monitored and evaluated, particularly those that are more prolonged.Associations between clinical outcomes and baseline demographic and molecular characteristics need to take into account the historical context of clinical practice. Twenty-four PARPi-naïve patients with t-MN after ovarian cancer diagnosis were identified and compared with 13 patients with post-PARPi t-MN, and the most significant difference was enrichment of BRCA1/2 carriers among those who received PARPi, which likely reflects the fact that initial studies with PARPi were restricted to BRCA1/2 carriers (2). From 69 patients with post-PARPi t-MN were identified from a national database, those treated with olaparib had a more complex karyotypes and worse overall survival compared with other PARPi. All these are confounded by the fact that olaparib's initial approval included heavily pretreated BRCA1/2 carriers while newer agents are used in earlier lines and include BRCA1/2 wild-type patients (3, 4).The OlympiA trial analyzed 1,836 patients with gBRCA1/2m and high-risk early breast cancer. After 3.5 years of median follow-up, the rate of myelodysplastic syndrome/acute myeloid leukemia was 0.3% with placebo and 0.2% with olaparib (5). Longer follow-up will be necessary to establish or disprove the strength of the link between PARPi and t-MN. Ongoing efforts will be critical to identify clinical, laboratory, and molecular characteristics associated with the risk of t-MN, and to distinguish the effects of PARPi from chemotherapy on hematopoietic stem cells.See the Response, p. 1158F. Batalini reports personal fees from Curio Science, Novartis, Grail, and Daiichi Sankyo outside the submitted work. No disclosures were reported by the other authors.

Abstract OT2-14-01: Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial

Abstract Objective: Trastuzumab-based adjuvant therapy was demonstrated to improve the prognosis of early human epidermal growth factor receptor 2 (HER-2) positive breast cancer, while about 10% of patients showed primary resistance. ExteNET study showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in women with HER2-positive breast cancer. Besides, for patients with early hormone receptor positive breast cancer within 1 year of prior trastuzumab with residual disease after neoadjuvant therapy, extended adjuvant neratinib showed prolonged overall survival, which suggested the potential benefit of extended adjuvant therapy for high-risk patients. Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting epidermal growth factor receptor, HER2, and HER4, which showed promising efficacy and manageable safety profiles in the treatment of HER-2 positive advanced breast cancer. In this study, we aimed to evaluate the efficacy and safety of extended adjuvant pyrotinib following trastuzumab-based adjuvant therapy in patients with high-risk early HER-2 positive breast cancer. Methods: In this ongoing multicenter, open-label, phase II trial at 23 centers in China, women with operable high-risk early HER-2 positive breast cancer and known hormone receptor status, who have completed trastuzumab-based adjuvant therapy within 6 months were enrolled. High-risk patients must meet one of the following criteria: N stage ≥1; T stage ≥2; did not achieve pathological complete response (pCR) after neoadjuvant therapy; had pCR after neoadjuvant therapy but with tumor size ≥ 5cm or N stage ≥2; or tumor size less than 2cm but with high Ki67, histologic grade 3 or with lymph node micrometastasis. Eligible patients were assigned to receive 6 month or 1 year of oral pyrotinib 400mg/day. The primary endpoint was the 2-year iDFS rate. Results: Between January, 2019 and February, 2022, a total of 142 eligible women were enrolled and assigned to receive pyrotinib, with a median age of 50 (range: 25-72) years old. Ninety-seven patients had a T stage ≥2. A total of 108 patients (76.1%) had node-positive disease, and 64 (45.1%) were hormone receptor positive. Twenty-five patients used neoadjuvant therapy previously, and all of them did not receive pCR (Table 1). After a median follow-up of 20 (range: 0.25-41) months, the 2-year iDFS rate was not available. Two and four patients reported invasive disease events after 6-month and 1-year of follow-up, with the 6-month and 1-year iDFS rates of 98.6% and 97.2%, respectively. The most common adverse events reported was diarrhea (78.2%), followed by fatigue (36.6%), lymphocyte count decreased (36.6%), nausea (33.1%) and hand-foot syndrome (33.1%). Forty-three patients experienced grade 3 diarrhea, and no grade 4 or higher adverse event was reported (Table 2). Adverse event leading to treatment discontinuation occurred in 12 (8.5%) patients. Conclusion: Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy was well-tolerated and showed potential efficacy in high-risk early HER-2 positive breast cancer. The follow-up is ongoing to determine the long-term benefit of extended adjuvant pyrotinib. Table 1. Baseline characteristics of patients ER: estrogen receptor; PR: progesterone receptor. Table 2. Treatment-emergent adverse event occurring in at least 10% of the patients Citation Format: Feilin Cao, Zhaosheng Ma, Guinv Hu, Xiaotao Zhu, Shuguang Li, Shuzheng Chen, Binglie Chen, Zhanwen Li, Weizhu Wu, Xiaochun Ji, Jingde Shu, Deyou Tao, Xiaoqing Hu, Min Zheng, Ouchen Wang, Qingjing Feng, Jing Hao, Xujun Li. Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 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 OT2-14-01.

Abstract P6-07-01: Costs of breast cancer recurrence after initial treatment for high risk early breast cancer using SEER-Medicare linked data

Abstract Background: Despite the good prognosis with treatment for most patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) early breast cancer (EBC), ~ 20–30% of patients experience locoregional or distant disease recurrence. To assist in value assessments of novel therapies in the adjuvant setting, this study aimed to determine the costs of treated breast cancer recurrence following treated EBC. Methods: This retrospective study analyzed linked patient data from the US Surveillance Epidemiology and End Results (SEER) registry (2010-2014) and Medicare claims (2009 to 2019, which included data from Part A, B, and Prescription Drug Events [Part D]). Data were analyzed for patients aged ≥65 years with HR+, HER2-, node-positive EBC at high risk of recurrence (consistent with monarchE trial high risk criteria). Treated recurrences were defined based on treatment events/procedure codes, including surgery, radiation and systemic therapy, after a 90-day gap following the last treatment for initial EBC. Recurrences were classified based on Medicare claim diagnosis codes or SEER registry data. Extra cost was defined as cost attributable to treated recurrence. Cumulative extra costs were estimated by calculating cost differences between patients with treated vs non/untreated recurrence. Cumulative extra costs were analyzed over the first 6 years following first treated recurrence, a duration which ensured adequate sample size. Costs were inflated to 2021-US$. Results: We identified 3081 eligible patients (mean age at diagnosis 74.5±7.1 years, 97.4% female, 87.8% White). We identified 964 patients with treated recurrence (distant=432, locoregional=128, contralateral=9, unclassified=347) and 2117 patients with non/untreated recurrence. Six-year cumulative extra costs were higher for patients with distant recurrences ($168,656) than for patients with locoregional recurrences ($96,465) (Table 1). Conclusions: Cost of recurrence in patients with high risk EBC is considerable, particularly in patients with distant recurrences. Most patients who recurred in this population experienced distant recurrence. Delaying or preventing recurrence may reduce long term costs in these high risk EBC patients. Table 1. Mean cumulative extra costs attributable to treated recurrence. Citation Format: Alexandra S. Vitko, Pamela A. Martin, Sheng Zhang, Adam F. Johnston, Robert L. Ohsfeldt, Shen Zheng, Astra M. Liepa. Costs of breast cancer recurrence after initial treatment for high risk early breast cancer using SEER-Medicare linked data [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 P6-07-01.

Abstract P2-02-07: Patients’ selection of daily timing of oral intake of adjuvant hormonotherapy (HT) and everolimus (EVE) for high risk early breast cancer in the UCBG-UNIRAD phase III trial

Abstract Background: Everolimus (EVE) addition to adjuvant hormonotherapy (HT) for high-risk early breast cancer (BC) did not improve 3-year disease-free survival (DFS) compared with ET alone in the randomized UNIRAD trial (NCT01805271) (1). Most patients (pts) withdrew from EVE for adverse events nearly midway before the expected treatment duration of 2 years. The main EVE target involves m-TOR-induced S6 protein phosphorylation, which is controlled by the molecular circadian clock in mice and cells. Toward the analysis of possible circadian time-dependencies in EVE toxicities and efficacy, we first determine the actual distribution of the daily times chosen by the patients for both oral EVE and HT intakes. Patients and methods: The registered pts were asked to record the clock hours they chose for both HT and EVE or placebo (PLAC) intakes within four possible daily 6-h slots, i.e. from 06:00 to 11:59 (morning), 12:00 to 17:59 (midtime), 18:00 to 23:59 (evening), or 24:00 to 05:59, (night) in a daily diary throughout their participation in the trial. Modifications in times of drugs intake were reported. Comparisons between groups involved Kruskal-Wallis sum test and Pearson’s Chi-squared and Fisher’s exact tests. Results: Out of 1,278 randomized patients, 1063 (83,1 %) recorded the times of EVE or PLAC intakes, 852 recorded those for HT intakes. Only 10 pts reported night EVE/PLAC intakes and were not considered here. Of the 1053 evaluated pts; 549 pts took EVE/PLAC in the morning, 82 pts at midtime and 422 in the evening. As compared with evening intakes, morning or midtime intakes of EVE or PLAC were significantly associated with an older age, and post-menopausal status, whilst younger and premenopausal women preferentially chose evening intakes (p&amp;lt; 0.001 for both). Consistently, HT with aromatase inhibitors (AI) were mostly taken in the morning or at midtime, whereas tamoxifene (TAM) was mostly taken the evening (p = 0.001). Tumor size, lymph nodes involvement, histological grade, hormonal receptors status, and EVE initial dose were similarly distributed among the three time slots (Table 1). A similar distribution of oral intake times as in the whole timing study population was found according to age, menopausal status and HT type in the EVE arm (N=508 pts), and in the HT population (+/- EVE or PLAC) (N=852 pts). Initial oral timing intake was modified for EVE by 50 of 508 pts (10%) and for HT by 10 of 852 pts (1%). Conclusion: To the best of our knowledge, it is the first time that the patients’ spontaneous selection of daily times for oral intakes of a targeted agent (EVE) and HT is reported in a large series of early breast cancer pts. Age and menopausal status were important determinants of patient-selected daily timing intakes of both EVE and HT, as well as HT types. These findings will be carefully considered in the analyses of possible EVE and HT timing effects on adverse events and efficacy of the current adjuvant regimens. 1) Bachelot T et al, J Clin Oncol. 2022 May 23 Citation Format: Sylvie Giacchetti, Anne-Sophie Hamy, Thomas Bachelot, Jérôme Lemonnier, Fabrice Andre, David A. Cameron, Judith Bliss, Sylvie Chabaud, Anne-Claire Hardy-Bessard, Magali Lacroix-Triki, Jean-Luc Canon, Hervé R. Bonnefoi, Mario Campone, Paul Cottu, Florence Dalenc, Annabelle Ballesta, Francis Lévi, Enora Laas. Patients’ selection of daily timing of oral intake of adjuvant hormonotherapy (HT) and everolimus (EVE) for high risk early breast cancer in the UCBG-UNIRAD phase III 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 P2-02-07.