bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of HER2 low status in I-SPY2 with molecular subtype, response, and survival.
Authors: Rugo Hope S. , Wolf Denise M. , Yau Christina , Petricoin Emanuel , Pohlmann Paula R , Pusztai Lajos , Symmans W. Fraser Fraser , Borowsky Alexander , Finestone Sandra , Yee Douglas , Hylton Nola , van 't Veer Laura , Esserman Laura , DeMichele Angela ,   I-SPY Investigators
Published: June 2023

514

Background: HER2low, defined as immunohistochemical (IHC) 1+ or 2+ without HER2 gene amplification, predicted improved progression free and overall survival with trastuzumab deruxtecan (TDXd) compared to chemotherapy in patients (pts) with metastatic breast cancer in Destiny Breast04. Controversy exists regarding the correlation of HER2low with molecular subtypes and outcome. We evaluated these associations in the neoadjuvant ISPY2 trial. Methods: We investigated HER2 IHC class in pts with clinically HER2-negative breast cancer (BC) enrolled in the first 10 arms of ISPY2. To explore the biology of HER2low, we used Fisher’s exact test to assess association of IHC class (0 vs 1+ or 2+) with Response Predictive Subtypes-5 (RPS-5; based on immune, DNA repair damage (DRD), HER2, and luminal markers; PMID: 35623341), SET index [endocrine responsiveness], and Mammaprint high1 (MP1) vs high2 (MP2). Association with pathologic complete response (pCR) was assessed using Fisher’s exact test, and association with distant recurrence free survival (DRFS) was assessed using Cox Proportional Hazards modeling. Results: Of 742 HER2negative pts enrolled in the first 10 arms of ISPY2, local HER2 IHC is available for 585; 299 hormone receptor + (HR+) and 286 triple negative (TN). 63% of pts are HER2low, with HER2low status more frequent in HR+ (71%) compared to TN BC (55%; OR = 1.97; p = 0.00011). There was no clear relationship between HER2low IHC and RPS-5 subtypes or endocrine sensitivity measured by the SET index. There was no significant association of HER2low with pCR overall or within treatment arms (p > 0.05); this was true for TN and HR+ subsets. 562 pts with HER2negative disease have distant recurrence free survival (DRFS) data with a median follow-up of 4.23 yrs. Pts with pCR had excellent outcome (5yr DRFS > 94%), with no impact from HER2low vs 0 status. For pts with nonpCR, after adjusting for HR+ status, the DRFS hazard ratio for HER2low vs 0 status is not significant [0.68(0.46-1.02)]. Within HR+, HER2low is found in > 70% for both SET low and high. HR+/MP1 pts (with generally low pCR rates) are significantly more likely to be HER2low (75%; (172/219)) compared to HR+/MP2 (61%; (49/80)) (OR: 1.79; Fisher p = 0.044). Importantly, 70% of HER2-Immune-/DRD- (78% HR+ and 56% TN), a subtype with low response to all ISPY2-tested agents, are HER2Low. Conclusions: In ISPY2 which enrolls patients with MP high risk BC, HER2low by IHC was frequent and higher in HR+ than TN disease. There was no clear association with molecular markers, pCR or DRFS. The frequency of HER2low in the immune-/DRD- subtype raises the potential for exploring T-DXd in this high risk, low-response setting. Clinical trial information: NCT01042379 .
Outcomes according to treatment received for small node-negative HER2+ breast tumors in the Surveillance, Epidemiology, and End Results (SEER) database, 2010-2019.
Authors: Waks Adrienne Gropper , Tarantino Paolo , Freedman Rachel A. , Lin Nancy U. , Tayob Nabihah , Vallejo Carlos Teodoro , Leone Julieta , Tolaney Sara M. , Leone Jose Pablo
Published: June 2023

517

Background: The magnitude of systemic therapy (tx) benefit for small, node-negative HER2+ breast tumors is unknown, with uncertainty about how benefit varies across stage I tumor sizes. We analyzed treatment patterns and outcomes for patients (pts) with stage IA (pT1N0) HER2+ breast cancer in the national SEER database. Methods: Pts with one lifetime diagnosis of pT1N0 HER2+ breast cancer between 2010-2019 were included. Receipt of chemotherapy (chemo) was categorized as yes vs no/unknown; receipt of endocrine tx is not available in SEER. All systemic tx was administered in the adjuvant setting. The primary outcome variable was breast cancer-specific survival (BCSS; recurrence events are not available in SEER), which was compared between treatment groups using a multivariate Cox model adjusted for age at diagnosis (dx), race, tumor grade/histology/size, hormone receptor (HR) status, radiation, marital status, income, rurality. Chemo use predictors were evaluated by multivariable logistic regression. Results: We identified 12,861 pts with pT1N0 HER2+ breast cancer; 9,513 (74%) HR-positive and 3,348 (26%) HR-. Median age at dx was 59 yrs. Median follow-up was 46 months. In the overall cohort, BCSS at 3, 5, and 7 yrs was: 99.3% (with chemo) vs 99.1% (without chemo); 98.6% (with chemo) vs 97.4% (without chemo); and 97.5% (with chemo) vs 96.4% (without chemo), respectively. Adjusted hazard ratio (HzR) for BCSS events in the chemo vs no chemo group of the overall cohort was 0.63 (p=0.004;). BCSS events by tumor size and HR status are shown; p values are not shown where event rates were too low to run an adjusted model. Chemo use increased significantly between 2010-2019 within each tumor size category (all p for trend < 0.04), except for T1a HR+/HER2+ and T1mi HR-/HER2+. Pts were less likely to receive chemo if they were older, Hispanic (vs non-Hispanic White), separated/divorced/widowed (vs single), or had lower median household income (vs >$75K). Pts were more likely to receive chemo if they had larger tumor size, HR- tumor, higher tumor grade, were married (vs single), or had later yr of dx. Conclusions: Receipt of chemo was associated with higher BCSS in the overall stage IA cohort and among pts with HR+/HER2+ stage IA tumors. Tumors ≤ 1cm had excellent outcomes with or without chemo. Sociodemographic factors including income, race, and marital status impacted chemo receipt. [Table: see text]
Long-term oncologic outcomes after omitting axillary surgery in older women with early stage, node-negative breast cancer: A systematic review and meta-analysis.
Authors: Rana Mariam , Lee Soyon , Lindsay Alistair , Silva Godinez Juan Carlos , Vakil Erik , Waugh Evelyn
Published: June 2023

525

Background: In 2016, Choosing Wisely recommended the omission of routine sentinel lymph node biopsy (SLNB) in early stage, clinically node-negative, hormone receptor-positive, Her2-negative breast cancer in women ≥70 years old, although data supporting this was limited. Our study aimed to examine the long-term impact of omitting axillary staging in elderly women undergoing surgery for early stage, clinically node-negative breast cancer. Methods: A systematic review and meta-analysis was conducted. Medline (Ovid) and Embase were searched for published papers and abstracts using a systematic search strategy. Randomized and observational studies comparing women aged ≥70 years of age with early-stage, clinically node-negative breast cancer undergoing surgery for breast cancer with and without axillary staging, were included. Included studies reported at least one of the following outcomes: axillary recurrence (primary outcome), disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival. Risk ratios (RR) were calculated as summary estimates for all outcomes. A weighted pooled mean difference and 95% CI was calculated using a random-effects inverse variance meta-analysis for each outcome. Heterogeneity was calculated using I2 statistics, and explored using meta-regression. The Newcastle-Ottawa Scale was used to assess the methodological quality of eligible trials, based on the selection of patients, comparability of cohorts, and the methods of outcome assessment. Results: Nine studies were eligible for meta-analysis, including data for 48,523 patients. For the primary outcome of axillary recurrence, data for 3,591 patients was meta-analyzed. Axillary staging was found to reduce the risk of axillary recurrence compared to no axillary staging, although this was not statistically significant (RR 0.59, 95% CI: 0.26 to 1.35, I2= 46.6%, p = 0.21). For overall mortality, data for 14,981 patients was meta-analyzed, and a statistically significant protective effect of axillary staging on overall mortality was demonstrated (RR 0.55, 95% CI: 0.33 to 0.90, I2= 78.1%, p= 0.003). No significant differences were observed in DFS (RR 1.02, 95% CI: 0.51 to 2.07, I2 = 0.0%, p = 0.37) and BCSS (RR 0.96, 95% CI: 0.57 to 1.62, I2 = 0.0%, p = 0.78). Conclusions: Omission of axillary surgery to stage the axilla may be associated with a higher risk of overall mortality in older women with early-stage breast cancer compared to those who undergo axillary surgery. Omission of axillary surgery in this patient population should be carefully tailored to the individual patient, taking into consideration co-morbidity, life expectancy, and formal measures of frailty. Randomized trials are required to further explore the oncologic safety of omitting axillary staging in women aged 70 years or older undergoing breast cancer surgery.
Efficacy of ovarian function suppression of 3-monthly versus monthly GnRH agonist as endocrine therapy for premenopausal breast cancer patients.
Authors: Audi Blotta Daniella , Gomes Jessica Ribeiro , Moreira Shermann Brandão Rodrigues , Colosimo Danielle Fortes , Cavalcanti Gonçalves Ferreira Carolina , Forgiarini Elaine Aparecida , Gagliato Debora De Melo , Buzaid Antonio C.
Published: June 2023

527

Background: The combined analysis of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) trials have shown significant survival benefit of adding ovarian function suppression (OFS) with GnRH agonists (GnRHa) to aromatase inhibitors (AI) versus tamoxifen in high-risk premenopausal patients (pts) with estrogen receptor (ER)-positive breast cancer (BC). In both studies, GnRHa was administered every 4 weeks. However, the efficacy of 3-monthly GnRHa plus AI has not been well studied. We conducted a retrospective study designed to assess the efficacy of OFS with 3-montlhy compared with monthly goserelin, associated with AI, in premenopausal pts with ER-positive BC. Methods: Medical records of premenopausal pts with ER-positive BC who received OFS with 10.8mg 3-montlhy goserelin plus AI or 3.6mg monthly goserelin plus AI, between June/2013 and January/2023 were reviewed. Patient characteristics, such as age, body mass index (BMI) and prior chemotherapy were analyzed. Estradiol (E2) levels were measured by gas chromatography tandem mass spectrometry. Pts with at least one E2 level above 2.72 pg/ml were considered to have ineffective OFS. Analysis of E2 measurements was divided into periods: < 3, 3 to 6, 6 to 9, 9 to 12, 12 to 18, 18 to 24 and > 24 months. E2 levels greater than 2.72 pg/ml were evaluated at each timepoint. Results: A total of 88 pts were included. 27 (30.7%) received monthly goserelin and 61 (69.3%) 3-monthly goserelin. Patient characteristics were well balanced between the groups. Relevant demographic data are shown in table. For E2 analysis, 20 (22.7%) pts had at least one measurement greater than 2.72 pg/ml, 11 (40.7%) in the monthly group and 9 (14.8%) in the 3-monthly group (p = 0.007). The percentages of E2 measurements ≥ 2.72 pg/ml, in each time period, were 0%, 40%, 12.5%, 16.7%, 33.3%, 50% and 50% in monthly group versus 8%, 4.2%, 10%, 14.3%, 4.8%, 8.3% and 5.6%, in 3-monthly group, respectively. Conclusions: Our study demonstrated that more pts who underwent 3-monthly goserelin had E2 levels below the defined threshold of 2.72 pg/ml compared with monthly goserelin, when associated with AI, with statistical significance. These findings suggest that 3-monthly goserelin may result in better efficacy in OFS when comparing with monthly and provide greater convenience for pts. [Table: see text]
Assessing the marginal costs of radiation therapy and antiestrogen therapy for post-lumpectomy, early-stage breast cancer across Medicaid and Medicare plans.
Authors: Wu Victoria , Khlopin Martha , Jagsi Reshma , McClelland Shearwood
Published: June 2023

529

Background: With recent Level I evidence (FAST FORWARD) supporting radiation therapy (RT) duration as short as one week and Level I evidence (CALGB9343) supporting RT omission in favor of antiestrogen endocrine therapy (ET) alone in select patients, the necessity of both RT and ET, adjuvantly, in early-stage breast cancer (BC) has been questioned. Evidence providing granular details on the role of insurance in the aggregate cost of RT and ET is lacking. This project disaggregates costs by insurance plan to increase transparency of out-of-pocket (OOP) cost estimates. Methods: National Comprehensive Cancer Network guidelines were utilized to determine the proper treatments, with FAST FORWARD radiation dose/fractionation (26 Gy in 5 fractions) representing RT. Treatments were identified using Current Procedural Terminology and Healthcare Common Procedure Coding System codes. OOP costs, deductibles, and copay/coinsurance were calculated for Medicaid, Original Medicare, Medigap Plan G, and Medicare Part D Rx. The medicare.gov, medicaid.oh.gov, aarpmedicareplans.com, and cms.gov were used to determine pricing. Price estimates reflect actual costs per insurance plan rather than costs estimated from claims data. All procedures were considered to be performed in an Ohio hospital setting, insurance coverages were based on the zip code 44106, and total expenses were based on all treatments plus a 5-year follow-up (not adjusted for inflation). Results: Treatment charges for ET include medical oncology initial consultation, biannual medical oncology follow-up, baseline bone density study, and Anastrozole cost (5-years). Treatment charges for RT include initial consultation, treatment planning, dosimetry calculations, treatment device, simulation and verification, RT delivery, on-treatment visits, and medical physics consultation. Original Medicare beneficiaries face an OOP cost of 20% for Medicare Part B claims with no cost cap for approved procedures after the deductible. Medications are covered under Medicare Part D with copays. This results in a marginal OOP treatment charge (after 5-year follow-up) of $767.54 for ET alone and $1,416.78 for ET + RT. Medigap Plan G beneficiaries face a marginal OOP charge of $1,225 for both ET alone and ET + RT, assuming the $226 Medicare Plan B deductible is met by the cost of lumpectomy during the year of RT. For Medicaid beneficiaries (assuming all treatments are approved by Medicaid), all expenses are covered without limit, resulting in no OOP expense for either treatment plan. Conclusions: Discussions of adding RT to ET for post-lumpectomy early-stage BC often involves considerations of treatment costs. This model (based on actual cost estimates per insurance plan rather than claims data) can help to enhance cost transparency by comparing expenses between Medicare and Medicaid plans.
Association between patient-reported outcomes and therapeutic outcomes in patients with breast cancer: A pooled individual-participant data analysis.
Authors: Modi Natansh , Abuhelwa Ahmad Y , Rowland Andrew , Menz Bradley D , McKinnon Ross Allan , Sorich Michael J , Hopkins Ashley Mark
Published: June 2023

530

Background: Patient-reported outcomes (PROs) are captured in validated tools to provide the patients’ perspective and voice on their physical, social, emotional, functional, and cognitive abilities. Pre-treatment PROs have shown prognostic importance in other cancer types, however, the prognostic value of PROs in breast cancer has been minimally explored. Methods: In a pooled analysis of contemporary clinical trial IPD from patients with breast cancer, cox-proportional hazard analysis and binary logistic regression was used to assess the association between potential predictors with overall survival (OS) and adverse event (grade ≥ 3) outcomes, respectively. PROs were recorded using the EORTC QLQ-C30 version 3.0 questionnaire in the pooled cohort. Statistical significance was set at a threshold of P<0.05 and was determined via the likelihood ratio test. Model fit and linearity of variable associations were assessed via the Akaike information criterion (AIC). All analyses were stratified by age, performance status, treatment arm, and study. The primary assessed outcome was OS, with grade ≥ 3 adverse events assessed as a secondary outcome. A forward inclusion process (starting with the variable of lowest AIC, PRO domains were retained in the model if they decreased the AIC by 2 or more on addition, and remained statistically significant) was used to evaluate the value of multiple PRO domains on prognostic performances. Results: Within data available, the EORTC QLQ-C30 version 3.0 questionnaire was used in a pooled cohort of 8,544 patients across 8 clinicals trials. In the pooled cohort, the association between PROs and outcomes was best described by a linear association. Patient-reported physical functioning, appetite loss, and pain were significantly associated with OS. On forward-inclusion, only physical functioning remained within the OS prognostic model. Except for patient-reported financial difficulties, all PRO domains were significantly associated with grade ≥ 3 adverse events. On forward-inclusion, physical functioning, pain, and constipation all remained statistically significant. Conclusions: Within large high-quality IPD, pre-treatment PROs demonstrated significant prognostic relationships with therapeutic outcomes in patients with breast cancer initiating contemporary anticancer treatments. Patient-reported physical functioning was found to be the most prognostic PRO domain for OS, while patient-reported physical functioning, pain, and constipation were retained in a multivariable model prognostic of grade ≥ 3 adverse events.
Does RSClin provide additional information over classic clinico-pathologic scores (PREDICT 2.1, Influence, CTS-5)? A TEAM Pathology substudy.
Authors: Beltran-Bless Ana-Alicia , Pond Gregory Russell , Bayani Jane , Barker Sarah , Spears Melanie , Mallon Elizabeth , Taylor Karen J , Hasenburg Annette , Markopoulos Christos , Dirix Luc Yves , Seynaeve Caroline M. , Van De Velde Cornelis J.H. , Rea Daniel William , Vandermeer Lisa , Hilton John Frederick , Bartlett John , Clemons Mark J.
Published: June 2023

533

Background: Gene-expression profiling tests (e.g. Oncotype, Mammaprint, Prosignia, Breast Cancer Index and EndoPredict) are widely used in the care of patients with early-stage hormone positive breast cancer (node negative or 1-3 lymph nodes). However, these tests are resource intensive, and few studies have compared their value with either free and widely available clinico-pathologic risk calculators (e.g. PREDICT 2.1, INFLUENCE 2.0, and CTS-5) or tools that combine genomic testing with clinico-pathologic data (e.g. RSClin). The TEAM pathology substudy population was used to compare these different predicted model scores with outcomes. Methods: The TEAM pathology study consists of 3284 postmenopausal hormone positive breast cancer patients treated with either exemestane or tamoxifen followed by exemestane. Accrual was from 2001 to 2006. Genes comprising the multi-parametric Oncotype Dx were used to train signatures to create true assay results. Patient data was then used to calculate recurrence scores through various tools. This included clinico-pathologic models and their respective endpoints PREDICT 2.1 (overall survival at 5 years), INFLUENCE 2.0 (distant metastasis at 5 years), CTS-5 (distant recurrence risk at year 5-10), the purely genomic Oncotype Dx trained results (distant recurrence risk at 9 years), as well as the new clinico-pathologic RSClin (distant recurrence risk at 10 years). We compared the level of association between these predictive model scores using Spearman correlation coefficients. The prognostic ability of each model was contrasted for each outcome using Harrell’s C-statistic. Results: Results were available for CTS-5 (3022 patients), INFLUENCE 2.0 (3485 patients), ODx-trained (3825 patients), and RSClin (3029 patients). Correlation coefficients showed low correlation between Influence ( r= 0.25) and CTS-5 ( r= 0.17) with Oncotype-Dx trained results, and high correlation between RSClin ( r = 0.84) and Oncotype-Dx trained results. The concordance index was similar (0.65 to 0.68) for all models with distant metastasis-free survival as the outcome. Analysis is ongoing and further results will be available at the time of presentation. Conclusions: Other clinico-pathologic tools such as Influence 2.0 and CTS-5 have good prognostic ability when compared to Oncotype Dx-trained results and RSClin. [Table: see text]
Image-only deep learning risk model performance in patients with known germline mutations.
Authors: Sodagari Faezeh , Lehman Constance Dobbins , Mercaldo Sarah , Carney Andrew , Lamb Leslie
Published: June 2023

536

Background: Mammograms contain highly predictive biomarkers of future breast cancer risk, which can be identified by deep learning (DL) risk stratification models. DL model performance in discerning risk in patients with known germline mutations has yet to be established. The aim of this study is to assess image-only DL model risk score performance in patients with and without a germline mutation undergoing screening breast MRI. Methods: This retrospective, multisite study included the first screening MRI of consecutive females ≥30 years from 3/1/2011 to 11/30/2021 at four facilities, with a prior bilateral screening mammogram containing a DL risk score and at least one year of follow-up. A mammography-based DL five-year model was used to assess risk, with an increased-risk threshold of ≥2.2 and high-risk of ≥5.8. Patient demographics, germline mutation status, and traditional risk factors were extracted from electronic medical records. Standard screening performance metrics including cancer detection rate (CDR) within one year of MRI were determined. Cancer outcomes were determined via linkage to a regional tumor registry. DL model performance was compared using Pearson’s chi-squared tests. Results: 4025 patients who underwent screening breast MRI met inclusion criteria. 381(9.5%) had a known germline mutation. There was no significant difference in age of those with or without a germline mutation (54.9y ± 10.5 vs 54.8y ± 8.8, p = 0.284) or family history of breast cancer (68.5% vs 65.3%, p = 0.205). Patients with a germline mutation were more likely to be White (95.0 vs 91.4%, p < 0.05), have non-dense breasts (52.8% vs 35.3%, p < 0.001) and less likely to have a personal history of breast cancer (25.7% vs 36.3%, p < 0.001). The CDR in those with a germline mutation was higher than those without a mutation (39.4 vs 20.3, p < 0.05). The median DL risk score in those with a germline mutation was lower than those without a mutation: 1.9 (IQR: 1.4-2.5) vs 2.3 (IQR: 1.7-3.8), p < 0.001. In patients with a germline mutation, the CDR in those with elevated DL scores was higher than those with low DL scores (47.6 vs 34.2, p = 0.512: increased-risk threshold; 60.6 vs 37.4, p = 0.512: high-risk threshold). A similar trend was seen in those without a germline mutation (26.4 vs 12.8, p < 0.01: increased-risk threshold; 27.1 vs 19.0, p = 0.203: high-risk threshold). Trends were demonstrated across all comparisons, but significance was only reached in the largest group. Conclusions: Compared to patients without germline mutations, those with mutations had higher CDRs on MRI but lower DL risk scores. Patients with higher DL risk scores had higher CDRs in those identified as increased or high-risk by DL model, regardless of germline mutation status. Further study to elucidate mechanisms to explain differential performance of DL models in patients with germline mutations is ongoing.
Effect of astragalus polysaccharides (PG2) treatment of adjuvant chemotherapy-induced fatigue in premenopausal patients with breast cancer.
Authors: Rau Kun Ming , Shen Wen-Chi , Chen Shin-Cheh , Wang Cheng-Hsu , Hsieh Ruey Kuen , Hung Chao-Ming , Peng Mengting , Liu Chien-Ting , Chang Yuehshih , Kuo Wen-Ling , Chou Hsu-Huan , Yeh Kun-Yun , Wu Tsung-Han , Wu Chun-Feng , Pei-Hung Chang , Huang Yen-Min , Yu Chi-Chang , Lee Chun-Hui
Published: June 2023

537

Background: Fatigue is one of the most common symptoms of breast cancer (BC) patients who are receiving adjuvant chemotherapy. Astragalus Polysaccharides (PG2) had been proved to relieve cancer-related fatigue in advanced BC patients. The aim of this study is to evaluate the efficacy of PG2 as a complementary treatment among stage II/III BC patients with adjuvant chemotherapy of epirubicin-cyclophosphamide(EC) regimen in reduction of chemotherapy-induced toxicity and encouraging compliance with chemotherapy. Methods: This double blind, multicenter, phase II trial randomized stage II/III BC patients who would receive adjuvant EC at least 4 cycles to either PG2 500 mg or placebo on day1, 3, 8 every 21 days as the combination. Changes in chemotherapy-related fatigue score (CRFS) was evaluated by the Brief Fatigue Inventory-Taiwanese Form and incidence of Grade 3/4 neutropenia were the primary endpoints. Results: A total of 66 eligible patients were enrolled and equally randomized to PG2 and placebo groups, 30 cases in each group completed this trial. In general, there was no significant difference in the mean change of CRFS and fatigue intensity between the groups. But the CRFS and fatigue intensity in premenopausal-PG2 group were less aggravated after 4 cycles of EC than that of postmenopausal-placebo group. Persisted significance difference in CRFSs from cycle 1 day 5 (PG2: 0.6; Placebo: 1.9, P = 0.023) to cycle 4 day 15 (PG2: -0.3; Placebo: 0.7, P = 0.002). In all population, a lower proportion of patients suffered from grade 3/4 neutropenia from cycle 1 to cycle 4 were observed in the PG2 group compared to the placebo group (78.8% vs. 87.9% in intent-to-treat population). Conclusions: PG2 combined with adjuvant EC significantly improved adjuvant EC-induced fatigue in premenopausal BC patients. PG2 assists these patients with maintaining normal daily life and job activities, also less need of family support during chemotherapy. Furthermore, patients treated with PG2 might have better compliance to complete the whole course of adjuvant chemotherapy. Clinical trial information: NCT03314805 .
Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer.
Authors: Takahashi Yuko , Sasada Shinsuke , Kondo Naoto , Hashimoto Hiroya , Terata Kaori , Sagara Yasuaki , Naito Yoichi , Kida Kumiko , Ueno Takayuki , Anan Keisei , Suto Akihiko , Kanbayashi Chizuko , Takahashi Mina , Nakamura Rikiya , Ishiba Toshiyuki , Tsuneizumi Michiko , Nishimura Seiichiro , Hara Fumikata , Shien Tadahiko , Iwata Hiroji
Published: June 2023

538

Background: Adjuvant endocrine therapy (ET) is the standard of care for Estrogen Receptor (ER)-positive early-stage breast cancer. However, many patients suffer from adverse events associated with ET. The prognosis of patients with T1a/bN0 breast cancer with ER-positive and human epidermal growth factor 2 (HER2)-negative is excellent, and it is not clear whether adjuvant ET should be recommended. Here we evaluate the effect of adjuvant ET for ER-positive and HER2-negative T1a/bN0M0 breast cancer. Methods: This study was a multicenter, retrospective cohort study that evaluated adjuvant ET for patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer. Patients who underwent surgery between 2008 and 2012 in 47 institutions of the Japan Clinical Oncology Group (JCOG) breast cancer group were eligible. We analyzed the cumulative incidence of distant metastasis as primary endpoint using the Gray test model and time to event endpoints (distant disease free survival and overall survival) using log-rank test between patients treated with and without adjuvant ET. We also used Gray test model for the analysis of the cumulative incidence of ipsilateral and contralateral breast cancer. Predictive factors were assessed using the Fine-Gray model and the Cox proportional hazards model. Results: The median follow-up period was 9.2 years. Of 4758 eligible patients (1202 T1a [25.3%] and 3556 T1b [74.7%] diseases), 3991 (83.9%) received adjuvant ET. The 9-year cumulative incidence of distant metastasis was 1.5% with ET and 2.6% without ET (adjusted subdistribution hazard ratio [sHR], 0.54; 95% CI, 0.32-0.93). In the multivariate analysis, the independent risk factors of distant metastasis were no ET, mastectomy, high grade, and lymphatic invasion. The 9-year overall survival was 97.0% and 94.4% (HR, 0.54; 95% CI, 0.38-0.77). Adjuvant ET reduced the incidence of ipsilateral and contralateral breast cancer (9-year rates; 1.1% vs 6.9%; sHR, 0.17; 95% CI 0.11-0.28, and 1.9% vs 5.2%; sHR, 0.33; 95% CI, 0.22-0.49). Conclusions: Adjuvant endocrine therapy significantly reduces distant metastases, however the absolute difference is small for ER-positive and HER2-negative T1a/bN0M0 breast cancer. Furthermore, it reduced ipsilateral and contralateral breast cancer as well. Shared decision making regarding the omission of adjuvant endocrine therapy is crucial, especially in patients with low risk of distant metastasis.
Impact of endocrine therapy adherence on racial disparities in breast cancer survival.
Authors: Lee Kimberley T , Buhlmann Melanie , Gwede Clement K , Gore L. Robert , Pan I-Wen , Luo Yi , Tworoger Shelley S , Vadaparampil Susan Thomas , Jim Heather S.L.
Published: June 2023

541

Background: Black women have worse breast cancer outcomes compared to their White counterparts, even for hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer (BC). This tumor type is usually treated with 5-10 years of adjuvant endocrine therapy (ET) to reduce risk of BC recurrence and improve survival. We investigated the impact of adherence to ET on racial differences in survival for HR+ HER2- BC survivors. Methods: We conducted a population-based, retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, which links demographic and clinical data with cause of death for persons with cancer and Medicare claims for covered health services. We examined 9,039 women with HR+ HER2- stage I-III BC diagnosed between 2007 and 2016, who received primary breast surgery and initiated ET. Adherence to ET was measured using the medication possession ratio (MPR), which assesses the proportion of time a patient has medication available via filled prescriptions. As in established literature, we defined ET adherence as MPR > = 80%. Causal mediation analysis was performed to measure to impact of adherence on survival disparities between Black and White BC survivors. Results: Mean age at diagnosis was 72 years, 6.5% were Black, and 20.9% were dual eligible for Medicaid (a surrogate for socioeconomic hardship). Most had stage I or II breast cancer (69.3%) and mastectomy as primary surgery (69.7%). Nineteen percent received chemotherapy and 62.5% received radiation. In univariate analyses, factors associated with ET adherence were Black race (OR 0.62, 95% CI 0.54-0.75), insured by Medicaid (OR 0.72, 95% CI 0.65-0.81), being married (OR 1.14, 95% CI 1.03-1.25), and increased comorbidities (Charlson score > = 2) (OR 0.88, 95% CI 0.78-0.99). Age, BC stage, type of surgery, and receipt of chemotherapy or radiation were not associated with ET adherence. In multivariable models adjusting for age, race, marital status, Medicaid eligibility, and Charlson score, Black race and Medicaid eligibility remained inversely associated with ET adherence (OR 0.70, 95% CI 0.59-0.83 and OR 0.77, 95% CI 0.69-0.87 respectively). Among those who were adherent to ET, Black women had 43% higher risk of mortality compared to White women (HR 1.43, 95% CI 1.17-1.76). In mediation analysis, 4.25% of the observed survival disparity between Black and White women can be explained by differences in ET adherence. Conclusions: We identified racial disparities in ET adherence and overall survival among women with BC. Adherence to ET accounted for a small percentage of racial disparities in survival. Further research is needed to delineate other factors contributing to ET non-adherence among Black women and to investigate additional factors contributing to known disparities in BC survival.
Validation of a novel and rapid reagent free assay to predict outcomes for adjuvant therapy decision making in hormone receptor-positive breast cancer.
Authors: Coombes Charles , Amrania Hemmel , Angelou Christina , Al-Khalili Zamzam , Ellis Ian O. , Francescatti Darius , Phillips Chris , Green Andrew R. , Wright Nicholas , Rakha Emad A. , Palmieri Carlo
Published: June 2023

545

Background: Digistain is a mid-infrared imaging technology that assesses aneuploidy by measuring the nuclear-to-cytoplasmic chemical ratio in the cellular content of tissues to generate the Digistain Index (DI). DI correlates with tumor grade and shows promise for risk stratification. Here we investigated whether DI could predict clinical outcomes in patients with early breast cancer to guide decision making regarding subsequent adjuvant chemotherapy. Methods: Infrared spectrometry was performed on existing tissue microarrays to determine the DI of 801 patients with hormone receptor-positive, HER 2-negative primary breast cancer with ≤3 positive lymph nodes who had received systemic endocrine therapy only. Multivariate logistic modelling incorporated the DI with pathological features to generate the Digistain Prognostic Score (DPS). Receiver operator characteristics curves were used to assess the ability of DPS to predict 5- and 10-year progression-free survival (PFS), recurrence and overall survival (OS). Results: In a Cox-regression analysis, the hazard ratio (HR) of DI to predict OS was 4.49 (95% CI 1.08–18.67; P=0.039) compared with HRs in the range of 1.04–1.81 (all P < 0.001) for age, tumor grade, tumor size and lymph node stage. In multivariate modelling analysis, DPS was consistently highly accurate and had negative predictive values for PFS, recurrence, and OS at 5 and 10 years that were similar, if not superior, to existing genomic-based tests. Using the DPS, the HRs for Kaplan-Meier curves for low- vs. high-risk classification were statistically significant (P<0.001) for PFS, recurrence and OS (1.80, 1.83 and 2.49, respectively). Conclusions: In patients with early breast cancer, DPS showed high accuracy and predictive performance, and was able to stratify patients into low or high risk. Considering its low cost and ability to provide almost immediate prognostic information, DPS has the potential to offer clinical utility to reduce the use of unnecessary chemotherapy.
Cardiac safety and efficacy for patients with early-stage breast cancer treated with pegylated liposomal doxorubicin (PLD) or doxorubicin.
Authors: Tang Lichen , He Min , Wu Jiong , Wang Zhonghua , Liu Guangyu , Yu Keda , Geng Cuizhi , Fan Zhimin , Ling Rui , Qiao Guangdong , Cai Li , Luo Ting , Jin Feng , Wang Haibo , Zhang Anqin , Zhang Hongwei , Zeng Xiaohua , Wang Xiaojia , Jiang Ming , Zhimin Shao
Published: June 2023

550

Background: Anthracyclines play an important role in the treatment of breast cancer (BC) while cardiotoxicity, a serious side effect, limits the clinical application. Pegylated liposomal doxorubicin (PLD) is a new dosage form of doxorubicin encapsulated in liposomes, which can reduce the plasma free level of doxorubicin and drug to normal tissue delivery, thereby reducing cardiotoxicity. The aim of this study was to evaluate the cardiac safety and efficacy of PLD compared with doxorubicin as adjuvant therapy in breast cancer patients. Methods: This is an open-label, randomized trial involving patients with operable breast cancer who were at high risk of recurrence after radical sugery (NCT03949634). Patients were randomized (1:1) to receive adjuvant PLD or doxorubicin (A) and cyclophosphamide followed by taxanes ± trastuzumab. The primary endpoint was cardiotoxicity, which was defined as congestive heart failure (CHF) with clinical symptoms, or no symptoms but with an abnormal left ventricular ejection fraction (LVEF). Secondary endpoints included 5-year disease-free survival (DFS) rate, 5-year overall survival (OS) rate and safety. Results: Between November 2017 and September 2019, 247 patients were randomized and received study treatment (PLD arm, 131; A arm, 116). The median age was 49 years (range, 26-67) in PLD arm and 48 years (range, 25-70) in A arm. The pathological stages were 18.3% stage I, 58.0% stage II, and 22.1% stage III in PLD arm, while those of A arm were 20.7% stage I, 59.5% stage II, and 19.8% stage III. The median follow-up time was 43.0 months. The incidence of abnormal LVEF was 0 in the PLD arm and 1.7% the A arm (P = 0.220). The incidence of CHF was 0 in the PLD arm and 0.9% the A arm (P = 0.470). Survival data analysis is immature. The exploratory analysis of cardiac-related biomarkers showed that the incidence of high-sensitivity cardiac troponin-T (hs-cTnT) was lower in PLD arm than in A arm (3.8% vs. 30.2%, P < 0.001). Grade 3/4 adverse events (AEs) occurred in 42.7% patients in PLD arm and in 61.2% patients in A arm. The most common grade 3/4 AEs in PLD arm and A arm included neutropenia (34.4% vs. 55.2%), leukopenia (30.5% vs. 39.7%), and hand-foot syndrome (4.6% vs. 0.0%). Conclusions: Hs-cTnT elevation may have a role in the AE prediction of antharcycline. PLD usage may present lower incidence of cardiotoxicity than doxorubicin in the adjuvant treatment of patients with early-stage breast cancer. Clinical trial information: NCT03949634 .
In situ immune impact of nivolumab + ipilimumab combination before standard chemoradiation therapy (RTCT) for FIGO IB3-IVA in patients (pts) with cervical squamous carcinoma: COLIBRI trial, a GINECO study.
Authors: Ray-Coquard Isabelle Laure , Kaminsky-Forrett Marie-Christine , Ohkuma Ryotaro , De Montfort Aymeric , Joly Florence , Treilleux Isabelle , Ghamry-Barrin Sarah , Bello-Roufai Diana , Saintigny Pierre , Angelergues Antoine , Michon Lucas , Hardy-Bessard Anne-Claire , Lainé Alexandra , Savoye Aude-Marie , Berthet Justine , Caux Christophe , Lecuru Fabrice , Dubois Bertrand , Lagarde Bétrian Sarah
Published: June 2023

5501

Background: We report the results of a window-of-opportunity phase 2 trial using neoadjuvant nivolumab + ipilimumab followed by standard chemoradiation therapy (RTCT) in cervical squamous cell carcinoma pts using the CD8+/FOXP3+ ratio as a surrogate marker of immune checkpoint blockade (ICB) in situ effect. Association with better clinical outcome after neoadjuvant chemotherapy and higher CD8+/FOXP3+ ratio was described in cervical cancer pts. However, immune modulation after ICB and correlation with treatment response needs to be characterized. Methods: The primary objective was to explore the changes in the ratio of CD8+/FOXP3+ in tumor biopsies performed before and after ICB (prior to standard RTCT) by multiplex-immunofluorescence (mIF) analyzing densities of CD8 effector T cells (CD8+: CD3+CD8+FOXP3-) and CD4 regulatory T cells (FOXP3+: CD3+CD8-FOXP3+). To normalize the distribution of the values, mIF data were log-transformed (log10). Targeted gene expression profiling of 2,549 genes using HTG technology allowed us to evaluate the 27-gene based ‘HOT’ score reported to be associated with immunologically active tumors (Foy J-P. et al., 2022, Eur J Can). Results: Pts received 1 cycle of nivolumab 3 mg/kg (D1D15) + ipilimumab 1 mg/kg (D1) before starting RTCT + brachytherapy. After RTCT, pts could continue nivolumab in maintenance 480 mg total dose every 28 days for 6 months. Forty pts were treated (including 50% FIGO III-IV). There were no new or unexpected toxicity. Grade≥3 AEs related to ICB occurred in 3 pts. mIF data of the 28 evaluable pts revealed an increase of total CD8+ cells (Wilcoxon, p=0.009), proliferating CD8+ cells (p=0.002) and CD8+/FOXP3+ ratio (p=0.03) between baseline and before RTCT. In the 37 pts evaluable by HTG, a significant increase of expression of the CD8A gene (paired t-test, p=2.2e-05) and the ‘HOT’ score (paired t-test, p=3.1e-06) was observed after ICB. The Objective Response Rate on primary tumor before, after, at the end of treatment (EOT) is reported in table. Correlation between CD8+/FOXP3+ ratio, the ‘HOT’ score and response to treatment will be presented. Conclusions: These data indicate that neoadjuvant nivolumab + ipilimumab is safe and orchestrates de novo immune responses in cervical squamous cell carcinoma. The 82.5% CR rate on primary tumor 6 months post RTCT suggests favorable clinical outcomes. Clinical trial information: NCT04256213 . [Table: see text]
Influence of adherence to adjuvant endocrine therapy in early breast cancer: Results from a large German real-world claims data analysis.
Authors: Dannehl Dominik , Engler Tobias , Dijkstra Tjeerd , Gutsfeld Raphael , von Au Alexandra , Hahn Markus , Hawighorst-Knapstein Sabine , Chaudhuri Ariane , Wallwiener Markus , Bauer Armin , Brucker Sara , Wallwiener Stephanie , Hartkopf Andreas Daniel
Published: June 2023

551

Background: In hormone-receptor positive (HR+) early breast cancer (EBC) adjuvant endocrine therapy (ET) significantly reduces recurrence and mortality. The most common way to estimate therapy adherence is the use of patient reported outcome measures. Yet, this method is inaccurate due to the social-desirability bias. We therefore aimed to analyze adherence to ET over the first 5 years of treatment by using claims data from a large German health insurance provider (AOK Baden-Wuerttemberg). Methods: Female patients diagnosed with HR+ EBC between July 1st 2010 and December 31st 2019 were included into the analysis. Adherence to ET was defined as the ratio of the summed number of pills of filled prescriptions for ET (either aromatase inhibitors or tamoxifen) and the duration of endocrine therapy in days (from the start of the first prescription after completion of surgery and chemotherapy, if applicable). ET administration was observed over 5 years. High/low adherence was defined as a ratio between 0.8 – 1 and 0 – 0.8, respectively. ET duration was divided into yearly intervals and adherence was calculated as above. Continuous high/low adherence was then defined as an adherence between 0.8 – 1 and 0 – 0.8 in each year. Distant recurrence-free survival (DRFS) was calculated from the day of the first diagnosis of EBC until onset of distant metastatic disease. Overall survival (OS) was defined as the period between first diagnosis of EBC until death. Results: In total, 20998 patients were included. 17006 patients (81%) were HR+. Regarding overall adherence during the first 5 years, average adherence was 0.81 ± 0.26, with 72% of all HR+ patients showing high adherence to ET. Of 17006 HR+ EBC patients, 8363 (49%) showed a continuous high adherence to ET and 1731 (10%) showed a continuous low adherence to ET over 5 consecutive years. Continuous adherence to endocrine therapy had a significant impact on DRFS (HR: 0.61; 95% CI: 0.52 - 0.71; p < 0.0001) and OS (HR: 0.52; 95% CI: 0.46 -0.59; p < 0.0001). The 10-year OS rate was 79% / 64% for patients with continuous high / low adherence to endocrine therapy. Conclusions: As measured by the number of prescribed pills, adherence during the first 5 years of endocrine therapy was higher than expected by literature. Continuous adherence to ET over 5 years has a significant impact on OS and DRFS. Future research should focus on identifying factors that influence therapy adherence in HR+ EBC patients.
Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC).
Authors: Liu Joyce F. , Fu Siqing , Richardson Gary Edward , Vranjes Zivko , Meniawy Tarek , Shannon Catherine M. , Hamilton Erika P. , Blank Stephanie V. , Mathews Cara Amanda , Alidzanovic Jasmina , Ruseva Rossitza Krasteva , Shi Qing , Harismendy Olivier , Ptaszynski Ann M. , Westin Shannon Neville , Meric-Bernstam Funda , Thaker Premal H.
Published: June 2023

5513

Background: Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor demonstrating single-agent antitumor activity. Azenosertib may inhibit CT-induced DNA damage repair and provide benefit in pts with platinum R/R EOC. Cyclin E1 amplification/overexpression is present in ≥35% of metastatic ovarian cancer. High expression/amplification of Cyclin E1 is a poor prognostic marker and predictive of lack of response to platinum-based CT. Ovarian models overexpressing Cyclin E1 have exquisite sensitivity to azenosertib in vitro and in vivo; forced Cyclin E1 overexpression sensitizes cell lines with low endogenous Cyclin E1 to azenosertib. Methods: This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Primary endpoint is safety and identification of RP2D of each combination. Secondary endpoints include clinical activity. Azenosertib was given continuously or intermittently QD in 21 or 28D cycles until PD or unacceptable toxicity. Results: 103 pts were enrolled; at data cut-off, 94 were efficacy evaluable. 26.6% had a partial response (PR) and median progression free survival (PFS) = 9.03 mo (95%CI: 5.52-11.01). Azenosertib + PAC demonstrated the highest ORR [9/18 (50%)], followed by Carbo [9/27 (33.3%)]; ORR for azenosertib + PLD or + GEM was 14.3% (5/35, 2/14 respectively). 80 pts had available Cyclin E1 expression data by IHC; higher Cyclin E1 (H-score >50) correlated with higher ORR and longer PFS (ORR = 31.3% vs 7.7%; PFS = 10.35 vs 3.25 mo, HR=0.3; Table). Frequent Grade ≥3 TEAEs (%) were neutropenia (44.4), thrombocytopenia (30.3), anemia (12.1), leukopenia (11.1), fatigue (10.1), diarrhea (6.1), nausea (5.1), and vomiting (5.1). Conclusions: Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC. Clinical trial information: NCT04516447 . [Table: see text]