Early-stage Hormone Receptor-positive Breast Cancer Research Articles

Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18

BackgroundStatins are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, statins may possess anticancer properties and interact with receptor activator of nuclear factor κB ligand expression. We aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18.Patients and methodsABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor-positive BC receiving a nonsteroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post hoc analysis, we investigated the effects of concomitant statin therapy on recurrence risk (RR) of BC, fracture risk and bone mineral density (BMD).ResultsIn the study population (n = 3420), statin therapy (n = 824) was associated with worse disease-free survival (DFS) [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.04-1.75; P = 0.023]. While no significant effect of lipophilic statins (n = 710) on RR was observed (HR 1.30, 95% CI 0.99-1.72; P = 0.062), patients on hydrophilic statins (n = 87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; P = 0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21-5.68; P = 0.014). However, this effect subsided after correction for confounders in the sensitivity analysis. No association between statin use and fracture risk or osteoporosis was observed.ConclusionAccording to this analysis, hydrophilic statins showed a detrimental effect on DFS in the main model, which was attenuated after correction for confounders. Our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins.

Abstract P1-15-01: Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18

Abstract Background Statins are a common class of cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, it was suggested that statins may possess anti-cancer properties and interact with RANK ligand expression. Therefore, we aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18. Methods ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor (HR) positive BC receiving a non-steroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post-hoc analysis, we investigated the potential effects of concomitant statin therapy on recurrence risk of BC, fracture risk and bone mineral density (BMD) using time-dependent Cox proportional hazards models. Sensitivity analyses accounting for immortal time and confounding bias were performed. Results In the analysis of the study population (n=3,420), statin therapy (n=824) was associated with worse disease-free survival (DFS) (HR 1.35, 95%; CI 1.04-1.75; p=0.023). Sensitivity analysis relativized these results (HR 1.22, 95% CI 0.94 - 1.59; p=0.14). While there was no significant effect of lipophilic statins (n=710) on recurrence risk (HR 1.30, 95% CI 0.99 - 1.72; p=0.062), patients on hydrophilic statins (n=87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; p=0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21 - 5.68; p=0.014). No association between statin use and fracture risk or osteoporosis was observed. Conclusion In this population of early-stage breast cancer patients from a prospective randomized study, an association of hydrophilic statins with increased recurrence risk was observed. According to this retrospective analysis hydrophilic statins may increase recurrence risk especially in patients treated with denosumab. Still, our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins. Therefore, no final conclusion is possible. This hypothesis generating result warrants further exploration. Citation Format: Christoph Minichsdorfer, Thorsten Fuereder, Michael Leutner, Christian F. Singer, Stephanie Kacerovsky-Strobl, Daniel Egle, Richard Greil, Marija Balic, Florian Fitzal, Georg Pfeiler, Sophie Frantal, Rupert A. Bartsch, Michael Gnant. Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-15-01.

Health-related quality of life among elderly breast cancer patients treated with adjuvant endocrine therapy: a U.S Medicare population-based study.

The evidence regarding the impact of individual adjuvant endocrine therapies (AET) on health-related quality of life (HRQoL) is limited. We aimed to assess the association between the type of AET and HRQoL and to examine the relationship between HRQoL and one-year mortality among women with breast cancer in the USA. This retrospective cross-sectional study used the 2006-2017 Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey database to identify older women with early-stage hormone receptor-positive breast cancer. Multivariate linear regressions were used to assess the association between types of AET (anastrozole, letrozole, exemestane, and tamoxifen) and HRQoL scores (physical component summary (PCS) and mental component summary (MCS)). Multivariate logistic regressions were used to predict the impact of PCS and MCS on one-year mortality. Out of 3537 older women with breast cancer, anastrozole was the most commonly prescribed (n = 1945, 55.0%). Regarding PCS, there was no significant difference between the four AET agents. Higher MCS scores, which indicate better HRQoL, were reported in patients treated with anastrozole (vs. letrozole [β = 1.26, p = 0.007] and exemestane [β = 2.62, p = 0.005) and tamoxifen (vs. letrozole [β = 1.49, p = 0.010] and exemestane [β = 2.85, p = 0.004]). Lower PCS and MCS scores were associated with higher one-year mortality, regardless of type of AET initiated, except for tamoxifen in MCS. Although there was no significant difference in physical HRQoL scores between AET agents, anastrozole and tamoxifen were associated with better mental HRQoL scores.

Can We Successfully De-Escalate Axillary Surgery in Women Aged ≥ 70 Years with Ductal Carcinoma in Situ or Early-Stage Breast Cancer Undergoing Mastectomy?

Omission of sentinel lymph node biopsy (SLNB) in older women with clinically node-negative, hormone receptor-positive (HR+) early-stage breast cancer undergoing lumpectomy is accepted, given established low rates of regional recurrence. The safety of omitting SLNB in women undergoing mastectomy is unknown and may differ depending on extent of breast disease and variation in radiotherapy use. From 2006 to 2018, 123 cTis and 328 cT1-2 HR+/HER2- tumors from 410 women aged ≥ 70 years who underwent mastectomy and SLNB were included (41 bilateral cases). The rate of nodal positivity and effect of nodal positivity on adjuvant therapy use were examined. Median age was 74 years; 21% of patients had positive sentinel lymph nodes, 7% had micrometastases, and 14% had macrometastases. Of cases of cTis tumors, 31% were upstaged to invasive carcinoma; 1% had macrometastases. Fewer cases of cT1 than cT2 tumors had macrometastases [13% (26/200) versus 29% (37/128); p < 0.001]. Eight percent of patients with pT1 tumors (18/228) and 27% of patients with pT2 tumors (30/113) received chemotherapy. Most patients with pT1, pN1 disease (78%; 25/32) did not receive chemotherapy. Rates of locoregional recurrence were similar between patients with cT1 or cT2 tumors with and without nodal metastases (median follow-up, 4.5 years). Women aged ≥ 70 years with cTis and cT1N0 HR+/HER2- tumors who underwent mastectomy had low rates of nodal positivity, similar to rates reported for lumpectomy. Given this and the RxPONDER results, omission of SLNB may be considered, as findings are unlikely to alter adjuvant therapy recommendations.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

Fatigue and endocrine symptoms among women with early breast cancer randomized to endocrine versus chemoendocrine therapy: Results from the TAILORx patient-reported outcomes substudy.

TAILORx (Trial Assigning Individualized Options for Treatment) prospectively assessed fatigue and endocrine symptoms among women with early-stage hormone receptor-positive breast cancer and a midrange risk of recurrence who were randomized to endocrine therapy (E) or chemotherapy followed by endocrine therapy (CT+E). Participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue, the Patient-Reported Outcomes Measurement Information System-Fatigue Short Form, and the Functional Assessment of Cancer Therapy-Endocrine Symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Linear regression was used to model outcomes on baseline symptoms, treatment, and other factors. Participants (n = 458) in both treatment arms reported greater fatigue and endocrine symptoms at early follow-up in comparison with the baseline. The magnitude of change in fatigue was significantly greater for the CT+E arm than the E arm at 3 and 6 months but not at 12, 24, or 36 months. The CT+E arm reported significantly greater changes in endocrine symptoms from the baseline to 3 months in comparison with the E arm; change scores were not significantly different at later time points. Endocrine symptom trajectories by treatment differed by menopausal status, with the effect larger and increasing for postmenopausal patients. Adjuvant CT+E was associated with greater increases in fatigue and endocrine symptoms at early time points in comparison with E. These differences lessened over time, and this demonstrated early chemotherapy effects more than long-term ones. Treatment arm differences in endocrine symptoms were more evident in postmenopausal patients. Participants in TAILORx (Trial Assigning Individualized Options for Treatment) with early-stage hormone receptor-positive breast cancer and an intermediate risk of recurrence were randomly assigned to endocrine or chemoendocrine therapy. Four hundred fifty-eight women reported fatigue and endocrine symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Both groups reported greater symptoms at early follow-up versus the baseline. Increases in fatigue were greater for the chemoendocrine group than the endocrine group at 3 and 6 months but not later. The chemoendocrine group reported greater changes in endocrine symptoms in comparison with the endocrine group at 3 months but not later.

Oncologists’ perspectives on omission of sentinel lymph node biopsy in women &gt;70 years with early-stage hormone receptor-positive breast cancer.

48 Background: Trial data show that omission of surgical axillary staging does not affect overall survival in women &gt;70 with cT1N0 hormone receptor-positive (HR+) breast cancer, and the Society of Surgical Oncology’s Choosing Wisely recommendations advise against routine use of sentinel lymph node biopsy (SLNB) in patients with early-stage HR+ cancers. Despite this, almost 80% of women eligible for omission still undergo SLNB. We sought to explore oncologists’ perspectives of omission of SLNB in this patient population. Methods: We conducted an exploratory qualitative study using semi-structured telephone interviews with surgical, medical, and radiation breast oncologists throughout North America from 3/2020 to 1/2021. Purposive snowball sampling ensured a range of practice types. Interviews were transcribed and a team trained in qualitative analysis undertook thematic analysis guided by grounded theory to identify emergent themes. Results: Participants included sixteen surgical, six medical, and seven radiation oncologists (55% female) (Table). Overall, while oncologists in all fields expressed acceptance regarding SLNB omission in certain women &gt;70 with cT1N0 HR+ disease, many viewed it as a complex choice based on patient comorbidities, chronologic age, patient preferences, and disease factors. Although patients’ physiologic age and life expectancy were also important decisional factors, almost all participants assessed these subjectively despite knowing that validated tools existed. Most surgeons perceived the data backing the Choosing Wisely recommendation as weak, although knowledge of specific supporting studies was low. While all participants agreed that SLNB omission does not affect survival, several radiation oncologists expressed anxiety about resultant increased regional recurrence risk. In the absence of known nodal status, medical and radiation oncologists stated they were more likely to order additional imaging, rely on OncotypeDX scores to make systemic therapy decisions, add high tangents, and be reluctant to offer partial breast irradiation. Conclusions: While surgeons are aware of the Choosing Wisely recommendation, high SLNB rates in patients eligible for omission may be driven by perceptions of the quality of the supporting data and differing ideas regarding appropriate candidacy for omission. There are downstream effects of SLNB omission on medical and radiation oncology treatment decision making and surgeons should engage in multidisciplinary discussion prior to surgery.[Table: see text]

Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics.

Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.

Competing Nomogram for Late-Period Breast Cancer-Specific Death in Patients with Early-Stage Hormone Receptor-Positive Breast Cancer

BackgroundMore than half of early breast cancer recurrences occur after 5 years from the initial diagnosis. An individualized estimate of the risk of late-period breast cancer-specific death (LP-BCSD) after 5 years of endocrine therapy (ET) can improve decision-making for extended endocrine therapy (EET). Materials and MethodsA total of 147,059 eligible patients with breast cancer who survived 5+ years after diagnosis between 1990 and 2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses based on the competing risk regression model were used to evaluate predictive factors for high risk of LP-BCSD or late-period non-breast cancer-specific death (LP-non-BCSD). Significant factors were used to build a nomogram to individualize estimates of LP-BCSD or LP-non-BCSD. ResultsThe 5- and 10-year LP-BCSD rates were 5.7% and 10.1%, respectively, and the 5- and 10-year LP-non-BCSD rates were 6.7% and 15.5%, respectively. Young age, black race, single marital status, poor differentiation, large tumor size, lymph node metastasis, and estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) status were independent predictive factors for high risk of LP-BCSD. Age was the most important factor for predicting high risk of LP-non-BCSD. The nomograms, which were based on significant factors identified by the competing risk regression model. A risk score system based on the competing risk nomogram was established to describe the relative risk of LP-BCSD and LP-non-BCSD. ConclusionThis study explored the novel endpoint of LP-BCSD for further clinical trials. The risk score system might be highly useful for patient counseling, especially in discussing EET options with elderly or comorbid patients.

Deep learning from HE slides predicts the clinical benefit from adjuvant chemotherapy in hormone receptor-positive breast cancer patients

We hypothesized that a deep-learning algorithm using HE images might be capable of predicting the benefits of adjuvant chemotherapy in cancer patients. HE slides were retrospectively collected from 1343 de-identified breast cancer patients at the Samsung Medical Center and used to develop the Lunit SCOPE algorithm. Lunit SCOPE was trained to predict the recurrence using the 21-gene assay (Oncotype DX) and histological parameters. The risk prediction model predicted the Oncotype DX score > 25 and the recurrence survival of the prognosis validation cohort and TCGA cohorts. The most important predictive variable was the mitotic cells in the cancer epithelium. Of the 363 patients who did not receive adjuvant therapy, 104 predicted high risk had a significantly lower survival rate. The top-300 genes highly correlated with the predicted risk were enriched for cell cycle, nuclear division, and cell division. From the Oncotype DX genes, the predicted risk was positively correlated with proliferation-associated genes and negatively correlated with prognostic genes from the estrogen category. An integrative analysis using Lunit SCOPE predicted the risk of cancer recurrence and the early-stage hormone receptor-positive breast cancer patients who would benefit from adjuvant chemotherapy.

Risk evaluation of early-stage hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer patients: a population-based study from Taiwan

To assess the prognostic value of the Dutch criteria for patients with early-stage hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer from the Taiwan Cancer RegistryDatabase. We included 8295 patients with early-stage node-negative breast cancer who underwent surgery during January 2008-December 2012. Patients were stratified into low- and high-risk groups based on the Dutch criteria. The Kaplan-Meier method and log-rank test were used to estimate the difference in breast cancer-specific survival (BCSS) and overall survival (OS) between groups. Multivariable analysis was used to evaluate the prognostic value of the Dutch criteria. Overall, the low-risk and high-risk groups comprised 5375 and 2920 patients, respectively. In the low- and high-risk groups, the 5-year BCSS rate was 99.6% and 98.2% (P < 0.0001) and the 5-year OS rate was 98.3% and 96.8% (P < 0.0001), respectively. The hazard ratio for BCSS was 4.18 (95% confidence interval [CI] 2.63-6.63, P < 0.0001), and the hazard ratio for OS was 1.94 (95% CI 1.48-2.55); both were significantly poorer in the high-risk group than in the low-risk group. In the low-risk group, the 5-year BCSS and OS of patients who did and did not receive adjuvant chemotherapy were similar (99.5% versus 99.6% [P = 0.927] and 98.8% and 98.1% [P = 0.0683], respectively). The prognosis of low-risk patients as classified using the Dutch criteria is excellent with or without adjuvant chemotherapy. The benefit of multi-gene testing for chemotherapy decision-making might be minimal in these patients.

Further Evidence That OPG rs2073618 Is Associated With Increased Risk of Musculoskeletal Symptoms in Patients Receiving Aromatase Inhibitors for Early Breast Cancer.

BackgroundAromatase inhibitors (AI) reduce recurrence and death in patients with early-stage hormone receptor-positive (HR +) breast cancer. Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common and may lead to early AI discontinuation. The objective of this study was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS.MethodsWomen with stage 0-III HR + breast cancer initiating adjuvant AI were enrolled in a prospective clinic-based observational cohort. AIMSS were assessed by patient-reported outcomes (PRO) including the PROMIS pain interference and physical function measures plus the FACT-ES joint pain question at baseline and after 3 and 6 months. For the primary analysis, AIMSS were defined as ≥ 4-point increase in the pain interference T-score from baseline. Secondary AIMSS endpoints were defined as ≥ 4-point decrease in the physical function T-score from baseline and as ≥ 1-point increase on the FACT-ES joint pain question from baseline. The primary hypothesis was that TCL1A rs11849538 would be associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL were also analyzed assuming a dominant genetic effect and prespecified direction of effect on AIMSS using univariate logistic regression with an unadjusted α = 0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane, and the type of AI using multivariable logistic regression.ResultsA total of 143 participants with PRO and genetic data were included in this analysis, most of whom were treated with anastrozole (78%) or letrozole (20%). On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS (odds ratio = 1.29, 95% confidence interval: 0.55–3.07, p = 0.56). In the statistically uncorrected secondary analysis, OPG rs2073618 was associated with AIMSS defined by worsening on the FACT-ES joint pain question (OR = 3.33, p = 0.004), and this association maintained significance after covariate adjustment (OR = 3.98, p = 0.003).ConclusionCarriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping can be used to identify individuals with HR + early breast cancer in whom alternate endocrine therapy or interventions to enhance symptom detection and implement strategies to reduce musculoskeletal symptoms may be needed.

The cost impact of unselective vs selective MammaPrint testing in early-stage breast cancer in Southern Africa

BackgroundMammaPrint (MP) has been applied in South Africa (SA) for decision-making in early-stage hormone receptor-positive breast cancer since 2006. The cost-impact of MP in SA has not been assessed. AimTo assess different MP testing strategies for cost-minimization in early-stage breast carcinoma using a funder perspective. MethodsClinico-pathologic information was extracted from a prospectively collected database. Clinical risk stratification was done using Adjuvant Online! (AOL) and the Predict V2.1 algorithm (www.predict.nhs.uk). An unselected MP testing strategy was compared to a selective strategy, testing only clinically high risk (cHigh) patients. Excluding human epidermal growth factor receptor-2 positive tumours, the costs for chemotherapy treatment and MP using funding data were used to evaluate the financial impact of these strategies. ResultsIn 583 patients with 601 tumours, 52% were clinically low risk (cLow) (AOL) while the average Predict 10-year survival with chemotherapy was 2.9%. MP correlated strongly with Predict and 318 (60%) patients were MP low risk. Unselective testing allowed omission of chemotherapy in 44 (8.4%) patients but escalated cost by 57.7%. Using a selective testing strategy, only 251 would be tested, de-escalating treatment in 138 (55%) and reducing cost by 19.5%. Considering a Predict value up to 3.2% as cHigh, cost would be up to 7.3% (p = 0.0467) lower with a selective testing strategy. ConclusionMP allowed reduction in the use of adjuvant chemotherapy. Unselective use of MP increases overall costs. A selective testing strategy through clinical risk stratification using AOL/Predict results in substantial cost saving.

Utility of the 70-gene MammaPrint assay for prediction of benefit from extended letrozole therapy (ELT) in the NRG Oncology/NSABP B-42 trial.

502 Background: The 70-gene MammaPrint (MP) assay predicts risk of distant recurrence (DR) in hormone-receptor positive early-stage breast cancer and classifies cancers as Low Risk or High Risk. NSABP B-42 evaluated ELT in patients (pts) who had completed 5 yrs of adjuvant endocrine therapy (tx). The primary objective was to determine the utility of MP to identify pts enrolled in NSABP B-42 who are likely to benefit from ELT. Methods: A total of 1,866 pts from B-42 had available MP results. Primary endpoint is DR. Secondary endpoints are disease-free survival (DFS) and breast cancer-free interval (BCFI). For the primary analysis, pts were classified as High Risk (MP-H) (MP score ≤0.000) or Low Risk (MP-L) (MP score &gt; 0.000). Exploratory analyses were performed for MP-L subcategories: MP Ultralow Risk (MP-UL) (MP score &gt; 0.355) and MP-L but not MP-UL (MP-LNUL) (MP score &gt; 0.000, ≤0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model was used for treatment by risk group interaction. Stratified log-rank test was used to compare treatment groups. Hazard ratios and 95% CI were computed based on the stratified Cox PH model. Results: Among 1,866 pts, 706 (38%) were MP-H and 1,160 (62%) were MP-L. Of the MP-L, 252 (22%) were MP-UL. There were no significant differences in the distribution of patient and tumor characteristics between the MP group and the rest of the B-42 cohort, except for HER2 status. ELT effect was more pronounced in the MP cohort than in the overall B-42 population. For DR, there was statistically significant ELT benefit in MP-L (HR = 0.43, 95% CI 0.25-0.74, p = 0.002), but not MP-H (HR = 0.65, 0.34-1.24, p = 0.19) (interaction p = 0.38). For DFS, there was statistically significant ELT benefit in MP-L, but not MP-H (interaction p = 0.015). Similar findings were observed for BCFI (interaction p = 0.006). Within subcategories of MP-L, there was statistically significant ELT benefit in MP-LNUL, but not in MP-UL for all three endpoints, however the power in MP-UL was limited due to low number of pts (Table). Clinical trial information: 00382070. Conclusions: Statistically significant ELT benefit was observed for MP-L, but not MP-H. The treatment by risk group interaction was not statistically significant for DR, but it was for DFS and BCFI. The benefit appears to be stronger in MP-LNUL than in MP-UL. NCT: 00382070. Support: U10CA180868, -180822, U24CA196067; Novartis; Agendia.[Table: see text]

Comparing practice patterns and outcomes for early-stage hormone receptor-positive and node-positive breast cancer patients with high-intermediate-risk Oncotype Dx scores in the National Cancer Database.

e12520 Background: Oncotype Dx (ODX) is a commercial diagnostic test primarily used to predict the likely benefit from chemotherapy in ER+, HER2-, and node negative breast cancer. The prognostic value (recurrence risk) has also been demonstrated to apply to early stage lymph node positive (LN+) disease in a number of retrospective and prospective studies. The ongoing RxPONDER trial aims to clarify the predictive value of RS in LN+ population. In light of the initial results, we analyzed the practice patterns and outcomes for HR+/Her2 -/node positive breast cancer patients receiving ODX testing in the years from 2010-2017 with RS 14-25 in a retrospective observational study of the NCDB. Methods: Women with HR+/Her2 -/node positive breast cancer receiving ODX testing from 2010-2017 were identified in the NCDB using TAILORx and RxPONDER patients’ inclusion criteria: ages 18-75, 6-50mm invasive tumors, N1, M0, ER+/HER2 -. The impact of ODX results in the high-intermediate range (14-25) and other clinico-pathologic variables on the receipt of chemotherapy were compared. Additionally, we examined the impact of chemotherapy on overall survival (OS). Frequencies, Kaplain-Meier analysis, and changepoint analysis using the Contal and O’Quigley method were utilized. Results: There were 109,652 T1-2 and N1 patients of whom 32,506 (29.6%) received ODX testing. 13,461 (41.4%%) women had scores in the high-intermediate (14-25) range. The majority tended to have only 1 LN involved (1LN: 77.2%, 2LNs: 17.5%, 3LNs: 5.3%), had a mean age of 57.8y, were Caucasian (86.4%), and were preferentially tested at academic or comprehensive community cancer programs (79.2%). 6,610 (49.3%) patients were recommended chemotherapy, the median ODX score for all women who were recommended chemotherapy was 20 compared to 17 for those whom chemotherapy was not recommended. 5,068 (76.7%) women had documentation of receiving chemotherapy which correlated with improved OS regardless of age. Conclusions: In the group of women with HR+/Her2 -/node positive breast cancer, clinicians appear to utilize ODX testing in less than one-third of patients, possibly finding RS to be most useful in guiding adjuvant therapy recommendations when only 1LN is involved. Both the recommendation and receipt of chemotherapy correlated linearly with increasing RS, as expected based on the current NCCN guideline recommendations. We identified an OS benefit when chemotherapy was administered, regardless of patient age. Long-term follow-up in the RxPONDER trial will likely continue to clarify the predictive value of RS &lt; 25 in the ER+/HER2-/node positive breast cancer population.

Prescription Patterns, Initiation, and 5-Year Adherence to Adjuvant Hormonal Therapy Among Commercially Insured Patients With Breast Cancer.

Tamoxifen and aromatase inhibitors (AIs) are used as adjuvant hormonal therapy (AHT) for early-stage hormone receptor-positive (HR+) breast cancer. Treatment for 5 years reduces cancer mortality by 30%. Despite this benefit, adherence to AHT has been suboptimal. Here, we evaluated AHT initiation and patient adherence in women with private health insurance. Female patients with breast cancer ≥ 18 years of age who underwent mastectomy or lumpectomy between 1999 and 2015 were identified in the IBM MarketScan Research Database. AHT initiation and adherence rates were estimated for all AHT users regardless of HR+ status. Initiation rates were standardized using HR+ breast cancer incidence rates in the Surveillance, Epidemiology, and End Results (SEER) program. Adherence was defined as medication possession ratio ≥ 80%. Risk ratios, odds ratios, and their 95% CIs were calculated for factors associated with patients' initiation and adherence. Among 80,224 patients, the raw initiation rate was 71.8% and the standardized rate was 87.5%. We found 61.2% patients initiated treatment with AIs and 38.8% with tamoxifen. Patients' 1-year adherence rate was 84.4% and the 5-year rate was 65.2%. Prescription by mail-in order, using a single AHT regimen, 50 to 69 years of age, monthly out-of-pocket drug payment ≤ $11, in US dollars, no depression, no comorbidity, living in the Northeast, treatment in recent years, and receipt of a combination of chemotherapy, radiation, and surgery were associated with better adherence. Five-year AHT adherence rates are low among female patients with breast cancer with private health insurance. Effective approaches to improve AHT adherence are needed.

Impact of obesity on clinical outcomes in hormone receptor-positive breast cancer: a systematic review.

The relationship between obesity and prognosis of early breast cancer is complex. Increased levels of aromatase present in adipose tissue of obese postmenopausal women may lead to suboptimal suppression of systemic estrogens. However, studies have been mixed with respect to the association between use of aromatase inhibitors (AIs) and clinical outcomes in obese women with early breast cancer. We conducted a systematic literature review following PRISMA guidelines to examine the impact of obesity on the efficacy of AIs in early-stage hormone receptor-positive breast cancer. Primary outcome measures included disease-free survival, relapse-free survival, distant recurrence-free survival, breast cancer-free survival, and overall survival. Of 491 studies identified, eight studies met criteria for inclusion: three retrospective cohort studies, one prospective cohort study and four randomized controlled trials. Four studies limited eligibility to postmenopausal women. Percentage of obese patients in studies ranged from 10 to 30%. Two studies examined use of AIs alone while the remainder included patients treated with either AIs or tamoxifen. Five out of seven studies suggested a negative impact of obesity on AI efficacy. The results of our systematic review highlight a need for further research exploring the optimal endocrine therapies for obese women. There is insufficient evidence at present to recommend tailoring adjuvant endocrine therapy with use of specific AIs or for dosing modifications of AIs in this patient population.

Gene Expression Signatures of BRCAness and Tumor Inflammation Define Subgroups of Early-Stage Hormone Receptor-Positive Breast Cancer Patients.

Patients with estrogen receptor- and/or progesterone receptor-positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors, gene expression analyses of 612 tumors was performed using the NanoString Breast Cancer 360 panel to interrogate 23 breast cancer pathways. Candidate signatures associated with disease subtype and event-free survival (EFS) were obtained by cluster analysis, Cox modeling, and conditional inference trees, and were independently tested in 613 patients from BreastMark. Tumor-infiltrating lymphocytes (TIL) were assessed on tissue sections, and mutational burden was assessed in 36 tumors by whole-exome sequencing. PAM50-derived classification distinguished lower-risk (Luminal A) from higher-risk subtypes (Luminal B, P = 0.04; HER2, P = 0.006; Basal, P = 0.008). In higher-risk patients, shorter EFS was associated with low androgen receptor [HR = 3.61; 95% confidence interval (CI), 1.72-7.56; P = 0.001] or high BRCAness signature expression (HR = 3.58; 95% CI, 1.19-10.7; P = 0.023). BRCAness was independently confirmed as a predictor of shorter EFS (HR = 2.64; 95% CI, 1.31-5.34; P = 0.007). About 13%-15% of patients, enriched for high-grade, higher-risk subtypes (P ≤ 0.0001), had strong expression of the Tumor Inflammation Signature (TIS) suggestive of an inhibited antitumor immune response. TIS scores were strongly associated with TIL numbers (P < 1e-30) but not with tumor mutation status. BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.

Cancer treatment delays caused by the COVID-19 pandemic may not hinder outcomes.

Cancer treatment delays caused by the COVID-19 pandemic may not hinder outcomes.

Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial

BackgroundThe ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC). Patients and MethodsExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab. ResultsHR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported. ConclusionNeratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.