Hormone Receptor-positive Early Breast Research Articles

Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives.

Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer. Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors). More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

The impact of extensive intraductal component (EIC) on the genomic risk of recurrence in early hormone receptor positive breast cancer

BackgroundEarly invasive ductal carcinoma (IDC) breast cancer often presents with a coexisting ductal carcinoma in situ (DCIS) component, while about 5 % of cases present with an extensive (>25 %) intraductal component (EIC). The impact of EIC on the genomic risk of recurrence is unclear. MethodsPatients with early hormone receptor-positive HER2neu-negative (HR + HER2-) IDC breast cancer and a known OncotypeDX Breast Recurrence Score® (RS) who underwent breast surgery at our institute were included. Using a rule-based text-analysis algorithm, we analyzed pathological reports and categorized patients into three groups: EIC, non-extensive DCIS (DCIS-L), and pure-IDC (NO-DCIS). Genomic risk was determined using OncotypeDX RS. ResultsA total of 33 (4.6 %) EIC cases, 377 (57.2 %) DCIS-L cases and 307 (42.8 %) NO-DCIS cases were identified. Patients in the EIC group were younger and had lower tumor grades than other groups. The distribution of genomic risk varied between the groups, with EIC tumors significantly less likely to have a high RS (>25) compared to DCIS-L and No-DCIS tumors (3 % vs 20 % and 20 %, respectively; p = 0.03). When adjusted to age, tumor size, grade and LNs involvement, both DCIS-L and NO-DCIS groups were significantly correlated with a higher probability of high RS compared to the EIC group (OR 12.3 and OR 13.1, respectively; p < 0.02). Moreover, patients with EIC had a lower likelihood for adjuvant chemotherapy recommendation. ConclusionsIn early HR + HER2- IDC, an EIC correlates with a reduced genomic recurrence risk. The impact on genomic risk seems to be influenced by the extent, not merely the presence, of DCIS.

The predictive role of Ki67 in pathological complete response (pCR) and invasive disease-free survival (IDFS) in HER2-positive breast cancer: A retrospective study of 246 cases.

e12610 Background: While Ki67 is a routine diagnostic measure for early hormone receptor positive breast cancer, it is not integrated into the standard procedure for patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer patients, given the substantial risk linked to HER2 expression alone. Consequently, the predictive significance of Ki67 in achieving pathological complete response (pCR) or invasive disease-free survival (IDFS) in this subgroup remains uncertain. Methods: This retrospective, bi-centric analysis focused on HER2-positive early breast cancer patients undergoing neoadjuvant chemotherapy from 2015 to 2023. We assessed the correlation between Ki67 values and the achievement of pathological complete response (pCR, defined as ypT0/is, pN0). Multivariable logistic regression analyzed the independent association of various clinical parameters, including Ki67, with pCR. Ki67 values were categorized into risk groups (low &lt;15%, intermediate 15.1-35%, high &gt;35%) following the GepardTrio data [1]. Kaplan-Meier estimator calculated differences in overall and invasive disease-free survival. Results: The study included 246 HER2-positive early breast cancer patients with known Ki67 expression, followed for a median of 42 months. The median age was 52 years. Final nodal status was pN0 in 80.5%, pN1 in 15%, and pN2 in 3.3%. Hormone receptor positivity was observed in 66% of patients. 147 patients (60%) achieved pCR. Median Ki67 was 30. When categorized, 13% were low, 41.5% intermediate, and 45.5% high risk. No correlation between Ki67 and pCR was observed (p=0.25). HER2 IHC score 3+ significantly increased pCR compared to IHC 2+ (62.2% vs. 44.6%, p=0.023). Hormone receptor-positive tumors had a lower pCR rate (52.7% vs. 72.4%, p=0.0016. 5-year overall survival was 96.5% for pCR and 83.8% for non-pCR (p=0.008). 5-year invasive disease-free survival showed no difference between low Ki67 (89.5%), intermediate Ki67 (79.9%), and high Ki67 (80.9%) groups (p=0.77). Conclusions: In this study, Ki67 did not predict pCR in HER2-positive breast cancer, providing no additional clinical value. HER2 IHC score and hormone receptor status were predictive indicators for pCR. Ki67 expression appears to lack additional value in HER2-positive breast cancer, considering resource implications. 1. Denkert C et al: Ann Oncol. 2013 Nov;24(11):2786-93. doi: 10.1093/annonc/mdt350. Epub 2013 Aug 22. PMID: 23970015.

Toxicity differences in CDK 4/6 inhibitors seen in Asian and Pacific Islanders.

e13086 Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors are the standard of care, first line treatment for hormone receptor positive metastatic breast cancer and adjuvant high-risk hormone receptor positive early stage breast cancer along with endocrine therapy. There have been multiple clinical trials validating the effectiveness, along with toxicities of these agents; however, the majority of these trials lack ethnic diversity. This shortcoming limits the ability to apply these findings in diverse patient populations, especially among Asian and Pacific Islanders in Hawaii. Objective: To determine if the toxicity profile of CDK 4/6 inhibitors in women with breast cancer is different among patients at a community oncology practice in Hawaii, in which the majority of patients are Asian, Pacific Islander or a combination of both when compared to three landmark trials. Methods: A retrospective analysis of thirty-two patients with hormone receptor positive, HER2 negative metastatic or high risk breast cancer who started endocrine therapy and CDK 4/6 inhibitor therapy (abemaciclib, ribociclib, or palbociclib) between 2018-2023. Graded toxicities of each individual patient based on CTCAE criteria V. 5, along with demographic data was reviewed and compared to three main registration trials for these agents (MONARCH-3, MONALEESA-2, PALOMA-2). Results: Combined results from the three large randomized trials reported an average of 75% of participants were Caucasian, as compared to 15% in the Hawaii data. While 19% percent of participants from the combined large randomized trials reported being of Asian descent, none of these trials reported a breakdown of Asians versus Pacific Islanders. In the Hawaii sample, 41% were reported as Pacific Islander and 41% reported as Asian, 15% Caucasian, with the final 3% reported as Hispanic. Collective analysis of the FDA registration trials contained 0% Pacific Islander, 19.8% Asian, 74.3% White, 1.5% Black, and 4.4% Other. The majority of all toxicities of all grades were higher in the Hawaii population as compared to the three national trials, except for neutropenia with ribociclib and diarrhea with palbociclib (Table). Conclusions: The Hawaii analysis that was primarily comprised of Asians and Pacific Islanders revealed an increased incidence of toxicities, despite starting at lower doses rates for all CDK 4/6 inhibitors. This data analysis begins to highlight the importance of representative populations in clinical trials for the most effective and safest care of diverse populations. [Table: see text]

Artificial intelligence (AI) –powered H&amp;E whole-slide image (WSI) analysis to predict recurrence in hormone receptor positive (HR+) early breast cancer (EBC).

571 Background: The recurrence risk (RS) based on transcriptomic profiles or Ki-67 level of HR+ EBC has been used for adjuvant treatment decisions and may also aid selecting patients who could benefit from novel treatments including CDK4/6 inhibitor or oral selective estrogen receptor degraders (SERDs). Artificial intelligence-powered H&amp;E whole slide image (WSI) models can be a practical approach for this biomarker without the need of additional tissue samples. We developed ML-based models of histopathologic features from an H&amp;E WSI to approximate RS of 21-gene assay (OncotypeDx) using various algorithms of different complexities. Methods: The development dataset was composed of 1,009 cases from TCGA-BRCA with gene expression profiles and 483 EBC cases from Samsung Medical Center with RS results. The prediction model was developed in two-stages. First, Lunit SCOPE, an AI-powered H&amp;E WSI analyzer, detects various cell types and segments tissue areas resulting in various cell densities in tissue regions of interest. Next, four traditional ML models were applied on top of the first stage results. In addition, a deep learning model based on multiple instance learning (DL-MIL) was developed using three features: a supervised convolutional neural network, a supervised cell detection model, and an AI-based pathology profiling analyzer, for extracting semantic contents. The model performance was validated using two independent EBC test sets: 248 cases for comparison with the RS results (set 1), and 708 cases with DFS (set 2). Results: The cross-validation performance of the four traditional ML algorithms had area under the curve of receiver operating characteristics curve (AUROC) ranging from 0.728 to 0.779, where mitotic cell density, tumor cell density, and fibroblast density in cancer area were the variables with the highest importance for all four models. The DL-MIL model had cross validation performance of AUROC 0.831. In test set 1, DL-MIL model showed the highest discrimination with AUROC of 0.828 compared to traditional ML models where logistic regression showed the highest discrimination with AUROC of 0.786 (Table). The DL-MIL model showed the highest performance among the models to predict DFS with hazard ratio (HR) of 2.48 (1.47-4.18). Conclusions: Histopathomic models can accurately predict the RS of high risk as well as poor DFS from only H&amp;E WSIs. These AI models can be a practical tool for treatment selection including emerging drugs such as SERDs. [Table: see text]

Delayed versus immediate use of zoledronic acid for postmenopausal patients with ER/PR positive early breast cancer who are using adjuvant letrozole.

8 Background: Aromatase inhibitors are the standard adjuvant therapy for postmenopausal women with hormone receptor (HR) positive early breast cancer (EBC). In such patients, a significant reduction in bone density was observed. To stop bone loss, bisphosphonates have a powerful effect on reducing bone resorption and improving the survival of patients with EBC. This study compared potential bone-protection of immediate versus delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. Methods: In a prospective two-arm comparative study, 65 postmenopausal patients with HR+ EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years), we included either (45) immediate ZOL treatment or (20) delayed ZOL treatment (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for fracture or increased bone pain or developed bone mineral density (BMD)T score = or &lt; -2.0. We aimed to assess the change in lumber spine BMD every 3 months for 24 months for both immediate and delayed arm patients, in addition to evaluating bone pain deterioration and the disease-free survival (DFS). Results: Analysis of data showed significant differences between immediate and delayed arms in the first three BMD measurements with mean values were -1.55± 0.4 vs. -1.9± 0.2, -1.56± 0.3 vs. -2.5± 0.3, and -1.4±0.3 vs. -3.5± 0.3 with p&lt;0.002, 0.001, 0.0001 respectively. Despite ZOL administration in delayed arm patients was initiated 6 months later than immediate arm patients, improvement of BMD was detected in delayed arm later on. The median DFS for immediate and delayed arms were 39± 0.6 months and 21± 0.4 months respectively with p&lt;0.001 in both. Although, in pre-ZOL bone pain scoring, most patients of delayed arm (75%) were found to have a score of 3 compared to 51.1% of immediate arm, significant improvement in bone pain scores in both arms separately after ZOL administration was noted with p-values 0.031, and 0.025 respectively. Conclusions: Immediate ZOL administration prevented bone loss, improved bone pain, and ameliorate DFS in postmenopausal women with HR+ EBC receiving adjuvant letrozole. Clinical trial information: PACTR202112813934276.

Identifying anatomopathological factors associated with a Oncotype DX 21-gene recurrence score higher than 25 in menopaused women.

e15156 Background: Oncotype DX recurrence score is a predictive assay clinically used to estimate the risk of distant recurrence for patients with hormone receptor positive (HR+) early breast cancer (EBC) and to predict the benefit of adjuvant chemotherapy, based on molecular factors of the tumor itself. This retrospective study examines the factors that are linked to a Recurrent score (RS) higher than 25, indicating adjuvant chemotherapy for menopaused women with hormone receptor positive early breast cancer. Methods: 157 patients diagnosed with HR+, HER 2 negative early breast cancer who underwent Oncotype DX testing during their treatment between November 2018 and December 2022 were included in the study. Of these 157 patients, 114 were older than 50 years old and with complete data. Univariate and multivariate logistic regression analysis were used to select pathological factors associated with a RS higher than 25. The receiver operating characteristic (ROC) curve was used to assess the optimal threshold of Estrogen receptor (ER), Progesterone receptor (RP) and Ki67. Results: Median age was 65 years (IQR: 59-71). 57 patients (47.5%) had a T1 tumor and 48% of patients had negative lymph nodes. Most of the patients had a Scarff-Bloom-Richardson (SBR) grade 1 (12%) or grade 2 tumor (70%), and 18% of the patients had grade 3 breast cancer. The cell proliferation marker Ki67 was higher than 30 % for 28 patients (23%). The RS was higher than 25 for 17 patients out of 120 patients. Multivariate logistic regression analysis showed that Ki67 higher than 30% was significant associated with RS &gt; 25 (p = 0.01). To predict a RS &gt; 25, the optimal threshold were respectively 80% for the PR, 90% for the ER and 30% for the Ki67. The area under the ROC curve (AUC) were respectively 0.70, 0.60 and 0.88. With the threshold of 30% for Ki67, the sensitivity was 0.76 and specificity 0.89. Conclusions: The use of the Oncotype DX test is validated and useful to better decide the absence of chemotherapy indication in adjuvant situation in some patients with HR+ cancers. However, access to it remains difficult and expensive in some countries with limited resources. Ki67 and SBR grade could be used as an indication for adjuvant chemotherapy but cannot replace Oncotype DX.

Impact of HER2 low expression in the Oncotype DX RS in patients with operable hormone receptor positive early stage breast cancer.

575 Background: Two thirds of breast carcinomas are human epidermal growth factor receptor 2 (HER2) low. To date, it is still unclear whether hormone receptor (HR) positive HER2 low tumors represent a distinct biological subtype. HER2 low status is not considered an independent predictive factor for benefit from adjuvant chemotherapy in HR positive early breast cancer. We aim to investigate the impact of HER2 low expression on the established predictive biomarker Oncotype DX RS in a cohort of patients with HR positive HER2 negative early breast cancer. Methods: Retrospective study of patients with stage I-III HR positive HER2 negative breast cancer treated with upfront surgery between 2019-2022 at the Weill Cornell Breast Center and for whom Oncotype DX RS test was available. Patients were grouped to HER2-0 (immunohistochemistry (IHC) score of 0) or HER2 low (IHC score of 1+ or, 2+ with non-amplified in situ hybridization) expression. Clinicopathological characteristics and Oncotype DX RS were compared across the different categories of HER2 expression. Results: Of 509 patients included, 37% and 63% were grouped as HER2-0 and HER2 low, respectively. Median age at diagnosis was 61 years [IQR 50-69]. Sixty-eight percent of patients were postmenopausal. Stage I, II and III corresponded to 76%, 23% and 1% of patients, respectively. Seven percent of patients had nodal involvement. Ductal carcinoma was the most common histological type (75%) followed by lobular carcinoma (17%). Most tumors had low-intermediate histological grade (81%) with a median Ki-67 of 10% [IQR 5-15]. No significant difference was observed in clinicopathological characteristics between the HER2-0 and HER2 low groups. The overall median Oncotype DX RS was 16 [IQR 11-21]. The median Oncotype DX RS based on a HER2 expression of 0, 1+ and 2+ was 15, 17 and 17, respectively. There was no statistically significant difference between the Oncotype DX RS score and HER2 expression, when comparing HER2-0 to HER2 low (p = 0.578), HER2-0 to HER2-1+ (p = 0.775) and HER2-0 to HER2-2+ (p = 0.157). In the pre-menopausal and lobular carcinoma subgroups, the median Oncotype DX RS was 15 [IQR 9-21] and 17 [IQR 12-22], respectively; and there was no statistically significant difference between the Oncotype DX RS score and HER2 expression (p &gt; 0.05). Post-surgery, 87%, 66% and 13% of patients received endocrine therapy, chemotherapy and radiation therapy, respectively. Median follow up time was 16 months [IQR 8-34]. Disease recurrence was documented in 9 (2%) patients. Conclusions: In this study, we found no differences in the Oncotype DX RS and the prognostic pathological features between the HER2-0 and HER2 low groups which is in line with previous retrospective studies. Survival analysis was limited by the median follow up. Further studies on the understanding of the biology of HER2-low and its clinical implications in early breast cancer are needed.

Methods for selection of neoadjuvant treatment with chemotherapy for patients with hormone receptor-positive and HER2-negative with early breast cancer.

e12591 Background: Neoadjuvant chemotherapy (NCT) in hormone receptor positive and HER2 negative early breast cancer used to achieve a poor pathological response although patients with residual tumor inferior to 10 mm had a better significant survival. Methods: We analyzed the pathologic response (complete or major response if the residual tumor is inferior to 10 mm) in a consecutive series of 333 patients treated in our center considering clinicopathological classical variables, oncotype RS score, and non-response to previous sort course of hormonotherapy measured by the decrease in the Ki67 index. Results: Median age was of 51 years (24-87), median tumor size of 32mm (9-10) and 54% had nodal involvement. Pathologic complete response (pCR) was achieved in 16,5% and pathologic response according Symmans method type 0 and I in 33,6 %. Variables associated with pCR were initial tumor size &lt; 30 mm (OR: 0,409; p: 0,004), progesterone receptor &lt; 100 by histoscore (OR: 0,289; p: 0,00001) and Ki67 index &gt; 30 (OR: 2,23; p: 0,008). When these 3 variables have been associated, the pCR increases by 45%. When use the ONCOTYPE RS score to select patients to NCT the pCR found was 23,5% that increases to 42% if the RS score was superior to 32 in a series of 136 patients. Considering the RCB pathologic response, RS&gt;32 achieved a total of 73% of RCB 0-1 response. Finally, using the hormone non-response in patients with short course of hormonotherapy with non-decreases the Ki67 index, we found a 30% of pCR and 63% of RCB type 0-1 pathologic response. Conclusions: Selecting patients with early breast cancer with positive hormone receptors for neoadjuvant treatment with chemotherapy achieves a high response rate, going from 16% and reaching 40% in selected cases. The genomic platform and hormonal testing through Ki67 changes are very useful tools to select these patients. [Table: see text]

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer

BackgroundProspective data on the risk of recurrence among women with hormone receptor–positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking.MethodsWe conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial.ResultsAmong 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort.ConclusionsAmong select women with previous hormone receptor–positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.)

Optimum duration of extended adjuvant endocrine therapy in patients with hormone receptor-positive breast cancer: protocol for a network meta-analysis of randomised controlled trials

IntroductionThe type of extended adjuvant endocrine therapy is not clear, nor is the optimum duration of extended adjuvant endocrine therapy for patients with early breast cancer. Our study aims to...

Abstract P3-05-27: The impact of co-existing ductal carcinoma in situ in invasive early hormone receptor positive breast cancer on the genomic and clinical risk of recurrence

Abstract Background: Invasive early breast cancer (IBC) often presents with a co-existing ductal carcinoma in situ (DCIS) component, while about 5% of the cases present with an extensive (&amp;gt;25%) intraductal component (EIC). The presence of a DCIS component was previously shown to be associated with favorable clinico-pathological characteristics and survival outcomes. However, the association between co-existing DCIS and genomic risk of recurrence is unclear. Methods: Patients with early hormone receptor positive (HR+) HER2neu-negative (HER2-) breast cancer and known OncotypeDX breast recurrence score (RS), who underwent breast surgery in our institute, were included. A natural language processing (NLP) algorithm was used to identify co-existence of extensive DCIS (DCIS-H) and non-extensive DCIS (DCIS-L) in surgical pathological reports. Genomic risk was determined using OncotypeDX RS, while clinical risk was calculated according to the MINDACT criteria, based on tumor size and grade. The genomic and clinical risks of DCIS-H, DCIS-L and pure IBC (No-DCIS) were compared. Results: A total of 45 (5%) DCIS-H cases, 468 (56%) DCIS-L cases and 328 (39%) No-DCIS cases were identified. DCIS-H cases presented with less aggressive clinico-pathological characteristics, such as lower proportions of histologic grade III (10% vs 26% vs 21%) and lower proportions of node-positive disease (13% vs 18% vs 21%), compared to DCIS-L and No-DCIS cases, respectively. The distribution of OncotypeDX RS significantly varied between the groups. DCIS-H tumors were less likely to have a high RS and more likely to have a low or intermediate RS compared to DCIS-L and No-DCIS tumors (High RS: 4% vs 20% vs 20%, Low + intermediate RS: 96% vs 80% vs 80%, respectively; p=0.04). Additionally, the proportions of high clinical risk cases were lower in the DCIS-H group compared to the DCIS-L and No-DCIS groups (42% vs 53% vs 50%, respectively; p=0.002). Based on genomic and clinical risk and current guidelines, we found that women presented with an extensive DCIS component (DCIS-H) had a lower probability of receiving an adjuvant chemotherapy recommendation compared to women presented with a non-extensive DCIS component (DCIS-L) or pure IBC (No-DCIS) (11% vs 29% vs 25%, respectively; p=.035). No differences in disease recurrence were detected between the groups. Conclusions: Co-existing extensive DCIS in invasive early HR+Her2- breast cancer is significantly correlated with lower genomic and clinical risk of recurrence and a smaller chance for chemotherapy recommendation. The rarity of this condition (5% of cases) limited our ability to detect differences in outcomes. These findings warrant future studies of the underlying genomic landscape of co-existing extensive DCIS. Citation Format: Yael Bar, Kfir Bar, Judith Ben- Dror, Didi Feldman, Meishar Shahoha, Ahuva Weiss-Meilik, Nachum Dershowitz, Wolf Ido, Amir Sonnenblick. The impact of co-existing ductal carcinoma in situ in invasive early hormone receptor positive breast cancer on the genomic and clinical risk of recurrence [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-27.

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.

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer

BackgroundLimited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor–positive early breast cancer receiving adjuvant endocrine therapy.MethodsWe performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor–positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and overall survival were also assessed.ResultsA total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.ConclusionsOmission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor–positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.)

Facing points of view: Representations on adjuvant endocrine therapy of premenopausal patients after breast cancer and their healthcare providers in France. The FOR-AD study.

Adjuvant endocrine therapy (ET) for 5-10 years is the backbone of the therapeutic strategy in patients with hormone receptor positive (HR+) early breast cancer (BC). However, long-term adherence to adjuvant ET represents a major challenge for most patients. According to prior studies, side effects of adjuvant ET are an important reason for poor adherence. In contrast, better communication and relational bond between patients and healthcare providers (HCPs) may improve adherence. The FOR-AD (Focus on non-adherence) study aimed at better understanding the representation of adjuvant ET by patients and their HCPs, in order to improve the care process. Three focus groups of premenopausal women (receiving adjuvant ET for variable amount of time) and two focus groups of HCPs (including oncologists, pharmacists, and nurses) were conducted, each including around ten participants. Thematic analyses using a general inductive approach were constructed to report participants' representations. Two main themes emerged across groups, and appeared of major importance. Representations on adjuvant ET were often homogenous within each group, but differed between patients and their HCPs. The relationship between both groups was considerably discussed, particularly its importance in facilitating adherence to adjuvant ET. Suggestions on improving the care process were also given, such as systematically including psychologists in follow-up care paths and having a nurse navigator follow patients under treatment with adjuvant ET. The present qualitative exploration may help buildi future tailored interventions to improve adherence to adjuvant ET, in particular regarding the role of nurse navigators.

Management of bone loss due to endocrine therapy during cancer treatment.

Bone modifying agents BMAs (oral and IV bisphosphonates, denosumab) are used to treat bone loss due to endocrine therapy in patients with hormone receptor positive (HR +) early breast cancer and non-metastatic prostate cancer (NMPC). Timely initiation of appropriate sequential therapy is imperative to reduce cancer treatment-induced bone loss (CTIBL). This narrative review summarizes current literature regarding management of CTIBL in HR + early breast cancer and NMPC patients. Risk factors for fragility fractures, screening strategies, optimal timing for the treatment, dosing/duration of therapy, and post treatment monitoring have not been clearly defined in HR + early breast and NMPC patients receiving endocrine therapy. This review aims to discuss the utility of fracture risk assessment (FRAX) tool for the prevention and management of CTIBL, osteoanabolic therapy for imminent fracture risk reduction, and sequential therapy options. Using predefined terms, PubMed, MEDLINE, and Google Scholar were searched for studies on CTIBL in HR + breast and NMPC patients. We included randomized clinical trials, meta-analysis, evidence-based reviews, observational studies, and clinical practice guidelines. Fracture risk assessment tools (FRAX) guide therapy for osteoporosis in patients with early HR + breast cancer and NMPC. BMAs to prevent bone loss should be initiated at higher T-score than recommended by FRAX in premenopausal HR + breast cancer patients with chemotherapy-induced ovarian failure, oophorectomy and gonadotropin releasing hormone (GnRH) therapy, post-menopausal women with HR + breast cancer receiving aromatase inhibitor therapy, and NMPC patients with androgen deprivation therapy. Sequential therapy with osteoanabolic agents as first line treatment offers a potential therapeutic strategy in patients with high imminent fracture risk. Due to limited data in cancer patients regarding management of osteoporosis, a dosing schedule similar to osteoporosis is considered appropriate. Risk stratification to identify vulnerable patient population, choosing the appropriate sequential therapy, and close monitoring of patients at the risk of bone loss can potentially reduce the mortality, morbidity, and health care cost related to CTIBL.

Cost-Effectiveness Analysis of the Oncotype DX Breast Recurrence Score® Test in Node-Negative Early Breast Cancer.

BackgroundThe 21-gene assay (the Oncotype DX Breast Recurrence Score® test) is a validated multigene assay which produces the Recurrence Score® result (RS) to inform decisions on the use of adjuvant chemotherapy in human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (HR+) early invasive breast cancer. A model-based economic evaluation estimated the cost-effectiveness of the 21-gene assay against the use of clinical risk tools alone based on the latest evidence from prospective studies.MethodsThe proportion of patients assigned to chemotherapy conditional on their RS result was obtained from retrospective data from the Clalit registry. The probability of distant recurrence with endocrine and chemo-endocrine therapy conditional on RS result was obtained from TAILORx and NSABP B-20 trials. The cost-effectiveness of the 21-gene assay compared to using clinical risk tools alone was estimated in terms of cost per quality-adjusted life-year (QALY) over a lifetime horizon.ResultsThe 21-gene assay was more effective (0.17 more quality-adjusted life years) at a lower cost (-£519) over a lifetime compared to clinical risk alone. The model results were sensitive to assumptions around the magnitude of benefit of chemotherapy in the high RS result subgroup. Other assumptions underpinning the model, such as the proportion of patients assigned to chemotherapy in the low and mid-range RS result subgroups and long-term distant recurrence probabilities, had a smaller impact on the results.ConclusionThe analysis showed that the cost-effectiveness of the 21-gene assay is sensitive to assumptions for chemotherapy sparing for patients with RS 0–25 whose outcomes with endocrine therapy are no worse compared to chemotherapy-assigned patients, and a chemotherapy benefit in the RS 26–100 group. Future studies need to incorporate a wider set of tumour profiling tests other than the 21-gene assay to allow a direct comparison of their cost-effectiveness.

Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

Prognostic Significance of Low HER2 Expression in Patients With Early Hormone Receptor Positive Breast Cancer.

A possible role of antibody-drug conjugates against tumors with low HER2-expression, leads to the emergence of a new "low-HER2" classification in breast cancer, encompassing tumors from the hormonal-receptor-positive and the triple-negative subgroups. There is a need for data (clinical trial data and real-world evidence) that will accurately describe this population, the risk of recurrence and the possible benefit of HER2 targeted therapies. We retrospectively analyzed 949 patients from our Department databases, with hormonal receptor-positive and HER2-negative early breast cancer, for whom detailed data for immunohistochemical HER2-staining could be retrieved. HER2-low expression was detected in 66.6% of patients (472 IHC +1 and 160 IHC +2 and ISH-negative). Lobular, or mixed lobular and ductal cancers had a statistically significantly lower chance of being HER2-low when compared to pure infiltrative ductal carcinomas (53.1% vs. 69.3% respectively). HER2-low status was not prognostic for recurrence-free survival or response to neoadjuvant chemotherapy. There was a non-significant trend for increased risk of recurrence for HER2-low, compared to HER2-0, in patients with lobular or mixed lobular and ductal carcinomas (HR=2.192, 95% CI=0.819-5.912). Low expression of HER2 in hormonal receptor-positive early breast cancer does not affect prognosis but may lead to a shorter progression-free-survival in lobular and mixed ductal and lobular cancers. Despite optimal management, a large proportion of hormonal receptor-positive patients will relapse. Targeting HER2 in HER2-low cancers may offer a potential additional treatment strategy to improve survival of this group.

Role of Oncotype-DX testing in older versus younger women with hormone receptor positive & Her-2 negative early stage breast cancer

Introduction: Oncotype DX Breast Recurrence Score (RS) has proven to be useful in predicting the risk of recurrence and the potential benefit of chemotherapy in hormone-receptor positive, HER-2 negative early-stage breast cancer patients. The aim of this study (part of service evaluation) was to explore the role of Oncotype DX recurrence scores in the treatment of older versus younger women, treated within the Hywel Dda Health-Board between 2010 to 2018.