Early Stage HR Research Articles

Association of Sarcopenia With Toxicity-Related Discontinuation of Adjuvant Endocrine Therapy in Women With Early-Stage Hormone Receptor–Positive Breast Cancer

Sarcopenia, an age-related decline in muscle mass and physical function, is associated with increased toxicity and worse outcomes in women with breast cancer (BC). Sarcopenia may contribute to toxicity-related early discontinuation of adjuvant endocrine therapy (aET) in women with hormone receptor-positive (HR+) BC but remains poorly characterized. This multicenter, retrospective cohort study included consecutive women with stage 0-II HR+ BC who received breast conserving therapy (lumpectomy and radiation therapy) and aET from 2011 to 2017 with a 5-year follow-up. Skeletal muscle index (SMI, cm2/m2) was analyzed using a deep learning model on routine cross-sectional radiation simulation imaging; sarcopenia was dichotomized according to previously validated reports. The primary endpoint was toxicity-related aET discontinuation; logistic regression analysis evaluated associations between SMI/sarcopenia and aET discontinuation. Cox regression analysis evaluated associations with time to aET toxicity, ipsilateral breast tumor recurrence (IBTR), and disease-free survival (DFS). A total of 305 women (median follow-up, 89 months) were included with a median age of 67 years and early-stage BC (12% stage 0, 65% stage I). A total of 60 (20%) women experienced toxicity-related aET discontinuation. Sarcopenia was associated with toxicity-related early discontinuation of aET (odds ratio, 2.18; P=.036) and shorter time to aET toxicity (hazard ratio [HR], 1.62; P=.031). SMI or sarcopenia were not independently associated with IBTR or DFS; toxicity-related aET discontinuation was associated with worse IBTR (HR, 9.47; P=.002) and worse DFS (HR, 4.53; P=.001). Among women with early-stage HR+ BC who receive adjuvant radiation therapy and hormone therapy, sarcopenia is associated with toxicity-related early discontinuation of aET. Further studies should validate these findings in women who did not receive adjuvant radiation therapy. These high-risk patients may be candidates for aggressive symptom management and/or alternative treatment strategies to improve outcomes.

Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.

Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. This was a single arm, interventional phase II clinical trial evaluating 4weeks (± 1week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Trial registration number: NCT03219476.

A Nomogram for Identifying HR+/Her2- Breast Cancer Patients with Positive Sentinel Lymph Nodes and Omitted Axillary Lymph Node Dissection Who Need Abemaciclib Therapy.

BACKGROUND The efficacy of abemaciclib in high-risk patients with early-stage HR+/Her2- breast cancer has been verified by MonarchE. However, accurately determining the number of axillary lymph node (ALN) metastases remains challenging. The Z0011 trial changed the axillary management strategy, eliminating the need for axillary lymph node dissection (ALND) in patients with 1-2 sentinel lymph node (SLN) metastases. Therefore, further exploration is needed to identify patients who could benefit from abemaciclib therapy. MATERIAL AND METHODS This retrospective study included cT1-2N0M0 HR+/Her2- patients with 1-2 positive SLNs who underwent ALND. Clinicopathological data were collected, and logistic regression analyses identified independent predictors for ≥4 positive ALNs. A predictive nomogram was developed, and discrimination and calibration were evaluated using the C-index and calibration curve. Clinical efficacy was assessed using decision curve analysis (DCA). RESULTS We enrolled 444 patients, with 77 (17.3%) having ≥4 positive ALNs. Independent predictors for ≥4 positive ALNs included abnormal ALN on ultrasound, mammographic calcifications, T stage, and the number of positive SLNs. The nomogram demonstrated an AUC of 0.777 (95% CI: 0.735-0.815, P<0.001), and internal validation showed good calibration and discrimination (C-index, 0.802; 95% CI: 0.779-0.824). DCA revealed a positive net benefit for risk levels ranging from 5% to 54%. CONCLUSIONS This nomogram is a convenient and reliable tool to predict the risk of ≥4 positive ALNs in HR+/Her2- patients. It aids in protocol selection by identifying SLN-positive patients who may benefit from abemaciclib therapy without ALND.

Artificial intelligence analysis of CCNG1 expression in tumors: A novel biomarker in development for anti-CCNG1 targeted therapy.

e15083 Background: Metastatic cancer is associated with an invariably fatal outcome. Therefore, innovative therapies are urgently needed. Although expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor gene, is on-going for an intermediate-size (n = up to 40) population of advanced sarcoma and pancreatic cancer, more data is needed to identify patients who are likely to benefit from DeltaRex-G gene therapy. In this study, we retrospectively analyzed CCNG1 expression in archived tumors of patients who were previously treated with DeltaRex-G and who are active candidates for DeltaRex-G therapy. Methods: Archived formalin-fixed paraffin embedded (FFPE) tumor specimens (n = 58) from patients with solid malignancies who are actively followed at the Cancer Center of Southern California were collected, processed, and subjected to RNA sequencing. Briefly, RNA-seq libraries were sequenced to generate 50 million reads that were aligned using Kallisto v0.42.4 to GENCODE v23 transcripts with default parameters. Only protein-coding, IGH/K/L- and TCR-related transcripts were retained for downstream processing, resulting in 20,062 protein coding genes. Gene expression was quantified as transcripts per million (TPM) and log2-transformed (Goldman et al., 2020). A gene expression level is presented as low/medium/high depending on the expression level of a such gene in patients of the reference cohort. Low = &lt; 17%; Medium = 17%-83%; High = &gt; 83%. Results: Thirty-two male and 26 female subjects, ages ranging from 16 to 86 years were studied. Forty-nine (84.4%) patients had sarcoma, 3 (5.2%) had urothelial carcinoma, 2 (3.5%) had breast carcinoma, 2 (3.5%) had pancreatic cancer, 1 (1.7%) had Sertoli cell tumor, 1 (1.7%) had adenocarcinoma of appendix. Eleven (19%) tumors showed high CCNG1 expression, 44 (76%) tumors had medium expression, and 3 (5.2%) tumors had low CCNG1 expression. Of note, the tumor of one 14-year survivor with metastatic pancreatic adenocarcinoma in sustained remission had 24 % CCNG1 expression, one 3-year survivor with metastatic chondrosarcoma metastatic to lung with stable disease had 74% CCNG1 expression, one 2-year survivor with early stage HR+ HER2+ breast cancer in remission had 23% CCNG1 expression, and one 2-year survivor with early stage triple negative breast cancer in remission had 74% CCNG1 expression. Conclusions: Taken together, these data indicate that (1) Medium to high CCNG1 expression was found in 95% of tumors studied, and (2) Patients with medium CCNG1 expression who received DeltaRex-G had clinical benefit and are alive in sustained remission or with stable disease 2-14 years from DeltaRex-G treatment initiation, and (3) Prospective studies are warranted to correlate CCNG1 expression level and response to DeltaRex-G therapy.

Evaluation of PAM50 intrinsic subtypes and risk of recurrence (ROR) scores in premenopausal women with early-stage HR+ breast cancer: A secondary analysis of the SOFT trial.

504 Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS. The purpose of this study is to assess the prognostic and predictive ability of PAM50 intrinsic subtypes and ROR scores in premenopausal women with HR+/HER2- breast cancer in the SOFT trial. Methods: Gene expression analyses were performed via the NanoString Breast Cancer 360 assay on RNA isolated from FFPE tumor samples from the SOFT trial that were HR+/HER2- (n=1245/3047). PAM50 subtype and ROR score were determined centrally by NanoString Technologies (Seattle, WA, USA), blinded to clinical characteristics, treatment and outcome. Median follow-up was 12 years. Primary endpoint in this study was distant recurrence-free interval (DRFI). Secondary endpoints were breast cancer-free interval (BCFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of PAM50 intrinsic subtypes and ROR categories (low vs intermediate vs high), and secondarily ROR score as a continuous variable. We also investigated differences between very young (&lt;40yrs) vs young (&gt;40yrs) women. Results: Tumor samples from 1084/1245 (87%) patients successfully completed PAM50 testing and are included in this analysis. Patient characteristics in this cohort were similar to the entire SOFT trial population. Intrinsic subtype and ROR category distribution is described below. Subtype distribution significantly differed between very young vs young premenopausal women, with fewer luminal A and more luminal B and non-luminal tumors seen in the very young (p&lt;0.001). The ROR score distribution also differed significantly: in node-negative patients there were significantly more ROR-high scores amongst very young compared to young women (36% vs 14%, p&lt;0.001). Conclusion: Breast cancer diagnosed in very young women has aggressive disease biology. Prognostic and predictive analyses of both intrinsic subtypes and the ROR score are ongoing and will be presented at the meeting. Clinical trial information: NCT00066690 . [Table: see text]

3MO HER2 expression and early response to patritumab deruxtecan (HER3-DXd) in early-stage hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC): A correlative analysis from SOLTI-TOT-HER3 trial

HER3-DXd and trastuzumab deruxtecan (T-DXd) are antibody-drug-conjugates (ADCs) directed against HER3 and HER2, respectively. Both drugs have shown efficacy in patients (pt) with HR+/HER2- BC. Baseline HER3 protein or mRNA levels do not predict efficacy from HER3-DXd. Here, we aimed to evaluate the association of early response to HER3-DXd with HER2 levels. TOT-HER3 (NCT04610528), a window-of-opportunity trial, evaluated a single dose of HER3-DXd in 77 pts with untreated HR+/HER2- early BC in Part A (6.4 mg/kg) and 17 in Part B (5.6 mg/kg). Primary objective was CelTIL score [a surrogate of response that combines tumor cellularity and tumor-infiltrating lymphocytes] variation between baseline and day 21 tumor samples. Here, CelTIL response was defined as an absolute increase of 20 at day 21. HER2 expression was determined by immunohistochemistry (IHC). RNA and DNA were purified from baseline FFPE tumor samples and analyzed using the nCounter and the VHIO-300 NGS platforms, respectively. Logistic regression models and area under the ROC Curve (AUC) estimated the performance of HER2 IHC, mRNA or copy-number (CN) levels with CelTIL response. In TOT-HER3 Part A, HER2 IHC status was 32% HER2 0, 38% HER2 1+ and 30% HER2 2+. Distribution of high CelTIL responders was 40% in HER2 0, 45% in HER2 1+ and 13% in HER2 2+ (p=0.034). High ERBB2 mRNA and RNA-based HER2 amplicon signatures were significantly associated with low CelTIL response (ERBB2: Odds Ratio [OR]=0.34, p<0.001, AUC=0.71; and HER2 amplicon: OR=0.20, p=0.005, AUC=0.74). The association of ERBB2 mRNA with CelTIL response was independent of HER2 IHC expression (p=0.002), PAM50 subtype (p=0.001) or proliferation (p=0.003). High HER2 CN signal was found associated with low CelTIL response (p=0.005). The association of HER2 IHC and ERBB2 mRNA with CelTIL response will be independently validated in TOT-HER3 Part B. Low HER2 IHC, mRNA or CN levels in early-stage HR+/HER2- BC are associated with high response to HER3-DXd. HER3-DXd might be highly active in HR+ BC with very low HER2 levels, thereby offering a new therapeutic paradigm to this subset of patients.

Abstract P2-03-01: Sarcopenia on baseline imaging is associated with toxicity-related discontinuation of endocrine therapy in women with early-stage hormone-positive breast cancer

Abstract Background Adjuvant endocrine therapy (ET) is standard of care in women with hormone receptor-positive (HR+) breast cancer (BC) with the goal to reduce recurrence. However, early discontinuation of ET occurs in 30-40% of women, largely attributable to toxicity, and leads to increased recurrence risk. There is considerable overlap in risk factors that predict toxicity from ET and chemotherapy, including age, co-morbidities, and geriatric conditions. Baseline low skeletal muscle area (SMA) on chest computed tomography (CT) is a surrogate marker for sarcopenia and predicts for significant toxicity and intolerance to chemotherapy in women with BC. No study has assessed the association of sarcopenia with toxicity-related discontinuation of ET in women with early-stage HR+ BC. Methods This single center retrospective cohort study included consecutive women with Stage 0-II HR+ BC who received ET and adjuvant radiotherapy (RT) from 01/2011-12/2017. Inclusion required a minimum of 5-year clinical follow-up after diagnosis. We used a validated deep learning pipeline to quantify SMA (cm2) at the tenth thoracic (T10) vertebral body on existing RT planning CT. The skeletal muscle index (SMI [cm2/m2] = SMA/(patient height (m))2) was calculated to adjust for patient height. Sarcopenia was defined as SMI&amp;lt; 32.3 cm2/m2, based on a previously validated independent cohort of young healthy women. The primary endpoint was toxicity-related discontinuation of ET less than 60 months after initiation of ET. Secondary endpoints included any NCI CTCAE v5.0 Grade 3-5 toxicity from ET and ipsilateral breast tumor recurrence. We assessed associations between ET discontinuation and SMI (continuous), as well as thoracic sarcopenia (dichotomous), using logistic regression adjusting for baseline characteristics. We used cox proportional hazards regression to assess disease-free survival (DFS), defined as ipsilateral breast tumor recurrence, locoregional recurrence, or distant metastasis adjusting for baseline and treatment characteristics. Results A total of 265 women (median age 67 years) met inclusion criteria. The majority of women had a comorbidity index of 0-1 (89%) and were Caucasian (89%). The median follow-up was 82 months, 5-year overall survival was 96% and 5-year DFS was 94%. Diagnoses included DCIS (12%), IDC (76%), or ILC (12%); most were T1 (69%) or T2 (18%) and N0 (85%), ER-positive (100%), PR-positive (85%), or HER2-negative (9%). Most common ET type was anastrozole (63%), letrozole (16%), and tamoxifen (17%). SMI (continuous) was not associated with older age, Charlson Comorbidity Index (CCI), race, or tumor stage. A total of 64 (24%) women experienced toxicity-related early discontinuation of ET. On multivariate analysis (MVA), lower SMI was associated with increased toxicity-related early discontinuation of ET (Odds Ratio [OR] 0.89 per 1 cm2/m2 SMI, p=0.001) independent of age, CCI, ET type, or receipt of adjuvant chemotherapy. Lower SMI was associated with higher risk of grade 3-5 toxicity from ET (OR 0.89 per 1 unit SMI, p=0.001) independent of age, CCI, ET type, or receipt of adjuvant chemotherapy. On MVA, sarcopenia was associated with higher risk of toxicity-related early discontinuation of ET (OR 2.43, p=0.019). DFS was associated with toxicity-related early discontinuation of ET (HR 8.06, p=0.005), grade 3 histology (HR 1.42, p=0.042), and multifocal disease (HR 2.55, p=0.040), but not age, histology, stage, or lymphovascular invasion (p&amp;gt;.05 for all). Conclusion Low baseline thoracic skeletal muscle is associated with toxicity-related early ET discontinuation in women with early-stage HR+ BC. Further studies should attempt to generalize this association to all HR+ BC who are candidates for ET. High-risk patients may be candidates for aggressive symptom management or alternative adjuvant therapies. Citation Format: Anurag Saraf, Ismail Tahir, Bonnie Hu, Anna-Sophia Dietrich, Paul Erik Tonnesen, Greg Sharp, Gayle Tillman, Florian Fintelmann, Rachel Jimenez. Sarcopenia on baseline imaging is associated with toxicity-related discontinuation of endocrine therapy in women with early-stage hormone-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-01.

Abstract GS1-06: Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial

Abstract Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. The benefit from the addition of OFS was most clinically meaningful for patients at higher clinico-pathologic risk of recurrence. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS and its resultant toxicities. The Breast Cancer Index (BCI) is a gene expression–based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence (DR) and predicts the likelihood of benefit from extended endocrine therapy in early stage HR+ breast cancer. The purpose of this study is to assess BCI’s prognostic and predictive ability in premenopausal women randomly assigned to 5-years treatment with E+OFS or T+OFS vs T alone in the SOFT trial. Methods: All available FFPE tumor samples from the SOFT trial (n=1718 of 3047) were included in the study. BCI testing was performed blinded to clinical characteristics, treatment and outcome. Median follow-up was 13 years. Primary endpoint was breast cancer-free interval (BCFI). Secondary endpoints were distant recurrence-free interval (DRFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of BCI (H/I) status (High vs Low), and secondarily H/I as a continuous score. Hypothesis testing for interaction was performed by stratified log-rank tests. Results: Tumor samples from 1687 (98%) patients (30.4% &amp;lt; 40 years, 64.1% T1, 50.1% G2, 65.8% N0, 85.5%% HER2-, 53.3% received prior chemotherapy) were successful in BCI testing and included in the final analysis. Patient characteristics in the translational cohort are representative of the parent SOFT trial. 42.4% of patients’ tumors had H/I-High status. Prognostic and predictive analyses are ongoing and will be presented at the meeting. Citation Format: Ruth O’Regan, Yi Zhang, Gini F. Fleming, Prudence Francis, Roswitha Kammler, Giuseppe Viale, István Láng, Meritxell Bellet Ezquerra, Hervé R. Bonnefoi, Sherene Loi, Marco Colleoni, Catherine A. Schnabel, Kai Treuner, Meredith Regan. Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT 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 GS1-06.

Abstract P3-07-25: Efficacy and safety of neoadjuvant pertuzumab biosimilar TQB2440, trastuzumab and docetaxel in HR negative, HER2 positive breast cancer: a single-arm trial

Abstract Background: Despite that dual anti-HER2 therapy (Trastuzumab and Pertuzumab, TP) is one of the commonly used regimens for neoadjuvant treatment of HER2-positive breast cancer, previous studies showed that its pCR rate rarely exceeds 63%. Additionally, it is associated with higher risk of cardiac adverse events. TQB2440, a biosimilar of pertuzumab, with strong affinity and specificity, can effectively bind with HER2 epitope. In the PDX mouse model, TQB2440 showed promising biological activity and minimal cardiotoxicity. In this study, we designed a single-arm trial of dual anti-HER2 therapy (TQB2440 and trastuzumab, TT) plus docetaxel in neoadjuvant therapy of HER2 positive breast cancer. We aimed to examine the efficacy and safety of TQB2440 and study whether new dual anti-HER2 therapy (TT) can boost pCR rate in the neoadjuvant treatment. The cardiotoxicity and other adverse reactions were closely monitored. Methods: Upon approval by the Medical Ethics Committee of Xijing Hospital, patients with HR negative HER2-positive breast cancer (cT2-3/N0-1/M0) receiving neoadjuvant therapy were enrolled. The patients were treated with docetaxel 75 mg/m2, trastuzumab 8 mg/kg loading, then 6 mg/kg, TQB2440 840 mg loading, then 420 mg, iv, q3w for 4 cycles, with strict monitoring of cardiotoxicity. The primary endpoint was pCR rate, and secondary endpoint was cardiotoxicity. Results: From April 2021 to February 2022, a total of 28 patients were recruited. Among the 28 patients with a median age of 52 (28-74), 12 patients had positive lymph node status. Overall, the pCR rate was 67.9% (19/28). The pCR rate was higher than that in the NeoSphere trial (pCR 63.2%) and the PEONY study (pCR 52.5%). The lymph-positive tumor achieved a higher pCR rate than lymph-negative tumor (70.8% vs 52.3%, p = .019). Multivariate regression analysis showed that for participants aged 50 or above, HER2 3+ (IHC) showed a statistically significant positive influence on pCR rate. The common adverse reactions of grade ≥3 were leukopenia (46.4%), neutropenia (35.7%), asthenia (3.6%), and peripheral sensory neuropathy (2.3%). Left ventricular insufficiency was detected in 1 patient, and no cardiotoxic events higher than grade 2 occurred during the neoadjuvant therapy. There was no treatment-related death. Conclusion: TQB2440 and trastuzumab plus docetaxel is a feasible and effective neoadjuvant therapy for early-stage HR negative HER2-positive breast cancer, showing high pCR rate and acceptable cardiotoxicity. These results support a further random controlled trial testing for dual anti-HER2 therapy using TQB2440 in neoadjuvant or adjuvant therapy of HER2 positive breast cancer. Citation Format: Jiang Wu, Jing Yu, Yuqing Yang, Xinxin Wen, Jixin Yang, Hongliang Wei, Xiaolong Xu, Yike Li, Liu Yang, Dongdong Xu, Lei Wang, Yijia Wang, Wen Ma, Nanlin Li. Efficacy and safety of neoadjuvant pertuzumab biosimilar TQB2440, trastuzumab and docetaxel in HR negative, HER2 positive breast cancer: a single-arm 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 P3-07-25.

Adjuvant Therapy in Breast Cancer Patients With Microscopic Residual Disease

IntroductionSurgical resection is the gold standard for early-stage breast cancer. Positive surgical margins are associated with poor outcome. Endocrine therapy (ET) is recommended as primary systemic treatment for hormone receptor positive (HR+) breast cancer after surgery. We hypothesized that chemoenocrine therapy (CET) would not be associated with improved survival relative to ET for patients with positive margins. Materials and methodsThe National Cancer Database was queried for pathologic stage I HR + HER2-breast cancer patients treated with partial mastectomy and adjuvant whole-breast irradiation between 2004 and 2017. The adjuvant treatment approaches to positive surgical margins were investigated and compared. Overall survival was compared between systemic treatment groups using multivariable cox proportional hazards regression. ResultsAmong 228,453 patients, a positive surgical margin (microscopic residual disease, R1) was identified in 3561 (1.6%) patients. Compared with complete resections, positive margin was associated with inferior overall survival (hazard ratio [HR] = 1.276, P = 0.003). Among the R1 patients, 78.7% received ET only, 11.7% received CET, 1.2% received chemotherapy only, and 8.5% received no systemic therapy. After controlling for patient, facility, and tumor characteristics, ET provided greatest survival benefit (relative to no therapy, HR = 0.378, P < 0.001) followed by CET (HR = 0.446, P = 0.020). Compared with ET alone, CET is not associated with additional overall survival benefit (HR = 1.179, P = 0.595). ConclusionsCET appeared not to be associated with an improved overall survival in early stage HR + HER2-breast cancer with microscopic residual disease relative to ET. Positive surgical margins therefore are probably not a relevant clinical factor for adjuvant chemotherapy decision-making.

Three year results of Blessed: Expanded access for DeltaRex-G for an intermediate size population with advanced pancreatic cancer and sarcoma (NCT04091295) and individual patient use of DeltaRex-G for solid malignancies (IND# 19130).

Background: Innovative treatments are urgently needed for metastatic cancer. DeltaRex-G, a tumor-targeted retrovector encoding a dominant-negative/cytocidal cyclin G1 (CCNG1 gene) inhibitor construct-has been tested in over 280 cancer patients worldwide in phase 1, phase 2 studies and compassionate use studies, demonstrating long term (>10years) survivorship in patients with advanced cancers, including pancreatic cancer, osteosarcoma, malignant peripheral nerve sheath tumor, breast cancer, and B-cell lymphoma. Patient and Methods: Endpoints: Survival, response, treatment-related adverse events. Study one is entitled "Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)". Study two is entitled "Individual Patient Use of DeltaRex-G for Solid Malignancies (Investigational New Drug#19130). In both studies, patients will receive DeltaRex-G at 1-3 x 10e11cfu i.v. over 30-45min, three x a week until significant disease progression or unacceptable toxicity or death occurs. Results: Seventeen patients were enrolled, nine sarcoma, two pancreatic adenocarcinoma, one non-small cell lung cancer, two breast carcinoma, one prostate cancer, one cholangiocarcinoma and one basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with United States Food and Drug Administration-approved cancer therapies. Five patients died before receiving DeltaRex-G. Efficacy Analysis: Of the 12 treated patients, 5 (42%) are alive 15-36months from DeltaRex-G treatment initiation. Two patients with early-stage HR + HER2+ positive or triple receptor negative invasive breast cancer who received DeltaRex-G as adjuvant/first line therapy are alive in complete remission 23 and 16months after DeltaRex-G treatment initiation respectively; three patients with metastatic chordoma, chondrosarcoma and advanced basal cell carcinoma are alive 36, 31, and 15months after DeltaRex-G treatment initiation respectively. Safety Analysis: There were no treatment-related adverse events reported. Conclusion: Taken together, the data suggest that 1) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy, 2) DeltaRex-G may act synergistically with standard chemotherapy/targeted therapies, and 3) Adjuvant/first line therapy with DeltaRex-G for early-stage invasive carcinoma of breast may be authorized by the USFDA when patients refuse to receive toxic chemotherapy.

Adherence to endocrine therapy in patients with hormone receptor-positive early-stage breast cancer: a retrospective study.

The persistence and adherence to endocrine therapy (ET) in hormone receptor-positive (HR +) breast cancer patients remain far less than optimal. This retrospective study aimed to evaluate adherence to ET and to identify influencing factors in early-stage HR + breast cancer patients. A stratified random sampling method was used to select patients admitted for breast cancer surgery at a university hospital in Shanghai, China. Patients who received ET medications in the hospital information system (HIS) were included. The primary outcomes were early discontinuation of and adherence to ET. Potential factors influencing the discontinuation and adherence were assessed using univariate and multivariate logistic regression analyses. In total, 706 patients were included, and 161 (22.8%) discontinued ET in less than five years from the first prescription. The discontinuation rates from the one-year to the five-year treatment were 5.38, 16.70, 32.27, 51.52, and 50.00%, respectively (P < 0.001). The rates of adherence (defined as medication possession ratio ≥ 80%) from the first to the fifth year were 85.18, 82.25, 82.18, 72.92, and 73.68%, respectively (P = 0.18). Age, insurance, and surgery type impacted ET discontinuation and adherence. However, the type of medication only impacted the adherence to ET. Persistence and adherence to ET in patients with breast cancer remain far from optimal and decrease over time. More attention should be paid to patients aged ≥ 70years and those without insurance who tend to have early discontinuation of ET.

Discordance in management of adverse events associated with oral therapies in hormone receptor–positive breast cancer among health care providers and experts: Findings from an online decision support tool.

382 Background: Oral targeted therapies (OTTs) inhibiting CDK4/6, PI3K, and mTOR have established roles across multiple lines of therapy in patients with advanced hormone receptor–positive, HER2-negative breast cancer (HR+ BC). Abemaciclib, a CDK4/6 inhibitor (i), now also is approved in the adjuvant setting for eligible patients with early-stage HR+ BC. These OTTs are associated with various adverse events (AEs), such as cytopenias, diarrhea, hepatotoxicity, and rash. Optimal AE management is critical to promote patient adherence and achieve the best possible outcomes. Here we report an analysis of healthcare professional (HCP) management of AEs associated with OTTs in HR+ BC using an online decision support tool. Methods: The online tool was developed with 5 BC experts providing recommendations on the management of AEs associated with OTTs. Within the online tool, HCPs were prompted to input relevant patient case details through a series of predefined questions, including which OTT and type of AE the patient is experiencing, along with their management approach. Participants were then shown an expert recommendation based on the specific characteristics of that case and were asked if their management plan changed based on that recommendation. Results: Between September 2021 and April 2022, 557 cases were entered by 390 participants. Among 291 cases of patients currently receiving oral therapy, CDK4/6i therapy was most commonly selected (82%), followed by PI3Ki (11%) and mTORi (8%) therapy. The most common AE reported for CDK4/6i, PI3Ki, and mTORi therapy were cytopenias (56%), hyperglycemia (64%), and stomatitis (57%), respectively. With CDK4/6i, HCPs were discordant with expert recommendations for management of AEs reported in 44%, 39%, and 35% of entered cases with ribociclib, abemaciclib, and palbociclib, respectively. The greatest variance between HCP and expert recommendations were with management of VTE, hepatotoxicity, QT prolongation, and rash (Table). Among HCPs with discordant results from the experts, 50% changed their AE management plan after viewing the expert recommendation. Conclusions: These data suggest that HCPs may be challenged to optimally manage AEs related to OTTs in patients with HR+ BC. Use of an online tool may enhance HCP management of these AEs for patients with HR+ BC. A detailed analysis of the tool, including HCP planned management vs expert recommendations, will be presented.[Table: see text]

Cost and Clinical Benefits Associated with Oncotype DX® Test in Patients with Early-Stage HR+/HER2- Node-Negative Breast Cancer in the Netherlands

Objectives Patients with early-stage HR+/HER2- N0 breast cancer may receive adjuvant chemotherapy in combination with surgery. However, chemotherapy does not always lead to improved survival and incurs high healthcare costs and increased adverse events. To support decision-making regarding adjuvant chemotherapy, genomic profile testing performed with tests such as the Oncotype DX® test can help healthcare practitioners decide whether chemotherapy provides any benefit to these patients. As such, a cost-consequence model was developed with the aim to estimate the economic impact of using different gene expression tests or no testing, in patients with node-negative early-stage breast cancer. Methods A cost-consequence model was developed to estimate the economic impact of three different scenarios in the Dutch setting: (1) Oncotype DX® test, (2) MammaPrint®, and (3) and no genomic profile testing. The model included chemotherapy costs, administration costs, short- and long-term adverse event costs, productivity loss, genomic profiling testing costs, cost of cancer recurrence, and hospitalization costs. Results A treatment paradigm with Oncotype DX resulted in average savings per patient of €6,768 vs. a paradigm with MammaPrint and €13,125 vs. a paradigm with no genomic testing. Furthermore, due to less patients receiving adjuvant chemotherapy through better targeting by the Oncotype DX test, fewer adverse events, sick days, practice visits, and hospitalizations were required compared to MammaPrint and no genomic profiling. Conclusions Testing with Oncotype DX test in Dutch clinical practice in patients with early-stage breast cancer proved to be cost-saving versus MammaPrint and no genomic profiling tests. Introducing the Oncotype DX test to the Dutch setting will likely reduce the economic resources that are required.

Does the 21-gene recurrence score have clinical utility in HR+/HER2+ breast cancer?

The 21-gene recurrence score assay has been validated as a predictive biomarker in early-stage HR+ and HER2-breast cancer. It is not indicated for use in HER2+ disease based on national guidelines. In this study, we assessed the value of 21-gene recurrence score (RS), or OncotypeDX (ODX), testing in HR+/HER2+ breast cancer.We used the National Cancer Database to identify patients with stages I-II, HR+/HER2+ breast cancer who received multi-gene testing with ODX. We then explored the prognostic and predictive value of this biomarker through various forms of survival modeling.ODX testing was performed in n = 5,280 patients. N = 2,678 patients (50.7%) had a RS < 26, while n = 2,602 (49.3%) had a RS ≥26. In Kaplan-Meier survival modeling for patients with recurrence scores <26, there was no significant difference in overall survival (p = 0.445) between patients receiving different systemic treatment regimens. However, when recurrence scores were ≥26, there was a statistically-significant difference in overall survival between systemic treatment regimens (p < 0.001). 5-year overall survival was highest (97.4%) for patients receiving triple therapy (anti-HER2 with chemotherapy and endocrine therapy), followed by those receiving dual therapy with endocrine and anti-HER2 (96.7%), and endocrine with chemotherapy (94.9%). Patients receiving endocrine therapy alone exhibited the lowest 5-year overall survival (88.5%). ResultsAnalysis from this large national cancer registry suggests that multigene testing may have predictive value in treatment selection for patients with early-stage, HR+/HER2+ breast cancer. Prospective trials are warranted to identify subgroups of patients with HR+/HER2+ breast cancer who can be spared anti-HER2 treatments and cytotoxic chemotherapy.

138MO Prognostic performance of Breast Cancer Index (BCI) in postmenopausal women with early-stage HR+ breast cancer in the TEAM trial

Early-stage HR+ breast cancer patients face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) and BCIN+ prognostic models are significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 breast cancer, respectively. Here, the prognostic performance of BCI and BCIN+ was evaluated in a cohort of HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial.

1423TiP CYCLONE 3: A phase III, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone plus prednisone in men with high-risk metastatic hormone-sensitive prostate cancer (mHSPC)

Landmark trials led to the integration of docetaxel (D) or novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) into the treatment paradigm for mHSPC. Recent data showed survival benefit for treatment intensification with ADT+D+NHA triplet therapy vs ADT+D in selected patients (pts). Yet, there is a significant medical need to expand therapeutic options especially for pts with poor prognoses, including those not candidates for chemotherapy. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 & 6) dosed on a continuous schedule, approved for the treatment of advanced or metastatic and certain types of high-risk early stage HR+, HER2- breast cancer.

The Utility of Breast Cancer Index (BCI) Over Clinical Prognostic Tools for Predicting the Need for Extended Endocrine Therapy: A Safety Net Hospital Experience

IntroductionExtended endocrine therapy (EET) benefits select patients with early-stage hormone-receptor positive (HR+) breast cancer (BC) but also incurs side effects and cost. The Clinical Treatment Score at Five Years (CTS5) is a free tool that estimates risks of late relapse in estrogen-receptor positive (ER+) BC using clinicopathologic factors. The Breast Cancer Index (BCI) incorporates 2 genomic assays to estimate late relapse risk and likelihood of benefit from EET. This retrospective study assesses the utility of BCI in selecting EET candidates in a safety net hospital. Materials and MethodsWe performed a retrospective chart review on 69 women with early-stage HR+, HER2- BC diagnosed at our institution from December 2009 to February 2016 on whom BCI was submitted. The CTS5 score was also calculated to assess clinical risk of late relapse. ResultsMedian age was 53 years. All patients included in our analysis had early ER+ HER2-negative BC. Roughly half of the patients (55%) were postmenopausal and 61% were of Hispanic origin. A total of 34 patients (49%) were deemed high-risk (>5%) for late relapse by CTS5, compared to 42 (61%) by BCI. BCI identified 31 (45%) patients that would benefit from EET and of those, 74%% were advised EET. 16 (47%) clinical high-risk patients were advised against EET due to low benefit predicted by BCI. In the clinical low risk group, 9 (26%) were recommended EET based on high benefit predicted by BCI. ConclusionBCI is reasonable to consider in early-stage HR+ BC and offered clinically relevant information over clinical pathologic information alone.

ASO Visual Abstract: How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women with Early-Stage HR+/HER2- Breast Cancer in the Post-RxPONDER Era?

ASO Visual Abstract: How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women with Early-Stage HR+/HER2- Breast Cancer in the Post-RxPONDER Era?

How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women with Early-Stage HR+/HER2- Breast Cancer in the Post-RxPONDER Era?

The RxPONDER trial reported no benefit to chemotherapy among postmenopausal patients with HR+/HER2- tumors, one to three positive nodes, and low recurrence scores, questioning the role of axillary staging in this population. Here, we evaluate the impact of sentinel lymph node biopsy (SLNB) results on adjuvant therapy decisions in postmenopausal women with HR+/HER2- breast cancer. Postmenopausal women with cT1-2N0, HR+/HER2- breast cancer treated with lumpectomy and SLNB from 2012 to 2018 were identified. Receipt of nodal irradiation, indication for axillary lymph node dissection (ALND) and chemotherapy, and partial breast irradiation (PBI) eligibility were reviewed with pre- and post-SLNB results. A total of 1786 women were identified: median age 62 years, 84% with pT1 tumors, and 16% with pT2-3 tumors. Of those, 85% (n = 1525) remained pN0, 14% (n = 244) were pN1, and 1% (n = 17) were pN2-3. A total of 20 (1%) patients had > 2 positive SLNs, necessitating ALND. Pre-SLNB, 1478 women were considered PBI eligible; post-SLNB, 227 (13%) converted to PBI ineligible. In total, 58 patients with positive nodes received nodal irradiation, representing 3% of the entire cohort and 22% of pN+ patients. Overall, 1401 patients had an Oncotype DX recurrence score available, including 1273 patients with pN0 stage and 128 with pN1, with 173 (14%) and 16 (13%), respectively, having a recurrence score > 25, warranting chemotherapy. While few cN0 postmenopausal women with HR+/HER2- tumors had nodal pathology that warranted ALND, receipt of nodal irradiation, or indicated need for chemotherapy, in 13%, SLNB would have an impact on consideration for PBI. Among patients eligible for PBI, findings from SLNB may help refine selection among postmenopausal women with this tumor profile.