Hormone Receptor-negative Tumors Research Articles

Differential expression of NAT1 pharmacogene in hormone receptor positive vs. negative female breast tumors may affect drug treatment.

Studies have reported overexpression of NAT1 gene for xenobiotic metabolizing arylamine N-acetyltransferase type 1 in estrogen receptor positive breast tumors, and this association has been linked to patient chemoresistance and response to tamoxifen. We probed the expression of NAT1, using quantitative reverse transcription PCR to screen clinically characterized breast cancer tissue cDNA arrays. Primers detecting all NAT1 alternative transcripts were used, and the protocol and results are reported according to consensus guidelines. The clinical information about 166 tumor samples screened is provided, including tumor stage, estrogen and progesterone receptor status and HER2 expression. NAT1 was found to be significantly (P < 0.001) upregulated in hormone receptor positive vs. negative tumors. No correlation was apparent between NAT1 and tumor stage or HER2 expression. Our findings demonstrate a strong correlation between the expression of NAT1 and steroid hormone receptors in breast tumors, supporting its possible utility as a pharmacogenetic biomarker or drug target. Of the two polymorphic NAT genes, NAT1 is the one primarily expressed in breast tissue, and is subjected to regulation by two differential promoters and more than one polyadenylation signal. Hormonal factors may enhance NAT1 gene expression at the transcriptional or epigenetic level, and tamoxifen has additionally been shown to inhibit NAT1 enzymatic activity. The outcome of tamoxifen treatment is also more favorable in patients with NAT1 overexpressing tumors. The study adds to the growing body of evidence implicating NAT1 in breast cancer and its pharmacological treatment.

ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.

Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.

Abstract PO2-18-12: Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer

Abstract Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced HER2-positive breast cancer. We now present the updated results of this trial. Methods: This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease &amp;lt; 1cm) rate, objective response rate (ORR) and safety. Results: From November 2021 to July 2023, 40 patients were enrolled in the trial. One patient received one cycle of the study treatment but was lost to follow-up without surgery, and five patients received one cycle of the study treatment and were still undergoing treatment, leaving 34 patients in the intention-to-treat (ITT) population. Among these 34 patients (82.4% in stage III), 22 patients completed the study treatment and surgery (per-protocol [PP] population) and 12 patients were still undergoing neoadjuvant treatment. The ORR was 91.2% (31/34) in the ITT population and 86.4% (19/22) in the PP population. Among the 22 patients in the PP population, 12 patients (54.5%) achieved pCR, and18 patients (81.8%) achieved npCR. The pCR rates for patients with hormone receptor (HR) negative and positive tumors were 80.0% (8/10) and 33.3% (4/12), respectively. The most common grade 3 adverse event was neutropenia (17.6%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Conclusions: Neoadjuvant therapy with TCbIP demonstrated promising efficacy and manageable toxicity in patients with HER2-positive locally advanced breast cancer. Registration number: NCT05749016 (www.clinicaltrials.gov). Citation Format: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li. Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-18-12.

Abstract PO4-15-10: HER2-low Status among Patients with Li-Fraumeni Syndrome and Breast Cancer

Abstract Background: The HER2-low status has gained significance as a target for HER2-directed antibody drug conjugates in breast cancer. It is observed in approximately 60% of hormone receptor-positive (HR+) tumors and 30% of hormone receptor-negative (HR-) tumors. Some studies suggest that the HER2-low status by itself does not influence tumor biology or prognosis. Breast cancer in the context of Li-Fraumeni (LFS) syndrome has been characterized by an enrichment in HER2-positive (HER2+, defined as +3 in the immunohistochemistry [IHQ] or +2 in the IHQ with positive in situ hybridization [ISH]) disease. Considering this, we aimed to evaluate whether LFS patients with breast cancer also exhibit a higher frequency of HER2-low status. Methods: This retrospective-prospective cohort study included patients diagnosed with breast cancer who had a pathogenic/likely pathogenic TP53 germline variant and were treated at two cancer institutions between 1999 and 2023. The primary objectives were to determine the overall proportion of HER2-low status and its distribution according to hormone receptor status. HER2-low was defined as IHQ +1 or IHQ +2 with negative ISH. Results: Fifty-three patients (52 female and 1 male) were included in the study. The most common germline TP53 variant was the TP53 R337H (71.7%). The median age at breast cancer diagnosis was 39 years (range 21–62). The majority of patients had breast cancer of no special type (79%) or lobular carcinoma (11.3%), grade 2 (54.7%) or grade 3 (24.5%), and stage I-II (67.9%). Breast cancer subtypes would classically be classified as HER2+ in 34%, HR+HER2- in 58.5%, and triple-negative breast cancer (TNBC) in 7.5% of the patients. Biopsy samples were obtained from the primary tumor in 96.3% of the cases and from lymph nodes in 3.7%. Overall, 15.1% of the cases exhibited HER2-low status, 34% were HER2-negative, and 17% were HER2-negative without IHC details (Table). In a hypothetical scenario assuming all cases without IHC details were HER2-low, the maximum estimated frequency of HER2-low status would be 32.1%. Among HR+ patients, 25.8% had HER2-low status, 45.2% were HER2-negative, and 29% were HER2-negative without IHC details. All four patients with TNBC exhibited HER2-zero status. Conclusion: Contrary to our initial hypothesis, the frequency of HER2-low status in this cohort of LFS patients with breast cancer was lower than anticipated. These results suggest that while breast cancer developing in the context of germline TP53 variants appears to be associated with HER2 amplification, it does not impact lower expressions of HER2. This observation reinforces the concept that HER2-low status does not seem to play a significant role as a driver of tumorigenesis. Further expansion of the study cohort and pathology analysis is planned to confirm these findings. Table HER2 status overall and according to hormone receptor-status (for HER2-negative patients). Abbreviations: IHQ, immunohistochemistry; HR+HER2- BC, hormone receptor-positive HER2-negative breast cancer; TNBC, triple-negative breast cancer. Citation Format: Luciana Auresco, Renata Colombo Bonadio, Vanessa Petry, Laura Testa, Camila Moniz, Jennifer Dos Santos, Maria Del Pilar Estevez-Diz, Rodrigo Santa Cruz Guindalini. HER2-low Status among Patients with Li-Fraumeni Syndrome and Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-10.

MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II–III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study

Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. Roche Netherlands.

Real-world experience with pertuzumab and trastuzumab combined with chemotherapy in neoadjuvant treatment for patients with early-stage HER2-positive breast cancer: the NEOPERSUR study.

HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC. A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR). A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 relatedtoxicities were reported in six (1.9%) patients. Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.

Clinical, Epidemiologic, and Pathologic Significance of ERBB2-Low Expression in Breast Cancer

It is unclear whether breast cancer (BC) with low ERBB2 expression (ERBB2-low) is a distinct clinical, pathological, and epidemiological entity from BC classified as no ERBB2 expression (ERBB2-negative). To evaluate the clinical, pathological, and epidemiologic features of BC with ERBB2-low expression compared with ERBB2-negative BC in a large population study. This cohort study was conducted as part of the Pathways Study, a prospective, racially and ethnically diverse cohort study of women with BC enrolled between 2006 and 2013 in Kaiser Permanente Northern California (KPNC). The hematoxylin and eosin slides underwent centralized pathology review, including the percentage of tumor infiltrating lymphocytes (TILs). Breast biomarker results were extracted from pathology reports, and women were included if they had a documented ERBB2 value that was not classified ERBB2-positive. Data were analyzed from February 2023 through January 2024. Clinical and tumor characteristics associated with BC and ERBB2-low or ERBB2-negative status. ERBB2-low was defined as immunohistochemistry score of 1+ or 2+ (negative by in situ hybridization); ERBB2-negative was defined as immunohistochemistry score of 0+. Other data were collected by self-report or extraction from electronic health records, including BC risk factors, tumor characteristics, treatment modality, and survival outcomes, with recurrence-free survival (RFS) as the primary outcome and overall survival (OS) and BC-specific mortality (BCSM) as secondary outcomes. The clinical, pathological, and epidemiological variables were compared between ERBB2-low and ERBB2-negative BC. Of 2200 eligible patients (all female; with mean [SD] age, 60.4 [11.9] years), 1295 (57.2%) had tumors that were ERBB2-low. Hormone receptors were positive in 1956 patients (88.9%). The sample included 291 Asian patients (13.2%), 166 Black patients (7.5%), 253 Hispanic patients (11.5%), 1439 White patients (65.4%), and 51 patients (2.3%) who identified as other race or ethnicity (eg, American Indian or Alaska Native and Pacific Islander). Within the hormone receptor-negative group, patients whose tumors had ERBB2-low staining, compared with those with ERBB2-negative tumors, had better OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91; P = .02), RFS (HR, 0.53; 95% CI, 0.30-0.95; P = .03), and BCSM (HR, 0.43; 95% CI, 0.22-0.84; P = .01). In multivariable survival analysis stratified by hormone receptor status and adjusted for key covariates, patients with ERBB2-low and hormone receptor-negative tumors had lower overall mortality (HR, 0.48; 95% CI, 0.27-0.83; P = .009), RFS (HR, 0.45; 95% CI, 0.24-0.86; P = .02), and BCSM (subdistribution HR, 0.21; 95% CI, 0.10-0.46; P < .001) compared with patients with ERBB2-negative and hormone receptor-negative tumors. Within the hormone receptor-negative subtype, patients with ERBB2-low and high TILs tumors had better survival across all 3 outcomes compared with patients with ERBB2-negative and low TILs tumors. Additionally, patients with ERBB2-low and low TILs tumors had better BCSM (subdistribution HR, 0.36; 95% CI, 0.14-0.92; P = .03). These findings suggest that there were clinical, pathological, and epidemiological differences between ERBB2-low and ERBB2-negative BC, raising the possibility that ERBB2-low might be a unique biologic entity.

BIRC5 expression by race, age and clinical factors in breast cancer patients

PurposeSurvivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse populations where aggressive breast cancers are prevalent.Experimental designWe studied BIRC5 expression in association with clinical and demographic variables and as a predictor of recurrence in 2174 participants in the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1113) and younger (< 50 years; n = 1137) participants with breast cancer. For comparison, similar analyses were conducted in The Cancer Genome Atlas [TCGA N = 1094, Black (n = 183), younger (n = 295)]. BIRC5 was evaluated as a continuous and categorical variable (highest quartile vs. lower three quartiles).ResultsUnivariate, continuous BIRC5 expression was higher in breast tumors from Black women relative to non-Black women in both estrogen receptor (ER)-positive and ER-negative tumors and in analyses stratified by stage (i.e., within Stage I, Stage II, and Stage III/IV tumors). Within CBCS and TCGA, BIRC5-high was associated with young age (< 50 years) and Black race, as well as hormone receptor-negative tumors, non-Luminal A PAM50 subtypes, advanced stage, and larger tumors (> 2 cm). Relative to BIRC5-low, BIRC5-high tumors were associated with poor 5-year recurrence-free survival (RFS) among ER-positive tumors, both in unadjusted models [HR (95% CI): 2.7 (1.6, 4.6)] and after adjustment for age and stage [Adjusted HR (95% CI): 1.87 (1.07, 3.25)]. However, this relationship was not observed among ER-negative tumors [Crude HR (95% CI): 0.7 (0.39, 1.2); Adjusted HR (95% CI): 0.67 (0.37, 1.2)].ConclusionBlack and younger women with breast cancer have a higher burden of BIRC5-high tumors than older and non-Black women. Emerging anti-survivin treatment strategies may be an important future direction for equitable breast cancer outcomes.

Predictive factors for complete pathological response in hormone receptor-negative breast cancer patients undergoing neoadjuvant chemotherapy

Complete pathological response (pCR) is a pivotal predictor of enhanced disease-free and overall survival rates in breast cancer patients. Accurate prediction of pCR is therefore of paramount clinical significance. This retrospective study aimed to delineate the factors associated with pCR through a comprehensive analysis encompassing clinical, pathological, and immunohistochemical profiling of patients diagnosed with hormone receptor-negative invasive ductal carcinomas. The study cohort was composed of 73 female patients. The cases were reviewed retrospectively using data from University Hospital "Tsaritsa Yoanna" in Sofia, spanning the ten-year period from 2010 to 2020. Univariate analyses demonstrated that patients diagnosed with a higher disease stage, specifically stage IIIb, exhibited a notable association with an unfavorable response to neoadjuvant chemotherapy (NCT) [OR 4.5455 (95%CI 1.6810 - 12.2910); p = 0.0029]. Invasive carcinomas containing a ductal carcinoma in situ (DCIS) component [OR 0.3333 (95%CI 0.1226 - 0.9063); p = 0.0313] or were classified as poorly differentiated [OR 0.3056 (95%CI 0.1159 - 0.8055); p = 0.0165] demonstrated an enhanced likelihood of achieving pCR. Tumors expressing CD10 [OR 0.1452 (95%CI 0.0515 - 0.4093); p = 0.0003] and tumors lacking EGFR [OR 3.9722 (95%CI 1.4691 - 10.7399); p = 0.0066] exhibited a markedly elevated rate of pCR. Multivariate regression analysis supported findings. In conclusion, hormone receptor-negative breast tumors stand to benefit from increased pCR rates if they encompass a DCIS component and exhibit CD10 expression while lacking EGFR expression. These findings underscore the importance of comprehensive profiling in predicting pCR outcomes in hormone receptor-negative breast cancer patients undergoing neoadjuvant chemotherapy.

HER2 categorical changes after neoadjuvant chemotherapy: A study of 192 matched breast cancers with the inclusion of HER2-Low category

Understanding the changes of HER2 expression after neoadjuvant chemotherapy (NAC) in breast cancer (BC) is more important than ever, since it may allow more patients to access the effective therapeutic drugs targeting HER2-low BC. 192 matched pre- and post-NAC BCs were analyzed. HER2 immunohistochemistry (IHC) was re-evaluated with consensus according to the current ASCO/CAP guidelines. Tumors were categorized into HER2-0 (IHC0+), HER2-low (IHC1+ or IHC2+/ISH-) and HER2-positive (IHC3+ or IHC2+/ISH+) subgroups. 55 (28.6 %) patients achieved pathologic complete response (pCR). HER2-low BC accounted for 75/192 (39.1 %) baseline tumors, and 48/133 (36.1 %) residual tumors. In the non-pCR cohort, 53 (39.9 %) patients had HER2 categorical change after NAC, most commonly converting from HER2-low to HER2-0 (20.3 %, n = 27). Among patients with residual tumor, 25.6 % (11/43) of patients with baseline HER2-0 expression experienced a categorical change to HER2-low after NAC, significantly higher (p < 0.05) in the hormone receptor (HR) positive (9/23, 39.1 %) compared to the HR negative tumors (10 %, 2/20). Exploratory analysis failed to reveal a statistically significant difference in disease free survival and overall survival in non-pCR patients with or without HER2 change. Our results suggest that a substantial number of patients may experience HER2 categorical change after NAC, supporting re-testing of HER2 status in post-NAC residual tumors. Retesting HER2 status may be particularly important for evaluating post-NAC HER2-low status, in order to better assess which patients will more likely benefit from therapeutic drugs targeting HER2-low BC.

Accuracy of Tumor Bed Biopsy for Predicting Pathologic Complete Response After Chemotherapy Among Women With Breast Cancer: Complete Responders in the Breast Study.

With the advent of taxanes and targeted agents in neoadjuvant chemotherapy (NACT) for breast cancer, the rates for pathologic complete response (pCR) have been steadily increasing. Surgery in these women serves as a biopsy to confirm or negate a pCR. All newly diagnosed patients with nonmetastatic breast cancer, planned for NACT, were screened. Eligible patients with a complete or near-complete response to NACT as seen on a mammogram and ultrasound (US) were recruited. A magnetic resonance imaging was performed for these patients for documentation. US-guided core biopsies of the tumor bed (Core Bx) using a 14G needle was performed (minimum four in number), and the results were compared with the final histopathology report after surgery for standard performance parameters. This study recruited 65 women of whom 94% were node-positive, and 60% were hormone receptor-negative. The pCR rate was 41.5% and 53.8% for the whole cohort and the hormone receptor-negative subgroup, respectively. The false-negative rate (FNR) for Core Bx was 42.1% (95% CI, 26.3 to 59.2), with a negative predictive value of 59.0% (95% CI, 42.1 to 74.4). Among the hormone receptor-negative tumors, the FNR was 44.4% (95% CI, 21.5 to 69.2) with a negative predictive value of 70.4% (95% CI, 49.8 to 86.2). The Complete Responders in the Breast study results suggest that ultrasound-guided 14G core needle biopsy of the tumor bed may not be a reliable predictor of pCR in the breast. These results highlight the importance of further research into the omission of surgery in the breast after chemotherapy. This study is registered with Clinical Trials Registry of India (CTRI/2018/01/011122).

BMI and mortality in hormone-negative breast cancer: A PLCO trial subgroup analysis.

e12544 Background: Body Mass Index (BMI) is a significant prognostic factor in the survival of patients with hormone receptor-positive breast cancer (BC).[1-2] However, the relationship between BMI and survival is not well-established in hormone receptor-negative (HR-) breast tumors. [3] Emerging data is mixed: some studies show that BMI does not impact outcomes in HR- tumors [4], while others reveal worse survival in patients with elevated BMI.[5] In this study, our objective was to corroborate recent evidence about the relationship between BMI and mortality in hormone-negative breast cancer. Methods: We used the PLCO cancer screening trial, a publicly available database containing information about 155,000 participants enrolled in the United States between 1993 and 2001. Data were collected on cancer mortality through 2018 (median follow-up of 19.2 years post enrollment). The methodology of the PLCO trial has been described previously.[6] All female patients with a diagnosis of HR- BC diagnoses were selected for data retrieval, including HR-/HER2+ and HR-/HER2- tumors. Patients with equivocal receptor status were excluded. We used multivariate Cox regression to analyze mortality by BMI category, after adjusting for all significant variables at the bivariate level ( p &lt;0.25). Results: 348 women with confirmed HR- BC at the time of study participation were included. Mean age was 69 years old, and 62 patients (17.8%) passed away due to breast cancer during study enrollment or follow-up. Patients who were of normal weight (BMI 25-&lt;30) at age of trial enrollment were not significantly more likely to survive compared to overweight or obese patients (Hazard Ratio 1.274, p= 0.623). Conclusions: Our results show no significant relationship between BMI and mortality in patients with HR- BC tumors. This finding adds to the growing literature about weight status in hormone receptor-negative tumors. Our data suggests that the mechanism of tumor progression in HR- breast tumors is unlikely to involve signaling mechanisms in adipocytes. Clinical trial information: NCT00002540 , NCT01696968 , NCT01696981 , NCT01696994 . [Table: see text]

De-escalating therapy dilemma in small HER2 positive node negative breast cancer.

e12626 Background: Neoadjuvant therapy (NAT) is the standard of care for locally advanced HER2 positive breast cancer (BC) and provides pathologic complete response (pCR), a key prognostic factor and indicator to decide whether to escalate to adjuvant T-DM1 in case of residual disease, as per the KRISTINE trial. However, optimal sequencing of treatment (NAT vs. surgery first) is less clear in T1cN0 (stage I) HER2 positive BC. Moreover, the long-term follow-up of the Adjuvant Paclitaxel and Trastuzumab (APT) trial showed that deescalating chemotherapy is a possible strategy for small HER2-positive node negative breast cancers when tumor size is 3 cm or less. In clinical practice, there is a recurrent debate in multidisciplinary boards to decide the adequate strategy in small HER2 positive node negative BC. Although these tumors are considered of good prognosis, recent results by An et al. 2022 fuels the debate. They showed in a large observational cohort that T1N0 HER2 positive BC APT eligible treated with NAT and not achieving pCR have similar survival to patients with T2N0 tumors with residual disease, suggesting a higher risk group among small tumors.The aim of the study was to analyze the profile and outcome of APT eligible patients treated with NAT using a detailed tumor size breakdown. Methods: APT eligible patients treated with NAT were identified among a real-world cohort of 340 early HER2 positive BC patients receiving NAT at Oscar Lambret Cancer Center (Lille, France). The outcome of the APT eligible patients (n = 115) was analyzed according to tumor size ( &lt; 15mm, 15-20mm, 21-30mm). Results: All patients were female with a median age of 54 years and received neoadjuvant anthracyclines followed by taxanes and trastuzumab. The ratio of hormone receptor (HR) positive / HR negative tumors was 72% / 28%. A similar distribution of grade 2 / grade 3 tumors was observed. Up to 75% of the patients did not have a complete pathologic response to NAT. In HR positive, the pCR rate was 43% in HER2 positive tumor of less than 15mm, 26% in tumors of 15-20mm, 25% in tumors of 21-30mm, and 32% in tumors of 31-50mm. In HR negative tumors, pCR rate was 81% in tumors of 15-20mm, 56% in tumors of 21-30mm, and 67% in tumors of 31-50mm. Conclusions: These results showed that APT eligible small HER2 positive and HR positive tumors had low chemosensitivity leading to adjuvant treatment escalation as per standard of care. It raises questions about the appropriate selection of patients for de-escalation in this population subset.

Clinical meaning of stromal tumor infiltrating lymphocytes (sTIL) in luminal early breast cancer.

572 Background: Luminal breast cancer (BC) is associated with lower immune activation. Although stromal tumor infiltrating lymphocytes (sTIL) are a marker of better prognosis and response in hormone receptor (HR) negative tumors, sTIL predictive and prognostic implications are less clear in luminal BC. Further insights on the clinical correlations of immune microenvironment in luminal disease may facilitate therapeutic improvement and prognostic stratification in these patients. Methods: Observational and single-center cohort of 345 women with early luminal (HR positive, HER2 negative) BC (2012-2020) treated with chemotherapy. Pre-treatment sTIL were determined in the diagnostic biopsy following validated standard methods. The correlation between sTIL and other tumor characteristics were analyzed (Spearman's Rho and Chi-squared tests). Association of sTIL with pathologic complete response (pCR) in patients treated with neoadjuvant chemotherapy (nCT) was evaluated with logistic regression models. Prognostic value of sTIL for overall (OS) or relapse free interval (RFI) was analyzed by Cox regression models. Results: Median age: 50 (range: 24-89); 48.1% premenopausal; 91.3% infiltrating ductal carcinoma; 30.1% grade 3; 87.2% progesterone receptor (PgR)+; 67.5% treated with nCT and 32.8% with adjuvant CT (aCT); 47.6% N0, 32.8% N1, 19.6% N2-3; median ki67: 30% (82.7% &gt;10%). A 29% of patients showed sTIL=0%. Median sTIL infiltration was 5 (Q1-Q3 range [IQR], 0-10), with higher values in premenopausal (p&lt;0.001), grade 3 (p&lt;0.001), N+ (p&lt;0.001) and luminal B tumors (defined as PgR- and/or grade 3 and/or Ki67&gt;15%) (p&lt;0.001). Ki67 was significantly correlated with sTIL (ρ:0.39; p&lt;0.001). The percentage of sTIL was associated with pCR after nCT (OR: 1.045, 95%Ci 1.02-1.07, p=0.001). No prognostic impact of sTIL for OS or RFI was found in luminal A tumors. In luminal B cases (n=286), any grade of lymphocytic infiltration (defined as sTIL &gt; 0%) was associated with a shorter RFI both in univariate (p=0.01) and multivariate Cox models (HR: 4.83, 95%CI 1.28-18.21, p=0.02), with a non-significant trend for poorer OS (p=0.06). Conclusions: In luminal BC, an increased level of sTIL is associated with luminal B subtype characteristics such as higher proliferation, higher tumor grade and nodal involvement. Lymphocytic infiltration has been found to be a predictor of pCR after nCT, but, in contrast with hormone receptor-negative BC, it is also associated with a poorer prognosis for recurrence and a trend towards worse overall survival in luminal B tumors. [Table: see text]

Neoadjuvant inetetamab combined with pertuzumab, paclitaxel, and carboplatin (TCbIP) for locally advanced HER2-positive breast cancer: Primary analysis of a phase II study.

e12597 Background: Inetetamab (Cipterbin) is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity (ADCC) effect. Unfortunately, no robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) exists for neoadjuvant therapy. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy of patients with locally advanced (LA) HER2-positive breast cancer. Methods: This phase II trial included patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients receive TCbIP treatment every 3 weeks for a maximum of 6 cycles, followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease &lt; 1cm) rate, objective response rate (ORR) and safety. Efficacy was analyzed in the intention-to-treat (ITT) and per-protocol (PP) populations. The ITT population included patients who received at least 2 cycles of TCbIP treatment but excluded those who were lost to follow-up without surgery and those who received other targeted therapy. The PP population included patients who met all the trial criterias, complianted with the protocol, and did not violate any major protocol. The safety population included all patients who received at least one dose of the study drugs and had available safety data. Results: A total of 24 patients were enrolled from November 2021 to February 2023. Of 24 patients, 1 patient received 1 cycle of study treatment and was lost to follow-up without surgery, and 4 patients received 1 cycle of study treatment and were still in treatment, leaving 19 patients in the ITT population. Among 19 patients in the ITT population (median age, 50 years; 78.9% in stage III), 12 patients completed the study treatment and surgery (PP population) and 7 patients were still in neoadjuvant treatment. ORR was achieved 78.9% in the ITT population (15 of 19 patients) and 91.7% in the PP population (11 of 12 patients). Among 12 patients of PP population, 8 patients (66.7%) achieved pCR and 10 patients (83.3%) achieved npCR. For patients with hormone receptor negative and positive tumors, the pCR rates were 71.4% (5/7) and 60.0% (3/5) ( P = 0.771), and the npCR rates were 85.7% (6/7) and 80.0% (4/5) ( P = 0.793), respectively. The most common grade ³3 adverse events were hair loss (41.7%) and neutropenia (12.5%). No significant reduction in the left ventricular ejection fraction was observed in any patient. No patients withdrew from the treatment due to adverse drug reactions. Conclusions: TCbIP displays a promising efficacy (pCR rate of 66.7%) and manageable toxicity in patients with HER2-positive LA breast cancer in the neoadjuvant setting. Clinical trial information: NCT05749016 .

Adherence to Cancer Prevention Lifestyle Recommendations Before, During, and 2 Years After Treatment for High-risk Breast Cancer

The American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown. To investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality. The Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor-negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023. An aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle. Disease recurrence and all-cause mortality. A total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59). In this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

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

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

Inferred Immune-Cell Activity Is an Independent Predictor of HER2-Negative Breast Cancer Prognosis and Response to Paclitaxel-Based Therapy in the GeparSepto Trial.

Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in patients with breast cancer. Here, immune-cell activity of breast cancer tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426). Pre-study biopsies from 279 patients with HER2-negative breast cancer in the G7 trial underwent RNA-seq-based profiling of 104 immune-cell-specific genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA "hot," "warm," or "cold" by comparison of iICA in the G7 cohort relative to that of 1,467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed tumor-infiltrating lymphocytes (TIL), and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) were determined. iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low. Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR, and survival were observed for HR-positive tumors versus HR-negative tumors, suggesting expanded study of the implication of these findings is warranted.

What Is Known about Breast Cancer in Young Women?

Breast cancer (BC) is the second leading cause of cancer-related death in women under the age of 40 years worldwide. In addition, the incidence of breast cancer in young women (BCYW) has been rising. Young women are not the focus of screening programs and BC in younger women tends to be diagnosed in more advanced stages. Such patients have worse clinical outcomes and treatment complications compared to older patients. BCYW has been associated with distinct tumour biology that confers a worse prognosis, including poor tumour differentiation, increased Ki-67 expression, and more hormone-receptor negative tumours compared to women >50 years of age. Pathogenic variants in cancer predisposition genes such as BRCA1/2 are more common in early-onset BC compared to late-onset BC. Despite all these differences, BCYW remains poorly understood with a gap in research regarding the risk factors, diagnosis, prognosis, and treatment. Age-specific clinical characteristics or outcomes data for young women are lacking, and most of the standard treatments used in this subpopulation currently are derived from older patients. More age-specific clinical data and treatment options are required. In this review, we discuss the epidemiology, clinicopathologic characteristics, outcomes, treatments, and special considerations of breast cancer in young women. We also underline future directions and highlight areas that require more attention in future studies.

Abstract ED3-1: Updates in the pathology of PABC

Abstract Updates in the Pathology of Pregnancy Associated Breast Cancer (PABC) Pregnancy associated breast cancer is defined as a breast cancer diagnosed during gestation, lactation and within 1 to 5 years postpartum. While the development of malignancy during pregnancy is rare, the incidence is increasing; breast cancer is one of the most common cancers diagnosed during pregnancy and the postpartum period occurring in up to 1 in 3000 deliveries. Of interest, breast cancer is the leading cause of cancer death in US women age 15-29. Pregnancy has a dual effect on breast cancer development: on one hand cancer protective and on the other cancer promoting. While a number of hypotheses have been proposed over the years to explain these effects, the most likely hypothesis for the development of PABC is the involution hypothesis. This hypothesis proposes that the involution pathways activated during pregnancy and the immediate postpartum period are remodeling programs similar to wound healing and inflammation that may be associated with tumor development and progression. Although PABCs can be any subtype of breast carcinomas, they are usually invasive ductal carcinomas of high tumor grade and large tumor size with higher stage at presentation and higher rates of lymph node involvement. Most PABCs are hormone receptor negative tumors with high Ki-67 proliferation rates; most frequently, they are either triple negative or HER2-positive carcinomas. A number of studies have shown that PABCs have different genomic signatures than the non-PABC tumors with PABCs having an increased expression of immune response mediators. Better understanding of the molecular pathways of tumor initiation and progression and prompt diagnosis and state-of-art treatment protocols in PABC is expected to lead to better outcomes for these young breast cancer patients. Citation Format: Kalliopi Siziopikou. Updates in the pathology of PABC [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 ED3-1.