Capivasertib and fulvestrant for patients with HR-positive/HER2-negative advanced breast cancer: analysis of the subgroup of patients from Japan in the phase 3 CAPItello-291 trial.

BACKGROUND: In CAPItello-291, capivasertib-fulvestrant significantly improved progression-free survival (PFS) versus placebo-fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib-fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan. METHODS: Adults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall and PIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint. RESULTS: Of 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib-fulvestrant and 41 to placebo-fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib-fulvestrant arm (hazard ratio 0.73; 95% CI 0.40-1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors, PFS favored the capivasertib-fulvestrant arm (hazard ratio 0.65; 95% CI 0.29-1.39), consistent with the global population. The adverse event profile of capivasertib-fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified. CONCLUSION: Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen.

Neoadjuvant Chemotherapy with Concurrent Letrozole for Estrogen Receptor-Positive and HER2-Negative Breast Cancer: An Open-Label, Single-Center, Nonrandomized Phase II Study (NeoCHAI).

The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33-63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo-endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype.

Patient-reported outcome and survival in premenopausal hormone receptor-positive breast cancer patients at moderate to high risk: comparing toremifene with aromatase inhibitor in a real-world study.

Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (p = 0.034) and mental health (p = 0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores (p = 0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (p = 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (p < 0.001) and a lower occurrence of morning stiffness (p < 0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles.

CHST4 associates with high-abundance immune infiltration in hormone receptor-positive breast cancer.

Hormone receptor-positive breast cancer (HR+ BRCA) with high-risk factors such as lymph node metastasis has a relatively poor prognosis. However, the biological basis of tumor cell migration is still poorly understood, especially as some of the metastatic events occur at an early stage. Here, we identified that carbohydrate sulfotransferase 4 (CHST4), which has an important role in lymphocyte homing, was abnormally down-regulated in HR+ BRCA and associated with lymph node metastasis. By enrichment analysis and immune infiltration evaluation, we predicted the potential ability of CHST4 to enhance immune cell infiltration. Then, IHC staining further demonstrated the contribution of CHST4 to the infiltration abundance of CD8+ T cells and CD4+ T cells in HR+ BRCA. IHC staining of MECA-79 further identified the correlation between CHST4 and sulfated perpheral lymphonode vascular addressin (PNAd). Finally, we demonstrated that CHST4 was connected to increased tumor-immune cell communication by analyzing single-cell sequencing data. In summary, our study provided novel insights into the regulation of HR+ BRCA immune infiltration by CHST4.

An Overview of Long-Acting GnRH Agonists in Premenopausal Breast Cancer Patients: Survivorship Challenges and Management.

Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship.

Tailoring neoadjuvant systemic therapy in breast cancer: "The advent of a personalized approach"-The Breast-Gynecological and Immuno-Oncology International Cancer Conference (BGICC) consensus and recommendations.

BACKGROUND: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus. METHODS: During the 14th Breast-Gynecological and Immuno-Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer. RESULTS AND CONCLUSIONS: The consensus recommendations addressed different escalation and de-escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

Correlating Predicted Adjuvant Therapy Benefit and Risk of Recurrence Between Breast Cancer Index (BCI) and the 21-Gene Oncotype DX Recurrence Score (RS).

INTRODUCTION: Breast Cancer Index (BCI) is a genomic assay that evaluates the benefit of extending endocrine therapy (ET) from 5 to 10 years and predicts recurrence risk (RR). We evaluated the association between BCI and Oncotype DX (ODX). PATIENTS: Women with hormone receptor (HR)-positive early-stage breast cancer (EBC) who had BCI and ODX performed were included. METHODS: We performed a retrospective review of women with HR-positive EBC. BCI was categorized as predictive of extended ET versus not and ODX recurrence score (RS) as low (0-10), intermediate (11-25), and high (26-100). Univariate and multivariable logistic and linear regression models assessed the relationship between BCI and ODX, factors associated with each, and discordance between scores. RESULTS: We identified 153 women, 22% were premenopausal and 18% were lymph node positive. The univariate logistic and linear models revealed an association between BCI predictive score and ODX RS (OR 7.84, CI, 2.63-23.36, P < .001) and log of BCI RR (Beta 0.04, CI, 0.02-0.06, P < .001). Seventy-four percent of BCI predictive scores were concordant with ODX RS and 83% of BCI RR was concordant with ODX RR. In a univariate logistic regression model, BCI predictive of ET benefit was associated with discordance (OR 28.00, CI, 10.58-74.02, P < .001). Higher ODX RR was associated with discordance (OR 1.92, CI, 1.42-2.59, P < .001). CONCLUSION: We found a significant association between ODX and BCI predictive and prognostic scores. BCI predictive of extended ET benefit was associated with discordance with ODX RS. Higher predicted RR on ODX was associated with discordance with BCI predicted RR.

Loss of Hormone Receptor Expression after Exposure to Fluid Shear Stress in Breast Cancer Cell Lines.

Following metastatic spread, many hormone receptor positive (HR+) patients develop a more aggressive phenotype with an observed loss of the HRs estrogen receptor (ER) and progesterone receptor (PR). During metastasis, breast cancer cells are exposed to high magnitudes of fluid shear stress (FSS). Unfortunately, the role for FSS on the regulation of HR expression and function during metastasis is not fully understood. This study was designed to elucidate the impact of FSS on HR+ breast cancer. Utilizing a microfluidic platform capable of exposing breast cancer cells to FSS that mimics in situ conditions, we demonstrate the impact of FSS exposure on representative HR+ breast cancer cell lines through protein and gene expression analysis. Proteomics results demonstrated that 540 total proteins and 1473 phospho-proteins significantly changed due to FSS exposure and pathways of interest included early and late estrogen response. The impact of FSS on response to 17ß-estradiol (E2) was next evaluated and gene expression analysis revealed repression of ER and E2-mediated genes (PR and SDF1) following exposure to FSS. Western blot demonstrated enhanced phosphorylation of mTOR following exposure to FSS. Taken together, these studies provide initial insight into the effects of FSS on HR signaling in metastatic breast cancer.

Impact of 5' Near Gene Variants of Mannose Binding Lectin (MBL2) on Breast Cancer Risk.

The immune system plays a bifaceted role in tumour development through modulation of inflammation. MBL binds to damage-associated molecular patterns and induces inflammation through the activation of complement pathway. Dysregulated inflammation plays a major role in breast cancer pathogenesis, thereby suggesting its contribution towards breast cancer risk. Literature asserts single-nucleotide polymorphisms (SNPs) modulating serum MBL levels. Therefore, studying MBL2 SNPs in breast cancer might provide valuable insight in the disease pathogenesis. The present case-control association study aimed to elucidate the association between MBL2 5' near gene SNPs and breast cancer risk. Breast cancer patients were recruited from Government Medical College, G.N.D. Hospital, Amritsar. The age- and gender-matched genetically unrelated healthy individuals, from adjoining regions, with no history of malignancy up to three generations were recruited as controls. The SNPs of MBL2 from the 5' near gene region with putative functional significance were selected based upon the in silico analysis and literature review. The genotypic, allelic and haplotype frequencies for the studied variants were assessed and compared in the study participants by ARMS-PCR and PCR-RFLP. No difference in allelic, genotypic and haplotype frequencies was reported for rs7096206, rs7084554 and rs11003125 in both the participant groups. rs7084554 (CC) was found to confer risk towards hormone receptor-positive breast cancer. An intermediate LD was observed between rs7084554 and rs11003125. The study reports association between MBL2 variant (rs7084554) and hormone receptor-positive breast cancer risk. Further research in this direction might validate the findings.

CDK4/6 inhibitors: The Devil is in the Detail.

PURPOSE OF REVIEW: Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. RECENT FINDINGS: Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

Current Status and Future Perspectives of Antibody-Drug Conjugates in Hormone Receptor-Positive Breast Cancer.

Breast cancer is the most common cancer type in women. The vast majority of breast cancer patients have hormone receptor-positive (HR+) tumors. In advanced HR+ breast cancer, the combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is considered the standard of care in the front-line setting. Nevertheless, resistance to hormonal therapy and CDK4/6 inhibitors eventually occurs, leading to progression of the disease. Antibody-drug conjugates (ADCs) comprise a promising therapeutic choice with significant efficacy in patients with HR+ breast cancer, which is resistant to endocrine treatment. ADCs typically consist of a cytotoxic payload attached by a linker to a monoclonal antibody that targets a specific tumor-associated antigen, offering the advantage of a more selective delivery of chemotherapy to cancer cells. In this review, we focus on the ADC mechanisms of action, their toxicity profile and therapeutic uses as well as on related biomarkers and future perspectives in advanced HR+ breast cancer.

Comparing survival outcomes between neoadjuvant and adjuvant chemotherapy within T2N1M0 stage hormone receptor-positive, HER2-negative breast cancer: a retrospective cohort study based on SEER database.

BACKGROUND: Guideline recommendations for the application of neoadjuvant chemotherapy (NACT) in T2N1M0 stage hormone receptor-positive, HER2-negative (HR + /HER2-) breast cancer are ambiguous. The debate continues regarding whether NACT or adjuvant chemotherapy (ACT) offers superior survival outcomes for these patients. MATERIALS AND METHODS: Female patients diagnosed with HR + /HER2- breast cancer at T2N1M0 stage between 2010 and 2020, were identified from the Surveillance, Epidemiology, and End Results database and divided into two groups, the NACT group and the ACT group. Propensity score matching (PSM) was utilized to establish balanced cohorts between groups, considering baseline features. Kaplan-Meier (K-M) analysis and the Cox proportional hazards model were executed to assess the efficacy of both NACT and ACT in terms of overall survival (OS) and breast cancer-specific survival (BCSS). A logistic regression model was employed to examine the association between predictive variables and response to NACT. RESULTS: After PSM, 4,682 patients were finally included. K-M curves showed that patients receiving NACT exhibited significantly worse OS and BCSS when compared with patients undergoing ACT. Multivariable Cox analysis indicated that not achieving pathologic complete response (non-pCR) after NACT (versus ACT), was identified as an adverse prognostic factor for OS (HR 1.58, 95% CI 1.36-1.83) and BCSS (HR 1.70, 95% CI 1.44-2. 02). The logistic regression model revealed that low tumor grade independently predicted non-pCR. CONCLUSION: Among T2N1M0 stage HR + /HER2- patients, OS and BCSS of NACT were inferior to ACT. Patients who attained non-pCR after NACT demonstrated significantly worse survival outcomes compared with those who received ACT.

Economic assessment of abemaciclib for the adjuvant treatment of luminal HER2- breast cancer from the perspective of the Spanish health system.

INTRODUCTION: Abemaciclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). Data from the clinical trial monarchE (2023) showed improved survival from invasive disease. The aim of the present article was to conduct an economic assessment of adjuvant treatment with abemaciclib in women with luminal, HER2- and node-positive breast cancer. METHODS: A Markov model was constructed with four mutually exclusive health states (disease-free, local recurrence, distal recurrence and death). Analyses were based on the clinical trial monarchE which compared an intervention group (abemaciclib + hormone therapy [HT]) with HT alone. The effectiveness measure used was quality-adjusted life years (QALY), with unit costs and utilities being obtained from existing literature. The incremental cost-utility ratio (ICUR) was used to compare the two treatment strategies. RESULTS: Total costs were €98,765 and €17,935 for the abemaciclib plus HT group and the HT alone group, respectively. The health outcome was 10.076QALY for the intervention group and 9.495QALY for the control group, with the ICUR being€139,173/QALY. CONCLUSION: Despite the significant gains of abemaciclib as adjuvant treatment in terms of progression-free survival, this treatment is not cost-effective for the Spanish National Health System at published prices. It may be cost-effective with an appropriate discount on the official price.

Aromatase inhibitor-induced arthralgia ameliorated by Mediterranean diet and active lifestyle guided by continuous glucose monitoring: a case report and review of the literature.

Aromatase inhibitors (AIs) are a cornerstone adjuvant treatment of many hormone receptor-positive breast cancers, and nearly half of women taking aromatase inhibitors suffer from AI-induced arthralgia (AIA), also known as AI-associated musculoskeletal syndrome (AIMSS), for which there are limited evidence-based treatments. Pharmacologic management and complementary methods including supplements, exercise, physical therapy, yoga, acupuncture, and massage have all shown mixed results. Comprehensive diet and lifestyle strategies are understudied in AIA/AIMSS despite their disease-modifying effects across many chronic conditions. Here we report a case of a woman with stage 2 estrogen and progesterone receptor-positive invasive ductal carcinoma on adjuvant anastrozole whose AI-induced arthralgia was durably controlled through a Mediterranean plant-forward diet and daily physical activity guided by continuous glucose monitoring. We posit that diet and a lifestyle inclusive of daily physical activity constitute a low-cost, low-risk, and potentially high-reward strategy for controlling common AI-induced musculoskeletal symptoms and that more investigation in this arena, including well-designed randomized trials, is warranted.

Menopausal Symptoms and Utian Quality of Life Scale Following a Breast Cancer Diagnosis and Its Impact on Endocrine Adherence.

Introduction Standard treatment for oestrogen-positive breast cancers involves a minimum of five years of adjuvant endocrine treatment with a significant improvement in survival. However, the side effects of endocrine treatments are often underestimated. We aimed to identify the frequency of side effects, adherence to treatment, and impact on the quality of life of breast cancer survivors. Methods All patients attending holistic needs assessment and health and wellbeing events with a clinical nurse specialist between March and October 2023 were given a menopause symptom proforma and Utian menopausal quality of life scale questionnaire. Results A total of 99/150 (66%) patients attending a health needs assessment with a clinical nurse specialist following a diagnosis of breast cancer returned forms. The mean age of respondents was 56.7 years, with a mean 2.5-year duration since diagnosis. Thirty-seven percent of respondents were premenopausal at diagnosis, and 63% were postmenopausal. Five percent stopped treatment early due to menopausal symptoms, and 2.2% changed endocrine treatment. Overall, the mean menopausal quality of life score was -0.454 (p=0.0052). Within the premenopausal cohort, 84% reported hot flushes, 81% a low-sex drive, 73% night sweats, 89% memory problems, 89% fatigue, and 76% joint aches. This group scored -0.20 SD on the quality of life scale. The postmenopausal group reported a 71% incidence of hot flushes, 79% both poor sleep and joint pain, 60% breast pain, and 86% fatigue. They demonstrated a mean of -0.58 SD on the quality of life scale. The failure to adhere to endocrine treatment was reported by 6% of respondents, who cited side effects as the reason for non-compliance. Conclusion In conclusion, there is a significant increase in menopausal symptoms following treatment for breast cancer, which is negatively impacting well-being, quality of life, and endocrine adherence.

Endocrine therapy plus HER2-targeted therapy, another favorable option for HR+/HER2+ advanced breast cancer patients.

Advanced breast cancer (ABC) that is positive for hormone receptors (HRs) and human epidermal growth factor receptor 2 (HER2) is a cancer subtype with distinctive characteristics. The primary treatment guidelines suggest that a combination therapy comprising anti-HER2 therapy and chemotherapy should be administered as the initial treatment for HR-positive/ HER2-positive (HR+/HER2+) ABC. However, crosstalk between the HR and HER2 pathways can partially account for the resistance of HR+/HER2+ disease to HER2-targeted therapy. This, in turn, provides a rationale for the concomitant administration of HER2-targeted therapy and endocrine therapy (ET). Many clinical studies have confirmed that the combination of HER2-targeted therapy and ET as a first-line treatment is not inferior to the combination of HER2-targeted therapy and chemotherapy, and support its use as a first-line treatment choice for HR+/HER2+ ABC. Other drugs, such as antibody-drug conjugates, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase-protein kinase B (AKT)-mammalian target of rapamycin inhibitors, and programmed cell death protein 1 or programmed cell death ligand 1 inhibitors, may also improve the prognosis of patients with breast cancer by blocking signaling pathways associated with tumor proliferation and break new ground for the treatment of HR+/HER2+ ABC.

Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis.

PURPOSE: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. METHODS: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. RESULTS: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44]. CONCLUSION: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.

Unveiling the HER2-low phenomenon: exploring immunohistochemistry and gene expression to characterise HR-positive HER2-negative early breast cancer.

PURPOSE: HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the 21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2-zero, obtained by immunohistochemistry (IHC). METHODS: Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1-10%). HER2 gene expression by ODX was negative if lower 10.7. RESULTS: The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 + . The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 [IQR: 8.70-9.60]. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC [OR 1.42, 95% CI 1.21 to 1.68, p < 0.001; OR 1.96, 95% CI 1.61 to 2.37, p < 0.001] compared to the HER2-zero group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups. CONCLUSION: Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2-zero IHC whose accurate identification is critical in the context of HER2-negative BC.

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.