Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer.

BACKGROUND: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863). METHODS: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise. FINDINGS: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months). INTERPRETATION: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.

Elacestrant in the treatment landscape of ER-positive, HER2-negative, ESR1-mutated advanced breast cancer: a contemporary narrative review.

Introduction: Estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer with ESR1 mutations presents a significant therapeutic challenge due to its adaptive resistance mechanisms to chemotherapy, especially endocrine treatment. Elacestrant, a novel oral selective estrogen receptor degrader (SERD), has emerged as a promising agent in this treatment-resistant era. Method: A comprehensive search was conducted on pivotal clinical trials, including the RAD1901-005 Trial, EMERALD TRIAL, ELIPSE, and ELEVATE, focusing on their methodologies, patient populations, treatment regimens, and outcomes. Discussion: This narrative review describes the available preclinical and clinical evidence on elacestrant, focusing on its pharmacodynamics, pharmacokinetics, efficacy, and safety within the existing literature. Elacestrant has demonstrated excellent activity against ESR1 mutations associated with resistance to first-line endocrine therapies. Clinical trials have shown improved progression-free survival in patients with advanced ER+/HER2-, ESR1-mutated breast cancer. Safety profiles indicate a tolerable side effect spectrum consistent with other agents. Its oral bioavailability offers a convenient alternative to injectable SERDs, with potential implications for patient adherence and quality of life. The review also discusses the comparative efficacy of elacestrant relative to existing endocrine therapies and its possible use in combination regimens. Conclusion: Ongoing clinical trials assessing elacestrant and other SERDs will yield data that might aid clinicians in determining the optimal selection and order of endocrine treatment drugs for ER+ breast cancer. The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in Breast Cancer treatment, moving towards more personalized and effective regimens.

Neoadjuvant Therapy: Current Landscape and Future Horizons for ER-Positive/HER2-Negative and Triple-Negative Early Breast Cancer.

OPINION STATEMENT: Navigating the complex landscape of breast cancer treatment involves distinct strategies for luminal and triple-negative subtypes. While neoadjuvant chemotherapy historically dominates the approach for aggressive triple-negative tumors, recent evidence highlights the transformative impact of immunotherapy, alongside chemotherapy, in reshaping treatment paradigms. In luminal cancers, endocrine therapy, notably aromatase inhibitors, demonstrates promising outcomes in postmenopausal patients with low-grade luminal A tumors. However, integrating targeted therapies like CDK4/6 inhibitors in neoadjuvant setting remains inconclusive. Identifying predictive factors for treatment response, especially in luminal tumors, poses a challenge, emphasizing the necessity for ongoing research. A multidisciplinary approach, tailored to individual patient profiles, is crucial for maximizing efficacy while minimizing toxicity. As we strive to optimize breast cancer management, a comprehensive understanding of the distinct characteristics and treatment implications of luminal and triple-negative subtypes, including the transformative role of immunotherapy, is essential for informed decision-making and personalized care.

The treatment pattern of advanced HR-positive and HER2-negative breast cancer in central southern China: a hospital-based cross-sectional study.

AIMS: This investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022. METHODS: Data from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment. RESULTS: First-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively. CONCLUSIONS: Compared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.

Pembrolizumab combined with chemotherapy versus placebo combined with chemotherapy for HER2-negative advanced gastric cancer in China: a cost-effectiveness analysis.

OBJECTIVE: This study aims to conduct a cost-effectiveness analysis of pembrolizumab in combination with chemotherapy for HER2-negative advanced gastric cancer in China. METHODS: A partitioned survival approach model was constructed to simulate the progression of HER2-negative advanced gastric cancer and evaluate the outcomes of different treatment strategies. We calculated incremental cost-effectiveness ratios (ICER) to assess the cost associated with each quality-adjusted life-year (QALY) gained. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess robustness and reliability. RESULTS: The analysis conducted in the base case demonstrated that the ICER associated with pembrolizumab was $177405.83/QALY gained in all population. In the subgroup analysis, it was found that individuals with a PD-L1 CPS ≥ 1 and those with a PD-L1 CPS ≥ 10 had ICERs of $152397.06/QALY and $109534.13/QALY, respectively. All ICER values for both the all population groups and the subgroups exceeded the WTP threshold in China. Our analysis shows the robustness of these results, as they remained consistent when input parameters were varied within a ± 25% range. CONCLUSION: The findings of this cost-effectiveness analysis suggest that pembrolizumab in combination with chemotherapy is not a cost-effective treatment option for HER2-negative advanced gastric cancer in China.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric/gastroesophageal junction cancer in the Chinese healthcare system.

BACKGROUND: This study compares first-line pembrolizumab plus chemotherapy with chemotherapy alone for patients with HER2-negative advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC) in China. METHODS: A Markov state-transition model was developed based on the phase 3 randomized KEYNOTE-859 clinical trial data. The health state utility values and direct medical costs were derived from the KEYNOTE-859 clinical trial, the relevant literature, and local charges. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). Probabilistic and one-way sensitivity analyses (OWSA) were performed to assess the uncertainty of the model. RESULTS: In the base analysis, the incremental effectiveness and cost of pembrolizumab plus chemotherapy versus chemotherapy alone were 0.22 QALYs and $16,627.31, respectively, resulting in an ICER of $76,936.60/QALY, which is higher than the willingness-to-pay threshold in China ($35,864.61/QALY). Subgroup analyses revealed that the ICERs of pembrolizumab plus chemotherapy versus chemotherapy alone were $72,762.68 and $34,813.70 in the populations with PD-L1 CPS of 1 or higher (CPS ≥ 1) and PD-L1 CPS ≥ 10 (CPS ≥ 10), respectively. CONCLUSIONS: As first-line therapy for patients with locally advanced or metastatic HER2-negative GC/GEJC in China, pembrolizumab plus chemotherapy is less cost-effective than chemotherapy alone, however, in the CPS ≥ 10 subgroup is more.

Efficacy and Safety of Chidamide in Combination with PD-1 Inhibitor and Radiotherapy for HER2-Negative Advanced Breast Cancer: Study Protocol of a Single Arm Prospective Study.

Purpose: As one of the most important breakthroughs in cancer therapy, immune checkpoint inhibitors have greatly prolonged survival of patients with breast cancer. However, their application and efficacy are limited, especially for advanced HER2-negative breast cancer. It has been reported that epigenetic modulation of the histone deacetylase (HDAC) inhibitor chidamide, as well as immune microenvironment modulation of radiotherapy are potentially synergistic with immunotherapy. Thus, the combination of chidamide, radiotherapy and immunotherapy is expected to improve prognosis of patients with advanced HER2-negative breast cancer. Patients and Methods: This is a single-arm, open, prospective clinical trial investigating the efficacy and safety of the combination of HDAC inhibitor chidamide, anti-PD-1 antibody sintilimab, and the novel immuno-radiotherapy, which aims to enhance efficacy of immunotherapy, in subsequent lines of therapy of HER2-negative breast cancer. Our study will include 35 patients with advanced breast cancer that has failed endocrine therapy and first-line chemotherapy. Participants will receive 30 mg of chidamide twice a week, 200 mg of sintilimab once every 3 weeks, combined with immuno-radiotherapy. Radiotherapy will be centrally 8 Gy for at least one lesion, and at least 1 Gy for the other lesions. We will complete three fractions of radiotherapy in one cycle. The primary endpoint is progression-free survival, and secondary endpoints are objective response rate, disease control rate and safety. Moreover, biomarkers including cytokines and lymphocyte subgroups will be explored. Conclusion: As a single-arm clinical trial, the analysis of the influence of each single treatment is limited. Besides, our study is an open study, which involves neither randomization nor blinding. In spite of the abovementioned limitations, this prospective clinical trial will give an insight into subsequent lines of therapy of HER2-negative advanced breast cancer, prolong the survival or achieve long remission for these participants, and identify potential responders.

Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Palbociclib combined with endocrine treatment in hormone receptor-positive, HER2-negative breast cancer patients with high relapse risk after neoadjuvant chemotherapy: subgroup analyses of premenopausal patients in PENELOPE-B.

BACKGROUND: The PENELOPE-B study demonstrated that the addition of 1-year post-neoadjuvant palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) did not improve invasive disease-free survival (iDFS) compared to placebo. Here, we report results for premenopausal women. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative BC at high risk of relapse [defined as no pathological complete response after neoadjuvant chemotherapy and a clinical, pathological stage, estrogen receptor, grading (CPS-EG) score ≥3 or 2/ypN+] were randomized to receive 13 cycles of palbociclib or placebo + standard ET. Ovarian function (OF) was evaluated by centrally assessed estradiol, follicle-stimulating hormone and anti-Müllerian hormone serum levels. RESULTS: Overall, 616 of 1250 randomized patients were premenopausal; of these, 30.0% were <40 years of age, 47.4% had four or more metastatic lymph nodes, and 58.2% had a CPS-EG score ≥3. 66.1% of patients were treated with tamoxifen alone, and 32.9% received ovarian function suppression (OFS) in addition to either tamoxifen or aromatase inhibitor (AI). After a median follow-up of 42.8 months (97.2% completeness) no difference in iDFS between palbociclib and placebo was observed [hazard ratio = 0.95, 95% confidence interval (CI) 0.69-1.30, P = 0.737]. The estimated 3-year iDFS rate was marginally higher in the palbociclib arm (80.6% versus 78.3%). Three year iDFS was higher in patients receiving AI than tamoxifen plus OFS or tamoxifen alone (86.0% versus 78.6% versus 78.0%). Patients receiving tamoxifen plus OFS showed a favorable iDFS with palbociclib (83.0% versus 74.1%, hazard ratio = 0.52, 95% CI 0.27-1.02, P = 0.057). Hematologic adverse events were more frequent with palbociclib (76.1% versus 1.9% grade 3-4, P < 0.001). Palbociclib seems not to negatively impact the OF throughout the treatment period. CONCLUSIONS: In premenopausal women, who received tamoxifen plus OFS as ET, the addition of palbociclib to ET results in a favorable iDFS. The safety profile seems favorable and in contrast to chemotherapy palbociclib does not impact OF throughout the treatment period.

Favorable outcome of neoadjuvant endocrine treatment than surgery-first in female HR-positive/HER2-negative breast cancer patients-A NCDB analysis (2010-2016).

PURPOSE: To assess the efficacy of neoadjuvant endocrine therapy in female HR-positive/HER2-negative breast cancer patients. DATA AND METHODS: We identified female patients aged ≥18 years with cT1-4N0-XM0, HR(+), and HER2(-) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as "surgery-first," while those who received NET before surgery were classified as "NET." Propensity score-matching, Cox proportional-hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. RESULTS: Among 432,387 cases, 2914 NET patients and 2914 surgery-first patients were matched. Compared with the surgery-first group, the NET group received less adjuvant chemotherapy (p < 0.001). Furthermore, the NET group exhibited higher survival probabilities compared with the surgery-first group (3 years: 91.4% vs. 82.1%; 5 years: 82.1% vs. 66.8%). Multivariate Cox analysis indicated that NET was associated with improved OS (surgery-first vs. NET: HR 2.17, 95% CI: 1.93-2.44). Age over 55 years old, having public insurance, higher CDCC score, higher NSBR grade, ER(+)PR(-), and advanced clinical stage were related to worse OS (all p < 0.05). There was an interaction between age, race, income, and home and treatment regimen (all p < 0.05). CONCLUSION: NET may be a more effective treatment procedure than surgery-first in female HR-positive/HER2-negative, non-metastatic breast cancer patients. Future clinical studies with more detailed data will provide higher-level evidence-based data.

Checkpoint inhibition for early-stage hormone receptor-positive breast cancer.

INTRODUCTION: Most patients with breast cancer have early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease. Even though the prognosis for most of these patients is good, there is a need to identify patients at risk for poor outcomes and to develop strategies to mitigate this risk. AREAS COVERED: The addition of immunotherapy to standard neoadjuvant chemotherapy represents a promising option for select patients with HR-positive early breast cancer. Three randomized clinical trials have shown favorable results to date. In this review, we discuss the findings of I-SPY2, CheckMate 7FL (NCT04109066), and KEYNOTE-756 (NCT03725059). EXPERT OPINION: Despite the promising results of these trials, there are unanswered questions that need to be considered before incorporating neo/adjuvant immunotherapy in the treatment paradigm of early-stage HR-positive breast cancer. One example of an unanswered question is patient selection. Because the regimens used in these protocols are associated with long-term toxicities, identifying the patients who are more likely to derive a benefit from these agents, such as through the use of biomarkers, is critical. A second example is the optimal integration of adjuvant therapies that improve invasive disease-free survival, such as abemaciclib and ribociclib, which are not safely administered concurrently with immunotherapy.

Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.

BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

Is neoadjuvant chemotherapy necessary for T2N0-1M0 hormone receptor-positive/HER2-negative breast cancer patients undergoing breast-conserving surgery?

INTRODUCTION: For HR-positive/HER2-negative patients who can undergo breast-conserving surgery (BCS) but have a tumor size of 2-5 cm or 1-3 lymph node metastases, neoadjuvant chemotherapy (NAC) is still controversial. METHODS: Patients with T2N0-1M0 HR-positive/HER2-negative BC who underwent BCS between 2010 and 2017 were selected from the SEER database. Propensity score matching (PSM) was used to minimize the influence of confounding factors. The overall survival (OS) and breast cancer-specific survival (BCSS) of patients were estimated by Kaplan‒Meier curves and Cox proportional hazard models. Independent prognostic factors were included to construct a nomogram prediction model. RESULTS: A total of 6475 BC patients were enrolled, of whom 553 received NAC and 5922 received adjuvant chemotherapy (AC). In the T2N0-1M0 population and T2N1M0 subgroup, AC patients before PSM had better OS and BCSS than NAC patients. After PSM, there was no significant difference in OS or BCSS between the two groups. However, in the T2N0M0 subgroup, there was no difference in survival between the AC and NAC groups before and after PSM. Stratified analysis revealed that for complete response (CR) patients, survival was roughly equivalent between the NAC and AC groups. However, the survival of no response (NR) and partial response (PR) patients was significantly worse than that of AC patients. Cox analysis revealed that radiotherapy after BCS was an independent protective factor for OS. NAC is an independent risk factor for NR and PR patients. The nomogram has good prediction efficiency. CONCLUSION: NAC before BCS is not necessary for T2N0-1M0 HR-positive/HER2-negative BC patients.

Prognostic Evaluation of HER2-positive Early Breast Cancers Using Clinico-pathological Criteria.

Background/Aim: HER2-positive breast carcinomas (BCs) generally behave more aggressively and show higher cytological and histological grade than HER2-negative BCs. However, the clinical properties of HER2-positive early BCs have not been studied extensively. Hence, the therapeutic significance of neoadjuvant chemotherapy (NAC) for this BC remains debatable. Patients and Methods: We retrospectively examined the clinicopathological features of 94 HER2-positive early BCs who perioperatively received anti-HER2 drugs, without undergoing NAC prior to surgery. Results: The patients' five year-disease free survival (DFS) and overall survival (OS) rates were 95.6% and 100%, respectively. Univariate analysis demonstrated significant differences in distant metastasis-free survival (DMFS) between clinical and pathological tumor stages (T stages). Pathological T1 stage and clinical T1 stage tumors showed significantly higher DMSF than pT2-3 and cT2-3 (p=0.0002 and 0.0294). Multivariate analysis disclosed no significant differences in DFS, OS, and DMFS with respect to preoperative clinical tumor stage, patient age, type of surgery, postoperative therapy, and pathological factors. Recurrences occurred in nine patients: four (4.3%) and five (5.3%) patients showed local and distant recurrences, respectively. One patient with cT2 BC died of disease. Interestingly, four of the five BCs with distant recurrence pathologically demonstrated lymph vessel invasion. The prognoses of patients with HER2-positive stage cT1/2N0M0 BC were highly favorable. Conclusion: The indications for NAC in small, localized, and node-negative HER2-positive BC should be carefully assessed based on the presence of a larger tumor size, postoperative pathological evaluation of tumor size, and lymph vessel invasion.

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States.

Aim: To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Methods: A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes. Results: When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments. Conclusion: Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.

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.

Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.

BACKGROUND: Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. METHODS: Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). CONCLUSIONS: First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

Long-term outcomes of a randomized, open-label, phase II study comparing cabazitaxel versus paclitaxel as neoadjuvant treatment in patients with triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE).

BACKGROUND: The GENEVIEVE study, comparing neoadjuvant cabazitaxel versus paclitaxel in triple-negative breast cancer (TNBC) and luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC), previously reported significant differences in pathological complete response (pCR) rates. Effects on long-term outcome are unknown. PATIENTS AND METHODS: GENEVIEVE randomized patients with cT2-3, any cN or cT1, cN+/pNSLN+, centrally confirmed TNBC or luminal B/HER2-negative BC (latter defined as estrogen/progesterone receptor-positive and >14% Ki-67-stained cells) to receive either cabazitaxel 25 mg/m2 q3w for four cycles or paclitaxel 80 mg/m2 weekly for 12 weeks. Anthracycline-containing chemotherapy was allowed in case of histologically proven invasive residuals as neoadjuvant treatment or after surgery as adjuvant treatment. Here we report the secondary endpoints invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: Of the 333 patients randomized, 74.7% and 83.2% completed treatment in the cabazitaxel and paclitaxel arms, respectively. After a median follow-up of 89.3 months (interquartile range 68.8-97.3 months), 80 iDFS events (43 after cabazitaxel and 37 after paclitaxel) and 47 deaths (23 after cabazitaxel and 24 after paclitaxel) were reported. IDFS rates were not significantly different between the cabazitaxel and paclitaxel arms after a 3-year (83.6% versus 85.0%) and 5-year follow-up (76.2% versus 78.3%) [hazard ratio (HR) = 1.27, 95% confidence interval 0.82-1.96, P = 0.294], respectively. DDFS rates at 3 years (88.6% versus 87.8%) and 5 years (82.1% versus 82.8%) for cabazitaxel and paclitaxel were comparable (HR = 1.15, P = 0.573). Similarly, OS rates at 3 years (91.6% versus 91.8%) and 5 years (89.2% versus 86.8%) showed no significant differences (HR = 1.05, P = 0.872). Subgroup analysis for TNBC and luminal B/HER2-negative BCs indicated no significant variations in 3- or 5-year iDFS, DDFS, or OS. CONCLUSIONS: The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.

Neoadjuvant Chemotherapy in Patients with HER2-Negative Breast Cancer: A Report from Clinical Breast Cancer Registry of Iran.

BACKGROUND: Neoadjuvant chemotherapy (NCT) has become an increasingly popular approach in management of breast cancer (BC). This study was conducted to evaluate the pathologic response and 36-month recurrence and survival rates of patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with different NCT regimens. METHODS: A total of 163 female patients with HER2-negative BC who received NCT during 2017-2020 were identified from the Clinical Breast Cancer Registry of Iran and entered the study. The prescribed NCT regimens included 4 cycles of doxorubicin plus cyclophosphamide, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of paclitaxel, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel or 6 cycles of doxorubicin plus cyclophosphamide plus docetaxel (TAC). RESULTS: Thirty-two patients (19.6%) experienced pathologic complete response (pCR). TAC regimen, triple negative-BC and ki67>10% were significantly associated with increased pCR. The recurrence, overall survival (OS) and disease-free survival (DFS) rate at 36 months for all patients were 16.6%, 84.7% and 79.8%, respectively. Type of neoadjuvant regimen as well as age, hormone receptor status, Ki67, grade, clinical stage, type of surgery and pathologic response to chemotherapy did not significantly influence the survival and recurrence; however, TAC results in improved recurrence, OS and DFS rates. CONCLUSION: This study provides further evidence that NCT is a viable treatment option for patients with HER2-negative BC. The TAC regimen resulted in a significantly higher pCR rate compared to other regimens, but did not result in a significant improvement in recurrence, OS and DFS and rates.

Comparison of neoadjuvant chemotherapy response and prognosis between HR-low/HER2-negative BC and TNBC: an exploratory real-world multicentre cohort study.

Objective: Hormone receptor (HR)-low/HER2-negative breast cancers (BCs) are more likely to be basal-like BCs, with similar molecular features and gene expression profiles to HR-negative (estrogen receptor <1% or negative and progesterone receptor <1% or negative) BCs. Recently, with the clinical application of adjuvant intensive therapy for triple-negative breast cancer (TNBC), the prognosis of TNBC patients without pathological complete response (pCR) has significantly improved. Therefore, it is necessary to reanalyse the prognostic characteristics of clinically high-risk HR-low/HER2-negative BC. Methods: According to the inclusion and exclusion standards, 288 patients with HR-low/HER2-negative BC and TNBC who received NAC and were followed up between 2015 and 2022 at three breast centres in Hunan Province, China, were enrolled. Inverse probability of treatment weighting (IPTW) was utilized to mitigate imbalances in baseline characteristics between the HR-low/HER2-negative BC group and TNBC group regarding event-free survival (EFS) and overall survival (OS). The primary clinical endpoints were pCR and EFS, while the secondary endpoints included OS, objective response rate (ORR), and clinical benefit rate (CBR). Results: The pCR rate (27.1% vs. 28.0%, P = 1.000), ORR rate (76.9% vs. 78.3%, P = 0.827) and CBR rate (89.7% vs. 96.5%, P = 0.113) after NAC were similar between the HR-low/HER2-negative BC and the TNBC group. EFS in patients with non-pCR from the 2 groups was significantly inferior in comparison to patients with pCR (P = 0.001), and the 3-year EFS was 94.74% (95% CI = 85.21% to 100.00%) and 57.39% (95% CI =43.81% to 75.19%) in patients with pCR and non-pCR from the HR-low/HER2-negative BC group, respectively, and 89.70% (95% CI = 82.20% to 97.90%) and 69.73% (95% CI = 62.51% to 77.77%) in the TNBC patients with pCR and non-pCR, respectively. Conclusions: In the real world, the therapeutic effects of NAC for HR-low/HER2-negative BCs and TNBCs were similar. EFS of patients with non-pCR in the HR-low/HER2-negative BC group was inferior to that of the TNBC group with non-pCR, suggesting that it is necessary to explore new adjuvant intensive therapy strategies for these patients.