Search

Simple Summary: This study explores the effectiveness and safety of a common breast cancer treatment in elderly patients, a group often overlooked in clinical trials. Specifically, it focuses on using CDK4/6 inhibitors with hormone therapy for treating metastatic HR+/HER2- breast cancer in patients aged 70 and older. This research aims to understand how well this treatment works and how tolerable it is for this vulnerable population, which faces unique challenges due to age and other health conditions. The results of this study may provide valuable insights for clinicians, enabling more informed treatment decisions which optimize therapeutic outcomes and enhance the quality of life for elderly patients with breast cancer. Background: Metastatic HR+/HER2- breast cancer is commonly treated with CDK4/6 inhibitors in combination with endocrine therapy. However, the efficacy and safety of this approach in elderly patients (≥70 years) remain unclear, particularly in the context of real-world clinical practice. This study aims to evaluate the clinical outcomes and tolerability of CDK4/6 inhibitor treatments in this fragile population, which is often under-represented in randomized clinical trials. Patients and methods: This retrospective multicenter study included elderly patients with metastatic HR+/HER2-negative breast cancer receiving first-line CDK4/6 inhibitors. The primary endpoint was progression-free survival (PFS). The secondary endpoints focused on the overall survival (OS), safety, and tolerability, considering variables such as tumor subtype, age, comorbidities, and treatment specifics. Results: The median PFS and OS were slightly lower than those reported in clinical trials, reflecting the inclusion of a more fragile population. The luminal B subtype was linked to a poorer PFS, while other factors like age, BMI, and ECOG status did not significantly affect the outcomes. A safety analysis indicated a higher incidence of grade 3 or higher toxicities, especially in frail patients, leading to dose reductions. Despite these challenges, CDK4/6 inhibitors were generally well-tolerated, allowing most patients to continue therapy. Conclusions: CDK4/6 inhibitors with endocrine therapy are effective in elderly patients with metastatic HR+/HER2- breast cancer, though careful management is crucial to balance efficacy and minimize adverse events. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Appropriate adverse event (AE) management and maintenance of therapeutic intensity are necessary to achieve therapeutic benefits of CDK4/6 inhibitors (palbociclib and abemaciclib) in hormone receptor-positive, HER2-negative metastatic/recurrent breast cancer. Objective: This study was aimed at clarifying the effect of AEs associated with palbociclib and abemaciclib on treatment. Methods: A total of 62 and 49 patients were prescribed palbociclib and abemaciclib, respectively, at our hospital from January 1, 2018 to June 30, 2023. The rate and reasons for treatment discontinuation, interruption of administration, and changes in dose and dosing schedule, treatment duration, and relative dose intensity (RDI) were compared between the groups of patients prescribed the 2 treatments. Results: Treatment discontinuation due to AEs occurred more frequently with abemaciclib (12 patients) because of interstitial lung disease and hepatic and renal events than with palbociclib (5 patients; P =.008). Administration was interrupted in 57 (91.9%) and 35 (71.4%) patients treated with palbociclib and abemaciclib, respectively (P =.004). Dose reduction occurred in 37 (67.3%) and 19 (47.5%) patients treated with palbociclib and abemaciclib, respectively (P =.053). The median [range] treatment duration was 301 [21-1643] days for palbociclib and 238 [70-1526] days for abemaciclib (log-rank test, P =.581). The median RDI was 59.7% and 59.6% for palbociclib and abemaciclib, respectively (P =.539). Although the AEs of palbociclib and abemaciclib affected the treatment considerably, the treatment duration and RDI were similar. Conclusion: CDK4/6 inhibitors should be selected based on the tolerability and manageability of each AE. [ABSTRACT FROM AUTHOR]

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer is the most common subtype, representing over two-thirds of new diagnoses. Adjuvant therapy, which encompasses various medications and treatment durations, is the standard approach for managing early stage HR+ HER2- breast cancer. Optimizing treatment is essential to minimize unnecessary side effects while addressing the biological variability inherent in HR+/HER2− breast cancers. Incorporating biological biomarkers into treatment decisions, alongside traditional clinical factors, is vital. Gene expression assays can identify patients unlikely to benefit from adjuvant chemotherapy, thereby refining treatment strategies and improving risk assessment. This paper reviews evidence for several genomic tests, including Oncotype DX, MammaPrint, Breast Cancer Index, RucurIndex, and EndoPredict, which assist in tailoring adjuvant therapy. Additionally, we explore the role of liquid biopsies in personalizing treatment, emphasizing the importance of considering late relapse risks and potential benefits of extended systemic therapy for HR+/HER2− breast cancer patients.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64–1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61–1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

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 rates. [ABSTRACT FROM AUTHOR]

Background: This head-to-head study compared a 3-week versus 4-week schedule of nab-paclitaxel in patients with metastatic breast cancer (mBC). Methods: Patients with HER2-negative mBC were enrolled and randomly assigned (1:1) to receive nab-paclitaxel for a 3-week schedule (125 mg/m2 on days 1 and 8) or a 4-week schedule (same dose on days 1, 8, and 15) until disease progression or treatment intolerance. Patients with intolerable toxicities were allowed to receive a maintenance regimen after benefiting from nab-paclitaxel. The primary endpoint was progression-free survival (PFS). Results: Ninety-four patients were included in the analysis (n = 47 in each arm). A longer median PFS (mPFS) was observed in the 3-week versus the 4-week schedule in the overall population (not reached vs. 6.8 months; hazard ratio [HR] = 0.44; P = .029). Patients in the 2 arms had a similar overall survival (28.0 vs. 25.8 months), objective response rate (51.1% vs. 48.9%), and disease control rate (93.6% vs. 80.9%). The 3-week schedule was associated with a lower rate of toxicity-related treatment discontinuation (8.5% vs. 29.8%) and dose delays (6.4% vs. 23.4%). Conclusion: This study demonstrated the better antitumor activity and safety profile of a 3-week over 4-week nab-paclitaxel schedule in HER2-negative mBC, suggesting that a 3-week schedule may be a better treatment regimen in clinical practice (ClinicalTrials.gov Identifier: NCT04192331). This study compared a 3-week versus 4-week schedule of nab -paclitaxel in patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

BackgroundFor estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2- ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2- breast cancer.MethodsPatients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life.ConclusionsAMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2- ABC.Clinicaltrials identifierNCT04478266.

Purpose: To explore the predictive value of multiple immune-inflammatory biomarkers including serum VEGFA and systemic immune-inflammation index (SII) in HER2-negative advanced gastric cancer (AGC) and establish nomograms for predicting the first-line chemotherapeutic efficacy, progression-free survival (PFS) and overall survival (OS) of patients with this fatal disease. Methods: From November 2017 to April 2022, 102 and 34 patients with a diagnosis of HER2-negative AGC at the First Affiliated Hospital of Bengbu Medical College were enrolled as development and validation cohorts, respectively. Univariate and multivariate analyses were performed to evaluate the clinical value of the candidate indicators. The variables were screened using LASSO regression analysis. Predictive models were developed using significant predictors and are displayed as nomograms. Results: Baseline VEGFA expression was significantly higher in HER2-negative AGC patients than in nonneoplastic patients and was associated with malignant serous effusion and therapeutic efficacy (all p<0.001). Multivariate analysis indicated that VEGFA was an independent predictor for first-line therapeutic efficacy and PFS (both p<0.01) and SII was an independent predictor for first-line PFS and OS (both p<0.05) in HER2-negative AGC patients. The therapeutic efficacy model had an R² of 0.37, a Brier score of 0.15, and a Harrell's C-index of 0.82 in the development cohort and 0.90 in the validation cohort. The decision curve analysis indicated that the model added more net benefits than VEGFA assessment alone. The PFS/OS models had Harrell's C-indexes of 0.71/0.69 in the development cohort and 0.71/0.62 in the validation cohort. Conclusion: The established nomograms integrating serum VEGFA/SII and commonly available baseline characteristics provided satisfactory performance in predicting the therapeutic efficacy and prognosis of HER2-negative AGC patients. [ABSTRACT FROM AUTHOR]

Purpose: The monarchE trial showed that the addition of abemaciclib improves efficacy in patients with high-risk early breast cancer (EBC). We analyzed the long-term outcomes of a population similar to the monarchE trial to put into context the potential benefit of abemaciclib. Methods: HR-positive/HER2-negative EBC patients eligible for the monarchE study were selected from 3 adjuvant clinical trials and a breast cancer registry. Patients with ≥ 4 positive axillary lymph nodes (N +) or 1–3 N + with tumor size ≥ 5 cm and/or histologic grade 3 and/or Ki67 ≥ 20%, who had undergone surgery with curative intent and had received anthracyclines ± taxanes and endocrine therapy in the neoadjuvant and /or adjuvant setting were included. We performed analysis of Invasive Disease-Free Survival (iDFS), Distant Disease-Free Survival (dDFS) and Overall Survival (OS) at 5 and 10 years, as well as yearly (up to 10) of Invasive Relapse Rate (IRR), Distant Relapse Rate (DRR) and Death Rate (DR). Results: A total of 1,617 patients were analyzed from the GEICAM-9906 (312), GEICAM-2003–10 (210), and GEICAM-2006–10 (160) trials plus 935 from El Álamo IV. With a median follow-up of 10.1 years, the 5 and 10 years iDFS rates were 75.2% and 57.0%, respectively. The dDFS and OS rates at 5 years were 77.4% and 88.8% and the respective figures at 10 years were 59.7% and 70.9%. Conclusions: This data points out the need for new therapies for those patients. A longer follow-up of the monarchE study to see the real final benefit with abemaciclib is warranted. Trial registration: ClinTrials.gov: GEICAM/9906: NCT00129922; GEICAM/ 2003-10: NCT00129935 and GEICAM/ 2006-10: NCT00543127. [ABSTRACT FROM AUTHOR]

Background: The SPOTLIGHT trial demonstrated that zolbetuximab plusmFOLFOX6 (ZOL-FO) as a first-line regimen compared with placebo plus mFOLFOX6 (PLB-FO) conferred clinical benefits to patients with CLDN18.2-positive, HER2-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, due to the high cost of zolbetuximab, whether ZOL-FO is cost-effective compared with PLB-FO is unclear. This study aimed to evaluate the cost-effectiveness of ZOL-FO as a first-line treatment option for CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma from the perspective of the Chinese healthcare system. Methods: Markovmodelswith three different health stateswere developed to assess the cost-effectiveness of ZOL-FO as a first-line treatment option for CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma. Clinical efficacy data were obtained from the SPOTLIGHT trial; the drug's cost was calculated at national bid prices, and other costs and utility values were obtained from the published literature. Outcomes included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The model's robustness was verified using one-way sensitivity and probabilistic sensitivity analyses. Results: The ZOL-FO group gained 1.64 QALYs at $87,746.35, while the PLB-FO group gained 1.23 QALYs at $11,947.81. The ICER for ZOL-FO versus PLB-FO was $185,353.28 per QALY gained. The parameters exerting an important impact on the model results were the price of zolbetuximab, body surface area, and progression-free survival utility. At a willingness-to-pay threshold of $38,201/QALY, ZOL-FO had a 0% probability of cost-effectiveness compared with PLB-FO. Conclusion: From the perspective of the Chinese healthcare system, ZOL-FO is unlikely to be cost-effective as the first-line treatment option for CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma. [ABSTRACT FROM AUTHOR]

Introduction: This study described, in routine clinical practice in Japan, the patient characteristics, treatment patterns, and outcomes of female patients with HR + /HER2- metastatic breast cancer (MBC) who started abemaciclib treatment. Methods: Clinical charts were reviewed for patients starting abemaciclib in 12/2018–08/2021 with a minimum of 3 months follow-up data post-abemaciclib initiation regardless of abemaciclib discontinuation. Patient characteristics, treatment patterns, and tumor response were descriptively summarized. Kaplan–Meier curves estimated progression-free survival (PFS). Results: 200 patients from 14 institutions were included. At abemaciclib initiation, median age was 59 years, and the Eastern Cooperative Oncology Group performance status score was 0/1/2 for 102/68/5 patients (58.3/38.9/2.9%), respectively. Most had an abemaciclib starting dose of 150 mg (92.5%). The percentage of patients receiving abemaciclib as 1st, 2nd, or 3rd line treatment was 31.5%, 25.8%, and 25.2%, respectively. The most frequent endocrine therapy drugs used with abemaciclib were fulvestrant (59%) and aromatase inhibitors (40%). Evaluation of tumor response was available for 171 patients, 30.4% of whom had complete/partial response. Median PFS was 13.0 months (95% CI 10.1–15.8 months). Conclusions: In a routine clinical practice setting in Japan, patients with HR + , HER2- MBC appear to benefit from abemaciclib treatment in terms of treatment response and median PFS, with the results broadly reflecting the evidence demonstrated in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Background We evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients. Methods HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed. Results Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon’s design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5–32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment. Conclusion Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit. Trial registration ClinicalTrials.gov and EudraCT (NCT03025880 and 2016–001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

Background: Approximately 5–10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials. Methods: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC. Results: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration. Conclusions: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology.

To compare the efficacies of exemestane and fulvestrant as first-line monotherapies for postmenopausal Chinese women having advanced oestrogen-receptor positive (ER+)/ human epidermal growth factor receptor 2 (HER2)-breast cancer (ER+/HER2- ABC) after a previous treatment for ≥2 years with an adjuvant non-steroidal aromatase inhibitor. In this randomised, open-label, multi-centre, parallel-controlled phase 2 FRIEND study, 145 postmenopausal ER+/HER2- ABC patients were assigned into fulvestrant (500 mg on days 0, 14 and 28, and then at every 28 ± 3 days, n = 77) and exemestane (25 mg/day, n = 67) groups. The primary outcome was progression-free survival (PFS), while the secondary outcomes were disease control rate, objective response rate, time to treatment failure, duration of response and overall survival. Exploratory end-points included gene mutation-related outcomes and safety. Fulvestrant was superior to exemestane regarding median PFS times (8.5 versus 5.6 months, p = 0.014, HR = 0.62, 95% confidence intervals: 0.42–0.91), objective response rates (19.5% versus 6.0%, p = 0.017) and time to treatment failure (8.4 versus 5.5 months, p = 0.008). The incidence of adverse or serious adverse events in the two groups was virtually identical. The most frequent mutations in 129 analysed patients were detected in the o estrogen receptor gene 1 (ESR1) (18/14.0%), PIK3CA (40/31.0%) and TP53 (29/22.5%) genes. Fulvestrant produced significant longer PFS times compared to exemestane but only for patients with an ESR1 -wild type (8.5 versus 5.8 months) (p = 0.035), although there was a similar trend also for the ESR1 mutation without statistical significance. All patients with c-MYC and BRCA2 mutations had longer PFS times in the fulvestrant versus the exemestane group (p = 0.049, p = 0.039). Fulvestrant significantly increased overall PFS for ER+/HER2- ABC patients and was well tolerated. NCT02646735, https://clinicaltrials.gov/ct2/show/NCT02646735. • The novel selective oestrogen receptor down regulator fulvestrant is administered to hormone receptor positive advanced breast cancer patients. • Exemestane, a steroidal aromatase inhibitors , is used to treat early and advanced breast cancer patients. • Fulvestrant was superior to exemestane regarding median progression-free survival times and time to treatment failure. • c-MYC and BRCA2 mutations led to longer progression-free survival times in the fulvestrant group. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. Methods: In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. Results: Of 44 enrolled patients (median age, 53.5 years; range, 34–69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3–4.1) and median OS was 15.0 months (95% CI 12.1–17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. Conclusion: PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568. [ABSTRACT FROM AUTHOR]

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.

Background: Approximately 75% of breast cancer (BC) is associated with luminal differentiation expressing endocrine receptors (ER). For ER+ HER2− tumors, adjuvant endocrine therapy (ET) is the cornerstone treatment. Although relapse events steadily continue, the ET benefits translate to dramatically lengthen life expectancy with bearable side-effects. This review of ER+ HER2− female BC outlines suitable adjuvant treatment strategies to help guide clinical decision making around appropriate therapy. Methods: A literature search was conducted in Embase, Medline, and the Cochrane Libraries, using ER+ HER−, ET BC keywords. Results: In low-risk patients: five years of ET is the standard option. While Tamoxifen remains the preferred selection for premenopausal women, AI is the choice for postmenopausal patients. In the high-risk category: ET plus/minus OFS with two years of Abemaciclib is recommended. Although extended ET for a total of ten years is an alternative, the optimal AI duration is undetermined; nevertheless an additional two to three years beyond the initial five years may be sufficient. In this postmenopausal group, bisphosphonate is endorsed. Conclusions: Classifying the risk category assists in deciding the treatment route and its optimal duration. Tailoring the breadth of ET hinges on a wide array of factors to be appraised for each individualized case, including weighing its benefits and harms.

Purpose: The purpose of this study was to examine the effect of chemotherapy on invasive disease-free survival (iDFS) and overall survival (OS) in a nationwide cohort of patients with estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative, T1abN0 breast cancer. Methods: Patients with ER-negative/HER2-negative, T1abN0 breast cancer registered in the Danish Breast Cancer Group database between 2007 and 2016 were identified. The effect of adjuvant chemotherapy on iDFS and OS was analyzed with Cox proportional hazards analysis. Results: In total, 296 patients were included in the statistical analyses. Of these, 235 (79.4%) received chemotherapy and 61 patients (20.6%) did not. Patients treated with chemotherapy were significantly younger, had a significantly higher proportion of grade 3 tumors, T1b tumors, and tumors of ductal subtype. With 7.7 years of median follow-up, treatment with chemotherapy was associated with a significant improvement in OS in the adjusted analysis, Hazard Ratio 0.35 (95% Confidence Interval (0.15–0.81), p = 0.02), chemotherapy vs. no chemotherapy. In the unadjusted analyses, patients with both T1a and T1b tumors had significantly improved OS with chemotherapy. At 5 years, OS was 100% vs. 94.4% and 93.8% vs. 81.3% for patients with T1a and T1b tumors, respectively, chemotherapy vs. no chemotherapy. With 4.9 years of median follow-up, iDFS was not significantly improved with chemotherapy. Conclusion: Patients with ER-negative/HER2-negative, T1abN0 breast cancer had significantly improved OS when treated with chemotherapy. This improvement was significant in patients with both T1a and T1b tumors, respectively. The effect was, however, limited in patients with T1a tumors. [ABSTRACT FROM AUTHOR]

Background: The benefit of pathologic complete response (pCR) in early breast cancer (eBC) is not well described in the real-world setting. This study used the nationwide Flatiron Health electronic health record-derived deidentified database to describe treatment patterns and survival outcomes by pCR status after neoadjuvant therapy (NAT) in women with triple-negative or HR+/HER2- eBC. Materials & methods: Observational cohort study analyzing women with eBC who started NAT between 2011 and 2018. Results: 496 women were included in the study; of those, 16.1% achieved pCR, of which 35.7% were triple-negative and 6.1% were HR+/HER2- eBC. More women with triple-negative eBC (95.2%) were exclusively treated with chemotherapy-based NAT versus HR+/HER2- eBC (56.1%). In multivariate analyses from NAT start, not achieving pCR was associated with increased risk of death and progression. Conclusion: pCR status may be a reliable prognostic indicator for survival in these eBC subtypes in the real-world setting. Response to treatment before surgery indicates better outcomes in breast cancer patients. To understand how well cancer treatments work, patients are compared on their overall survival. This measures the number of people in a study or treatment group who are still alive after a certain amount of time from when they were diagnosed or started treatment. Overall survival shows how well patients are doing in their cancer journey, but it takes time to understand how good treatments are when using this measure. In women with early-stage breast cancer, a quicker way to understand how well patients react to their treatment is called pathologic complete response (pCR). Some people have whole-body treatments such as chemotherapy before surgery (known as neoadjuvant treatment). For these patients, pCR may occur after neoadjuvant treatment, meaning all signs of cancer are gone when they have surgery. In real-life clinical settings, little research has been done to understand how pCR can measure breast cancer survival. In this study, the authors investigate whether women who had a pCR were more or less likely to have their cancer become worse or experience death than those who did not achieve pCR. The health records of 496 women diagnosed with early breast cancer over an eight-year period were assessed. The results show that women who did not have a pCR were more likely to have their cancer become worse or die. This means that pCR could be a better way than overall survival to identify which treatments work well in early breast cancer, and importantly, change the course of a patient's journey. This study used data from the Flatiron Health database to explore real-world outcomes by pathologic complete response (pCR) status in women with early #BreastCancer. Those who did not achieve pCR had an increased risk of progression/death. [ABSTRACT FROM AUTHOR]

Background: We evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients.Methods: HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed.Results: Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon's design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5-32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment.Conclusion: Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit.Trial Registration: ClinicalTrials.gov and EudraCT (NCT03025880 and 2016-001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively. [ABSTRACT FROM AUTHOR]

Approximately 5–10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC. Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration. The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology. • Use of PARP-inhibitors in BRCA-related HER2-advanced BC has been addressed by the Italian Association of Medical Oncology. • The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach has been adopted. • HR+/HER2-and triple-negative BC subtypes have been addressed in two separate clinical questions. • Germline BRCA testing in HER2-advanced BC has a predictive value, being indicated independently from familial criteria. [ABSTRACT FROM AUTHOR]

Abstract Background Eribulin methylate (eribulin) improved the overall survival (OS) of eribulin-treated patients with HER2-negative advanced breast cancer (ABC) in prospective and retrospective studies. However, the effect of eribulin on OS as first-line chemotherapy and the characteristics of the patients who benefited from eribulin remain unclear. Methods Between January 2011 and December 2016, 301 patients with HER2-negative ABC who started first-line chemotherapy at 3 institutions were retrospectively evaluated for OS from the initiation of first-line chemotherapy. Results We identified 172 patients (119 estrogen receptor-positive [ER+], 47 ER−, 6 unknown) who received eribulin (eribulin group) and 129 patients (92 ER+, 31 ER−, 6 unknown) who did not receive eribulin (non-eribulin group). The median OS from the initiation of first-line chemotherapy in the two groups was not statistically significant (869 vs. 744 days, P = 0.47, log-rank); however, in patients who received eribulin in later lines (≥3rd-line) and who had a history of perioperative chemotherapy with anthracycline- and/or taxane-based regimens, the median OS improved (1001 vs. 744 days, P = 0.037; and 834 vs. 464 days, respectively P = 0.032, respectively; Wilcoxon). Multivariate analyses revealed that a history of perioperative chemotherapy with anthracycline- and/or taxane-based regimens was a predictive factor (hazard ratio, 0.39; 95% confidence interval, 0.21–0.70) for OS. Conclusions This study successfully identified subgroups of HER2− ABC patients with improved OS by eribulin therapy. Selecting patients according to their background and line of treatment will maximize the efficacy of eribulin therapy.

Abstract Background About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody–drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC). Patients and methods The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included. Results As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74–1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68–1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients. Conclusion Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.

Background: CDK4/6 inhibitors (CDKi), namely, palbociclib, ribociclib, and abemaciclib, combined with either an aromatase inhibitor (AI) or fulvestrant are the standard first/second line for hormone receptor-positive(HR+)/HER2- negative(neg) metastatic breast cancer (MBC). However, the choice of one specific CDKi is arbitrary and based on the physician's experience with the drug, toxicity profile, and patient's preferences, whereas biomarkers for optimal patient selection have not been established so far. Moreover, upfront chemotherapy is still recommended in case of clinical presentation with visceral crisis, despite no evidence of superior benefit for chemotherapy regimens against CDKi-based regimens. Recent correlative biomarker analyses from pivotal trials of palbociclib and ribociclib showed that HR+/HER2-neg MBC might respond differently according to the molecular intrinsic subtype, with Luminal A and B tumors being sensitive to both CDKi, Basal-like being insensitive to endocrine therapy, irrespective of CDKi, and HER2-enriched tumors showing a benefit only with ribociclib-based therapy. Clinical case: We hereby present a paradigmatic clinical case of a woman affected by a relapsed HR+/HER2-neg MBC with bone and nodal lesions, presenting with a visceral crisis in the form of lymphangitis carcinomatosis and diagnosed with a molecularly HER2-enriched tumor, successfully treated with upfront ribociclib + fulvestrant. The patient experienced a complete symptomatic and radiologic remission of the lymphangitis with a partial response as best response, according to RECIST 1.1 criteria. The progressionfree survival (PFS) was of 20 months, in line with the median PFS observed in the ribociclib + fulvestrant pivotal trial, where, however, patients with visceral crisis had been excluded. Conclusions: This clinical case confirms in the real-world setting that nonluminal subtypes can be found in HR+/HER2-neg disease and may have potential therapeutic implications in the metastatic setting. It also questions the recommendation of upfront chemotherapy in the case of a visceral crisis in the era of CDKi-based regimens. These issues merit further evaluation in prospective and larger studies. [ABSTRACT FROM AUTHOR]

Prognostic gene expression signatures can be used in combination with classical clinicopathological factors to guide adjuvant chemotherapy decisions in ER-positive, HER2-negative breast cancer. However, long-term outcome data after introduction of genomic testing in the treatment decision-making process are limited. In the prospective RASTER study, the tumours of 427 patients with cTanyN0M0 breast cancer were tested to assess the 70-gene signature (MammaPrint). The results were provided to their treating physician to be incorporated in the decision-making on adjuvant systemic therapy. Here, we report the long-term outcome of the 310 patients with ER-positive, HER2-negative tumours by clinical and genomic risk categories at a median follow-up of 10.3 years. Among the clinically high-risk patients, 45 (49%) were classified as genomically low risk. In this subgroup, at 10 years, distant recurrence free interval (DRFI) was similar between patients treated with (95.7% [95% CI 87.7–100]) and without (95.5% [95% CI 87.1–100]) chemotherapy. Within the group of clinically low-risk patients, 56 (26%) were classified as genomically high risk. Within the clinically low-risk group, beyond 5 years, a difference emerged between the genomically high- and low-risk subgroup resulting in a 10-year DRFI of 84.3% (95% CI 74.8–95.0) and 93.4% (95% CI 89.5–97.5), respectively. Interestingly, genomic ultralow-risk patients have a 10-year DRFI of 96.7% (95% CI 90.5–100), largely (79%) without systemic therapy. These data confirm that clinically high-risk, genomically low-risk tumours have an excellent outcome in the real-world setting of shared decision-making. Together with the updated results of the MINDACT trial, these data support the use of the MammaPrint, in ER-positive, HER2-negative, node-negative, clinically high-risk breast cancer patients. ISRCTN71917916 • Clinical high-risk, genomic low-risk tumours have similar DRFI with or without chemo. • Genomic ultralow-risk tumours have a good outcome largely without systemic therapy. • 10-year DRFI in clinical low-risk, genomic high-risk tumours suggest undertreatment. [ABSTRACT FROM AUTHOR]

Simple Summary: There are limited treatments for patients with HER2-negative breast cancer, especially for patients with metastatic breast cancer. This study aimed to observe the efficacy and safety of low-dose apatinib combined with chemotherapy in real-world clinical diagnosis and treatment of HER2-negative metastatic breast cancer. A total of 128 patients were treated with 250 mg apatinib, and we observed the median progression-free survival (PFS) and overall survival (OS) were 4.7 months and 15.3 months, respectively. This observation also indicated that the breast cancer susceptibility gene (BRCA) mutation predicted a better response to apatinib and that combination of immunotherapy or paclitaxel-platinum regimens might be an optimal treatment option. Importantly, a lower dose of apatinib showed mild side effects that improved the patients' life quality. Treatment options for human epidermal growth factor receptor (HER2)-negative breast cancer patients are limited in comparison to the HER2-positive patients, particularly for metastatic breast cancer patients. Apatinib is a small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we reported the apatinib-based therapy data in HER2-negative metastatic breast cancer. Apatinib was taken at a dose of 250 mg orally once per day and combined with standard chemotherapy regimens. The PFS and OS of 128 patients were 4.7 months and 15.3 months, respectively. The objective response rate (ORR) and the disease control rate (DCR) were 22.7% and 80.5%, respectively. Patients with breast cancer susceptibility gene (BRCA) mutations were found to have a longer PFS and OS. Moreover, combination immunotherapy or paclitaxel-platinum regimens shared an improved response to other regimens. Most of the adverse effects (hypertension, anaemia, and hand-foot syndrome) were grade 1 to 2. Metastatic breast cancer patients could benefit from apatinib therapy at a low dosage, and the adverse effects are mild in real-world clinical practice. Furthermore, BRCA may be a putative biomarker for apatinib in HER2-negative breast cancer. Immunotherapy or paclitaxel-platinum regimens may be recommended to combine with apatinib therapy. [ABSTRACT FROM AUTHOR]

Background: Apatinib, a tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptor 2, contributes to the inhibition of angiogenesis. Vinorelbine, a semisyn-thetic vinca alkaloid, primarily inhibits metaphase mitosis of cancer cells through its interactions with tubulin. This study aimed to evaluate whether apatinib combined with vinorelbine was ef-fective and safe for refractory human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who failed taxanes and/or anthracycline and analyze the possible mechanism of drug resistance through metabolomic analysis., Methods: Eligible patients were HER2-negative, inoperable, locally advanced, or metastatic breast cancer patients who progressed after at least one chemotherapy regimen in this present prospective phase II study. Patients took oral apatinib (250-500 mg/day) plus intravenous infusion of vinorelbine (25 mg/m2 on day 1, day 8 at 3-week intervals). Objective response rate (ORR) was our primary endpoint, while disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity were our secondary endpoints. The exploratory purpose was to identify biomarkers or drug resistance mechanisms through metabolomics changes before and after the combination therapy., Results: Between September, 2019 and June, 2022, a total of 34 patients were included. ORR and DCR were 32.4% (11/34) and 85.3% (29/34), respectively. The median PFS was 5.0 months (95% CI, 3.766-6.234), while the median OS was 13.0 months (95% CI, 8.714-17.286). Side effects included hematologic toxicity, gastrointestinal reaction, and sinus tachycardia, which were mild to moderate. The mainly disturbed metabolic pathways were the cAMP signaling pathway, the alanine/aspartate/glutamate metabolism, the central carbon metabolism in cancer, the beta-alanine metabolism, the butanoate metabolism, and the glyoxylate and dicarboxylate metabolism, which may lead to the resistance of patients to this combination therapy., Conclusion: Apatinib combined with vinorelbine is effective and safe in patients with locally advanced or metastatic refractory HER2-negative breast cancer. The findings of this study con-tribute to a better understanding of the metabolic effect of apatinib and vinorelbine therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Previously used anthracycline-based triplet regimens are no longer used routinely due to toxicity and lack of superior efficacy. We hypothesized that the addition of nab-paclitaxel to FOLFOX (FOLFOX-A) would induce higher efficacy and better tolerability., Patients and Methods: Eligible patients with chemotherapy-naïve advanced unresectable HER2-negative gastric or GEJ adenocarcinoma were enrolled in this phase II single-arm trial of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46-48 hours) + nab-paclitaxel (150 mg/m2) every 14 days of a 28-day cycle. Evaluable disease according to RECIST v1.1 for solid tumors was required. The primary endpoint was the objective response rate. Simon's optimal 2-stage design was used to test 5% versus 20% response rate with 90% power and 10% one-sided type I error rate., Results: The study enrolled 39 patients. Median age was 63 (range 20-80) years, 30 (77%) were male, 34 (94%) were White, and 21 (57%) had gastric tumors. The median number of cycles completed was 4.5 (range: 0-36), and 25 patients required dose reductions or discontinuation of at least one component due to toxicity. Of the 38 patients evaluable for response, 15 (42.9%) had complete/partial response (CR/PR) as the best response, and 13 (37.1%) had stable disease. progression-free survival (PFS) and OS data were available for 38 patients, with a median follow-up duration of 27 months (range: 18.2-51.9 months for censored patients). Median PFS was 6.6 months (95% CI: 5.6-12.9), with 31.0% (95% CI: 18.4%-52.4%) 12-month PFS rate. The median OS was 10.5 months (95% CI: 8.8-20.7), 12-month OS rate was 44.7% (95% CI: 31.4%-63.7%). Treatment-related grade 3-4 toxicities included peripheral sensory neuropathy and anemia (18.4% each), neutropenia (15.8%), and diarrhea and lymphopenia (7.9% each)., Conclusions: FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody-drug conjugates., Patients and Methods: This retrospective, observational study included adults with HR+/HER2- mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment., Results: Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment., Conclusions: This real-world study demonstrates that for patients with HR+/HER2- mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

BackgroundCDK4/6 inhibitors (CDKi), namely, palbociclib, ribociclib, and abemaciclib, combined with either an aromatase inhibitor (AI) or fulvestrant are the standard first/second line for hormone receptor-positive(HR+)/HER2-negative(neg) metastatic breast cancer (MBC). However, the choice of one specific CDKi is arbitrary and based on the physician’s experience with the drug, toxicity profile, and patient’s preferences, whereas biomarkers for optimal patient selection have not been established so far. Moreover, upfront chemotherapy is still recommended in case of clinical presentation with visceral crisis, despite no evidence of superior benefit for chemotherapy regimens against CDKi-based regimens. Recent correlative biomarker analyses from pivotal trials of palbociclib and ribociclib showed that HR+/HER2-neg MBC might respond differently according to the molecular intrinsic subtype, with Luminal A and B tumors being sensitive to both CDKi, Basal-like being insensitive to endocrine therapy, irrespective of CDKi, and HER2-enriched tumors showing a benefit only with ribociclib-based therapy.Clinical caseWe hereby present a paradigmatic clinical case of a woman affected by a relapsed HR+/HER2-neg MBC with bone and nodal lesions, presenting with a visceral crisis in the form of lymphangitis carcinomatosis and diagnosed with a molecularly HER2-enriched tumor, successfully treated with upfront ribociclib + fulvestrant. The patient experienced a complete symptomatic and radiologic remission of the lymphangitis with a partial response as best response, according to RECIST 1.1 criteria. The progression-free survival (PFS) was of 20 months, in line with the median PFS observed in the ribociclib + fulvestrant pivotal trial, where, however, patients with visceral crisis had been excluded.ConclusionsThis clinical case confirms in the real-world setting that non-luminal subtypes can be found in HR+/HER2-neg disease and may have potential therapeutic implications in the metastatic setting. It also questions the recommendation of upfront chemotherapy in the case of a visceral crisis in the era of CDKi-based regimens. These issues merit further evaluation in prospective and larger studies.

Background: Updated evidence was required to compare the efficacy and safety of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for patients with hormone receptor-positive and HER2-negative metastatic breast cancer. Methods: A systematic review and network meta-analysis was conducted utilizing data from randomized controlled trials (RCTs) that contained interventions of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were primary outcomes of interest. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% credible intervals (CrIs) were used to assess the survival outcomes and safety profiles, respectively. Results: A total of 28 RCTs with 12,129 participants were included. Pooled analysis showed that CDK4/6 inhibitors significantly prolonged PFS than PI3K/AKT/mTOR inhibitors (HR, 0.81; 95% CrI, 0.69-0.94), whereas no significant differences were detected regarding OS. After balancing the treatment lines and metastatic sites, the superiority of CDK4/6 inhibitors only appeared in the visceral and non-visceral subgroups. Among CDK4/6 inhibitors, abemaciclib was significantly better than others in ≥3 grade neutropenia (OR, 0.04; 95% CrI, 0.01-0.15). The incidence of stomatitis and digestive disorders was different among diverse kinds of PI3K/AKT/mTOR inhibitors. Discrepancies appeared regarding TRAEs of hepatotoxicity, diarrhea, and hyperglycemia among different interventions. Conclusions: CDK4/6 inhibitors showed better efficacy in PFS, but the benefits disappeared when taking treatment line into consideration. Specific and discrepant safety profiles were found in two categories of agents. [ABSTRACT FROM AUTHOR]

Purpose: Resistance to endocrine therapy poses a major clinical challenge for patients with hormone receptor-positive (HR +), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC). We present the preplanned 24-month final overall survival (OS) results, alongside updated progression-free survival (PFS), and objective response rate (ORR) results. Methods: nextMONARCH is an open-label, controlled, randomized, Phase 2 study of abemaciclib alone or in combination with tamoxifen in women with endocrine-refractory HR + , HER2– MBC previously treated with chemotherapy. Patients were randomized 1:1:1 to: abemaciclib 150 mg and tamoxifen 20 mg (A + T), abemaciclib 150 mg (A-150), or abemaciclib 200 mg and prophylactic loperamide (A-200). OS was the main prespecified secondary endpoint. PFS, ORR, and safety at 24 months were compared to previously reported primary analysis results. Results: Of the 234 patients enrolled, 12 were receiving study treatment at data cutoff (28Jun2019). Median follow-up was 27.2 months. Median OS was 24.2 months in the A + T arm, 20.8 months in A-150, and 17.0 months in A-200 (A + T versus A-200: HR 0.62; 95%CI [0.40, 0.97], P = 0.03 and A-150 versus A-200: HR 0.96; 95%CI [0.64, 1.44], P = 0.83). PFS and ORR results at 24 months were consistent with the primary analysis. The safety profile corresponded with previous reports. Conclusion: The addition of tamoxifen to abemaciclib demonstrated greater OS benefit than monotherapy. This study confirmed the single-agent activity of abemaciclib in heavily pretreated women with endocrine-refractory HR + , HER2– MBC, as well as the previously reported primary PFS and ORR results, with no new safety signals observed. Trial Registration ClinicalTrials.gov Identifier: NCT02747004. [ABSTRACT FROM AUTHOR]

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Approximately 75% of breast cancer (BC) is associated with luminal differentiation expressing endocrine receptors (ER). For ER+ HER2− tumors, adjuvant endocrine therapy (ET) is the cornerstone treatment. Although relapse events steadily continue, the ET benefits translate to dramatically lengthen life expectancy with bearable side-effects. This review of ER+ HER2− female BC outlines suitable adjuvant treatment strategies to help guide clinical decision making around appropriate therapy. Methods: A literature search was conducted in Embase, Medline, and the Cochrane Libraries, using ER+ HER−, ET BC keywords. Results: In low-risk patients: five years of ET is the standard option. While Tamoxifen remains the preferred selection for premenopausal women, AI is the choice for postmenopausal patients. In the high-risk category: ET plus/minus OFS with two years of Abemaciclib is recommended. Although extended ET for a total of ten years is an alternative, the optimal AI duration is undetermined; nevertheless an additional two to three years beyond the initial five years may be sufficient. In this postmenopausal group, bisphosphonate is endorsed. Conclusions: Classifying the risk category assists in deciding the treatment route and its optimal duration. Tailoring the breadth of ET hinges on a wide array of factors to be appraised for each individualized case, including weighing its benefits and harms. [ABSTRACT FROM AUTHOR]

An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81–1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81–1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT). • Overall survival (OS) was assessed in patients with metastatic breast cancer (MBC). • OS was similar for palbociclib + fulvestrant and capecitabine in AI-resistant MBC. • The results were independent of the ESR1 mutational status. • In wild-type ESR1 tumours, palbociclib + ET and capecitabine also had similar OS. • Progression-free survival 2 was similar in both treatment arms. [ABSTRACT FROM AUTHOR]

Objective: Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer. Methods: Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5–10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers. Results: Twenty-six eligible patients were enrolled, with a median age of 56 (30–75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86–6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroid-stimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%). Conclusion: Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.

Abstract Background The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence. Methods We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases. Results Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p

Ami Vyas,1 Meghan Gabriel,2 Sobha Kurian3 1Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USA; 2Pharmacy Quality Alliance, Alexandria, VA, USA; 3West Virginia University, School of Medicine, Morgantown, WV, USACorrespondence: Ami VyasDepartment of Pharmacy Practice, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USATel +1-401-874-7255Fax +1-401-874-2717Email avyas@uri.eduBackground: Data on guideline-concordant initial systemic treatment among women with HER2-negative metastatic breast cancer (MBC) are limited. We determined the proportion of women with HER2-negative MBC who received guideline-concordant treatment and the extent to which independent variables explained differences in guideline-concordant treatment by hormone receptor (HR) status.Methods: We conducted a retrospective cohort study using the SEER-Medicare database. We included women age > 65 years diagnosed with HER2-negative MBC during 2010– 2013. We used the National Comprehensive Cancer Network treatment guidelines to determine guideline-concordant initial treatment within the first 6 months of a cancer diagnosis. We conducted a multivariable logistic regression to identify the significant predictors of guideline-concordant treatment and a non-linear decomposition method to examine disparities by HR status.Results: Among 1089 eligible women, 72.3% received guideline-concordant treatment. Compared to women who did not receive guideline-concordant treatment, women who received guideline-concordant treatment were more like to be comparatively older (p< 0.05), married (p=0.0171), resided in areas with higher proportion of people age ≥ 25 years with at least four years of college education, and had positive HR status (p< 0.0001). Approximately 8% of the disparity in guideline-concordant treatment by HR status was explained by their observed characteristics. Need-related factors explained the highest proportion (66.9%) of the disparity.Conclusion: Our findings indicate improvement of care for older women, who are single/divorced, have negative HR status, and who live in area with lower education levels. Unexplained disparities in guideline-concordant treatment by HR status can be attributed to patient preferences for treatment, physician-level factors, and perceptions.Keywords: guideline-concordant treatment, decomposition, HER2-negative, breast cancer, SEER-Medicare database

Uncertainty exists around the need to include an anthracycline if taxane-based adjuvant chemotherapy is being used for human epidermal growth factor receptor-2 (HER2) negative and axillary lymph node negative (LNN) breast cancer. We identified all patients who were diagnosed with HER2-negative, LNN breast cancer treated with docetaxel-cyclophosphamide for four cycles (DC4) or an anthracycline-taxane (AT) regimen following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with AT to up to four patients treated with DC4 on potentially confounding clinicopathologic and treatment variables. We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) and assessed the effect of the type of adjuvant chemotherapy on these outcomes using Cox regression. Of the 726 eligible patients, 657 (90.5%) were treated with DC4 and 69 (9.5%) were treated with AT. Matching created a group of 202 women treated with DC4 and eliminated differences in clinicopathologic and treatment factors. There was no statistically significant difference for the treatment effects of matched DC4 patients compared to the AT patients on iDFS (75.7% vs. 76.8%, p = 0.75; hazard ratio (HR) = 1.05, 95% CI = 0.65 to 1.8), BCSS (88.1% vs. 87%, p = 0.8; HR = 0.91, 95% CI = 0.42 to 1.9), or OS (87.1% vs. 86.9%, p= 0.96; HR = 0.98, 95% CI = 0.46 to 2.1). Four cycles of DC as compared with an AT regimen yielded similar 10-year iDFS, BCSS and OS amongst patients with HER2-negative, LNN breast cancer.

The present goal of therapy for early HR+/HER2- breast cancer (BC) is to optimize disease-free survival (DFS) and overall survival (OS) rates with the currently available therapies while avoiding any relevant long-term sequalae. Local therapies have evolved toward less aggressive techniques (i.e. breast-preserving surgery, sentinel lymph node biopsy and intraoperative radiotherapy), which significantly reduce the long-term sequalae observed with more radical treatments. Endocrine therapy (ET) is still the cornerstone of adjuvant treatment because it significantly reduces BC relapse and mortality. Adjuvant chemotherapy is today recommended only for a particular subset of patients with a high risk of recurrence with ET alone, identified through genomic assays, age and/or disease stage. Bisphosphonates reduce the risk of bone metastasis and produce a slight although statistically significant improvement in survival in postmenopausal women. The CDK 4/6 inhibitor abemaciclib has been recently approved by the US FDA for patients at high risk of relapse. [ABSTRACT FROM AUTHOR]

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of molecular biology and genomics, molecular targeted therapy has become one of the most active areas in breast cancer treatment research and has also achieved remarkable achievements. However, molecular targeted therapy is mainly aimed at HER2-positive breast cancer and has not yet achieved satisfactory curative effect on HER2-negative breast cancer. This article describes the potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc. , and explores possible inhibitors for the treatment of HER2-negative breast cancer, such as PI3K inhibitors, AKT inhibitors and m-TOR inhibitors that inhibit the PI3K/AKT signaling pathway, small molecule tyrosine kinase inhibitors that restrain angiogenesis, CDK inhibitors, aurora kinase inhibitors and HDAC inhibitors that block cell cycle, as well as the drugs targeting breast cancer stem cells which have been a hit, aiming to provide a new idea and strategy for the treatment of HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of molecular biology and genomics, molecular targeted therapy has become one of the most active areas in breast cancer treatment research and has also achieved remarkable achievements. However, molecular targeted therapy is mainly aimed at HER2-positive breast cancer and has not yet achieved satisfactory curative effect on HER2-negative breast cancer. This article describes the potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc., and explores possible inhibitors for the treatment of HER2-negative breast cancer, such as PI3K inhibitors, AKT inhibitors and m-TOR inhibitors that inhibit the PI3K/AKT signaling pathway, small molecule tyrosine kinase inhibitors that restrain angiogenesis, CDK inhibitors, aurora kinase inhibitors and HDAC inhibitors that block cell cycle, as well as the drugs targeting breast cancer stem cells which have been a hit, aiming to provide a new idea and strategy for the treatment of HER2-negative breast cancer.