Comparative effectiveness analysis of survival with first-line palbociclib or ribociclib plus AI in HR + /HER2- advanced breast cancer (CEPRA study): preliminary analysis of real-world data from Thailand.

BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.

Incidence of infusion hypersensitivity reaction after withholding dexamethasone premedication in early breast cancer patients not experiencing two previous cycles of infusion hypersensitivity reaction for weekly paclitaxel chemotherapy.

BACKGROUND: Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid's adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions. METHOD: Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected. RESULTS: Eighty-one of 85 patients who did not undergo infusion HSR after 2 cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51 years (range 27-74 years). Only 16% of the patients had a BMI greater than 30 kg/m2, 57.8% were premenopausal, 67.9% had no comorbidity, none had a history of allergy or asthma, 65.4% received weekly paclitaxel as a single agent, and 34.6% received weekly paclitaxel in combination with trastuzumab. Five of 81 patients reported grade I-II HSR (6.25%), which occurred mostly during the first 6 cycles (60%). Temporary discontinuation of paclitaxel infusion was observed in all HSR patients. No differences regarding age, BMI, menopausal status, and underlying disease between the HSR and no HSR groups were identified. Concerning the safety profile, peripheral neuropathy (gr I 60%, gr II 13.5%, and gr III 2.4%), myalgia (43.4%), and edema (10.5%) were commonly reported, whereas dyspepsia (5.3%) and insomnia (14.5%) were rarely described in withholding patients. CONCLUSION: Withholding dexamethasone premedication in non-experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects.

A Difference in the Incidences of Hypersensitivity Reactions to Original and Generic Taxanes.

PURPOSE: To compare incidences of hypersensitivity reaction (HSR) between original and generic taxanes including paclitaxel and docetaxel. METHODS: We conducted a prospective study enrolling all patients receiving taxanes at King Chulalongkorn Memorial Hospital. Taxanes were infused accordingly to the step-wise rate escalation protocol at this hospital. Active surveillance for HSRs was performed. During the study period, there was only 1 generic brand used for each taxane. We primarily compared the incidences of HSR between original and generic drugs for each taxane. RESULTS: During the period from January 1 to December 31, 2013, a total of 258 consecutive patients receiving taxanes were enrolled; 128 received paclitaxel, i.e. 65 and 63 in the original (Taxol) and generic arms, respectively, and 130 received docetaxel, i.e. 66 and 64 in the original (Taxotere) and generic arms, respectively. Premedication, including antihistamines and dexamethasone, was administered to all patients 30 min before taxane infusion. There were 26 (10.0%) HSR events including 24 grade 2 and 2 grade 3 HSRs. In the paclitaxel group, there were 9 (13.8%) and 7 (11.1%) HSRs in the original and generic arms, respectively (p = 0.791). In the docetaxel group, there were 9 (13.6%) and 1 (1.6%) HSRs in the original and generic arms, respectively (p = 0.017). No life-threatening symptoms or permanent discontinuation of taxanes occurred. CONCLUSIONS: In this prospective study, the incidences of HSR were similar with generic and original paclitaxel but significantly different with generic and original docetaxel.

Home-Based Buddhist Walking Meditation Mitigates Cardiotoxicity of Anthracycline Chemotherapy in Breast Cancer Patients: A Randomized Controlled Trial.

Purpose: To investigate the effect of walking meditation on vascular function, aerobic fitness, and quality of life in breast cancer patients receiving anthracycline chemotherapy and compare with the nonexercising control group. Methods: Patients aged 40-60 years with newly diagnosed, histologically confirmed resected stage I-II breast cancer were studied in a parallel randomized controlled trial. The participants were randomly assigned to either the nonexercising control group (n = 15) or the Buddhist walking meditation group (n = 15). All participants received four cycles of anthracycline chemotherapy every 3 weeks starting at 2 weeks before the start of the exercise intervention. The walking meditation group performed home-based mindfulness walking exercises at a moderate exercise intensity for 30 min/session, 3 times/week for 12 weeks. The primary outcome measures were vascular reactivity (flow-mediated dilation [FMD]) and arterial stiffness (brachial-ankle pulse wave velocity [baPWV]). Results: Eleven participants from each group completed the entire study. Analysis of variance with repeated measures indicated that FMD and peak oxygen consumption (VO2peak) decreased in both groups after the initiation of anthracycline chemotherapy (all p < 0.05). After the exercise intervention, FMD, VO2peak, peak stroke volume, and peak cardiac output remained lower in the controls, but improved in the walking meditation group (all p < 0.05). baPWV increased in the control group, while no such change was observed in the walking meditation group. There were no significant changes in blood cortisol, malondialdehyde, and interleukin-6 concentrations in both groups. Overall quality of life decreased after 2 weeks of anthracycline chemotherapy in both groups (all p < 0.05). However, the walking meditation group improved many of these symptoms significantly (all p < 0.05), while no such changes were observed in the control group. Conclusions: Buddhist walking meditation exercise was effective in mitigating cardiotoxicity of anthracycline chemotherapy on vascular function, aerobic fitness, and quality of life in breast cancer patients. Clinical trial registration number: NCT02676531.

A label-free electrochemical immunosensor based on 11-mercaptoundecanoic acid grafted chitosan and poly(N-methylaniline) for the detection of carcinoembryonic antigen.

Carcinoembryonic antigen (CEA) is a cancer marker used for monitoring cancer treatment. Herein, a label-free electrochemical immunosensor for determining CEA concentration composed of the thiolated chitosan (tCHI) and the doped poly(N-methylaniline) (dPNMA) is proposed. The tCHI served as a support matrix for the immobilization of CEA antibodies (anti-CEA) and was prepared by using 11-mercaptoundecanoic acid (MUA) as a grafting agent on chitosan (CHI). The excellent electrical conductivity of the dPNMA was utilized as an electron transfer layer for the proposed immunosensor. The successful preparation of the tCHI was confirmed by the attenuated-total reflection Fourier transform spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). Cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) were used to illustrate the performance of the proposed immunosensor. The determination of CEA concentration was relied on the decrease in the DPV current response with increasing CEA concentration from the creation of the antigen-antibody immunocomplex. The proposed immunosensor demonstrated a broad concentration range of 0.01 to 30 ng mL-1 with a low limit of detection (LOD) of 0.01 ng mL-1. In addition, the present sensor exhibited excellent selectivity, reproducibility, and long-term stability, suggesting its potential use to determine CEA in clinical immunoassay.

Lactic acidosis, a potential toxicity from drug-drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report.

BACKGROUND: Ribociclib, one of the cyclin-dependent kinases (CDK) 4 and 6 inhibitors, in combination with endocrine therapies has been approved in the treatment of hormonal receptor positive, HER-2 negative metastatic breast cancer worldwide. Long-term usage of ribociclib with concomitant drugs, potential drug-drug interaction may develop which can limit the therapeutic value of CDK4/6 inhibitor. CASE: A 62-year-old with history of non-insulin dependent diabetic, dyslipidemia, and essential hypertension was diagnosed with HR-positive, HER-2 negative metastatic breast cancer and treated with fulvestrant plus ribociclib. Four weeks after administration, elevated serum creatinine was observed, and then severe lactic acidosis with acute respiratory failure was subsequently reported. Ribociclib and fulvestrant were temporarily discontinued. Three days after renal replacement therapy, her clinical was stabilized. Combination ribociclib with metformin resulted in high plasma metformin levels and dangerous consequences. Hence, special precaution should be considered during concomitant treatment with sensitive transporter substrates. CONCLUSION: Metformin associated lactic acidosis may potentially occur after combination with ribocilib, an uncommon but lethal complication from the interaction of these drugs, especially in patients who had preexisting renal impairment.

Development and validation of a rapid psychosocial well-being screening tool in patients with metastatic breast cancer.

Objective: The aim of this study was to develop and validate a rapid psychosocial well-being screening tool for metastatic breast cancer patients (MBC-PsySoc-Well-being). Methods: Applying a mixed method approach, the study was conducted in two phases. Phase 1, a focus group method was employed for item development, and three focus group sessions were conducted, with patients, caregivers, and medical professionals, respectively. Phase 2, validity and reliability testing were performed. Five experts reviewed items for content validity. Construct validity, criterion-related validity, internal consistency, and test-retest reliability were conducted among a sample of 53 patients with metastatic breast cancer. Results: Six themes were qualitatively analyzed based on focus group participants' responses. Eight items were then developed based on these themes. The index of Item-Objective Congruence scored by the experts ranged from 0.6 to 1.0. An exploratory factor analysis yielded three factors: Being curious and active in information seeking, Enthusiasm to return to a normal life, and Adjusting to positive lifestyle. The total scores of MBC-PsySoc-Well-being and the European Organization for Research and Treatment of Cancer's Quality of Life Core Questionnaire (EORTC QLQ-C30) were moderately correlated (r = 0.404, P = 0.003). Cronbach's α coefficient of the overall scale was 0.686. Pearson correlation coefficients of items between two tests within 14-day ranged from 0.410 to 0.673. Conclusion: This study represents an initiative to develop a rapid psychosocial well-being screening tool for patients with metastatic breast cancer. The results from validity and reliability testing indicate that the scale is moderately suitable for application to patients with metastatic breast cancer. However, a larger scale study should be further administered to confirm the validity and reliability of the measurement.

Disparities in Access to Systemic Treatment for Breast Cancer in Thailand and Major Asian Territories.

PURPOSE: Breast cancer (BC) treatment has shifted from chemotherapy to targeted therapy. Several targeted agents have demonstrated an improvement in survival. Given that national healthcare resources were correlated with the cancer mortality-to-incidence ratio, we compared access to BC drugs in Thailand with that in other Asian countries. METHODS: BC experts involved in the Breast International Group (BIG)-Asia in six representative groups for countries or special administrative region (SAR) in Asia (Hong Kong SAR, Japan, Korea, Taiwan, Thailand, and Singapore) were invited to participate in the survey. The questionnaire addressed national health reimbursement schemes, molecular testing for early BC (EBC), availability and accessibility of BC drugs. Accessibility and reimbursement of the drugs were reported based on their listing as essential medicines in the World Health Organization Model List of Essential Medicines (WHO-EML) and their nomination as effective drugs in the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The study was approved by all participating BIG-Asia organizations in November 2021. RESULTS: Genomic tests for EBC were non-reimbursable in all surveyed territories. Reimbursement and co-payment of BC drugs vary between and within these regions (particularly Thailand). Most drugs in the WHO-EML and ESMO-MCBS (A/B for EBC and 4/5 for advanced BC) were accessible in all surveyed territories. However, the accessibility of effective but costly WHO-EML and ESMO-MCBS drugs was not uniform in Thailand. There was an evident disparity for individuals covered by the Thai Social Security/Universal Health Coverage schemes. CONCLUSION: Essential BC drugs are generally accessible in selected BIG-Asia countries or SAR. There is a disparity in accessing high-cost drugs in Thailand compared with other Asian territories.

Changes in Triple-Negative Breast Cancer Molecular Subtypes in Patients Without Pathologic Complete Response After Neoadjuvant Systemic Chemotherapy.

PURPOSE: Lehmann et al have identified four molecular subtypes of triple-negative breast cancer (TNBC)-basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor-and an immunomodulatory (IM) gene expression signature modifier. Our group previously showed that the response of TNBC to neoadjuvant systemic chemotherapy (NST) differs by molecular subtype, but whether NST affects the subtype was unknown. Here, we tested the hypothesis that in patients without pathologic complete response, TNBC subtypes can change after NST. Moreover, in cases with the changed subtype, we determined whether epithelial-to-mesenchymal transition (EMT) had occurred. MATERIALS AND METHODS: From the Pan-Pacific TNBC Consortium data set containing TNBC patient samples from four countries, we examined 64 formalin-fixed, paraffin-embedded pairs of matched pre- and post-NST tumor samples. The TNBC subtype was determined using the TNBCtype-IM assay. We analyzed a partial EMT gene expression scoring metric using mRNA data. RESULTS: Of the 64 matched pairs, 36 (56%) showed a change in the TNBC subtype after NST. The most frequent change was from BL1 to M subtypes (38%). No tumors changed from M to BL1. The IM signature was positive in 14 (22%) patients before NST and eight (12.5%) patients after NST. The EMT score increased after NST in 28 (78%) of the 36 patients with the changed subtype (v 39% of the 28 patients without change; P = .002254). CONCLUSION: We report, to our knowledge, for the first time that the TNBC molecular subtype and IM signature frequently change after NST. Our results also suggest that EMT is promoted by NST. Our findings may lead to innovative adjuvant therapy strategies in TNBC cases with residual tumor after NST.

Immunogenicity of ChAdOx1-nCoV-19 vaccine in solid malignancy patients by treatment regimen versus healthy controls: A prospective, multicenter observational study.

Background: Limited data exists regarding the efficacy of ChAdOx1-nCoV-19 vaccine against Severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) in solid cancer patients. We aimed to assess the immunogenicity of the ChAdOx1-nCoV-19 vaccine and the impact of different anticancer therapies for solid malignancies on immune response. Methods: This prospective, longitudinal observational study of immunogenicity following ChAdOx1-nCoV-19 vaccination among 385 solid cancer patients on active cancer treatment was conducted in two oncology centers. Participants received the first dose between June 18 and July 27, 2021 and the second dose at 8-10 weeks later. Blood samples were evaluated for total immunoglobulins against the receptor-binding of SARS-CoV-2 spike protein (anti-RBD total-Ig) before, and 4-week after the first- and second-doses. The primary endpoint was the geometric mean titers (GMT) of antibody among solid cancer patients compared to healthy controls and the impact of different cancer treatment types. Findings: Among solid cancer patients, the antibody level increased more slowly to significantly lower levels than achieved in healthy controls. The GMT at 4-weeks post-vaccination in cancer vs. healthy were 224.5 U/ml (95%CI 176.4-285.6) vs. 877.1 U/ml (95%CI 763.5-1008), p<0.0001), respectively. For different types of cancer treatments, chemotherapy agents, especially anthracyclines (GMR 0.004; 95%CI 0.002-0.008), paclitaxel (GMR 0.268; 95%CI 0.123-0.581), oxaliplatin (GMR 0.340; 95%CI 0.165-0.484), and immunotherapy (GMR 0.203; 95%CI 0.109-0.381) showed significantly lower antibody response. Anti-HER2, endocrine therapy and 5-fluouracil or gemcitabine, however, had less impact on the immune response. Interpretation: Suboptimal and heterogeneous immunologic responses were observed in cancer patients being treated with different systemic treatments. Immunotherapy or chemotherapy significantly suppressed the antibody response. Funding: Quality Improvement Fund, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society and Center of Excellence in Clinical Virology at Chulalongkorn University and Chulalongkorn Medical Oncology Research Fund.

What is the best systemic treatment for newly diagnosed inflammatory breast cancer?-a narrative review.

OBJECTIVE: The propose of this review to discuss of the systemic treatment options for newly diagnosed inflammatory breast cancer (IBC) including the recent data of immune checkpoint inhibitor, CDK4/6 inhibitor and anti-HER2 therapy. Aim to provide a pragmatic treatment in a gray area or concerning issues of real-world practice. BACKGROUND: IBC is a rare and aggressive disease. Upfront systemic treatment followed by surgery and radiation therapy or "Tri-modality" treatment is a standard of care for newly diagnosed IBC. Due to its rarity, the data of systemic treatment for IBC has been extrapolated mostly from non-IBC clinical trials. METHODS: We summarized the recent data of systemic treatment stratified by concerning topics and breast cancer subtypes. Some topics are less likely to have strong data from IBC clinical trial to supports. Therefore, we interpolate the non-IBC data to support our review. CONCLUSIONS: IBC is challenging in the clinical management. The development of novel systemic treatment is urgently needed, especially for IBC-specific clinical trials.

Optimizing outcomes for patients with metastatic prostate cancer: insights from South East Asia Expert Panel.

AIMS: Clinical decision making is challenging in men with metastatic prostate cancer (mPC), as heterogeneity in treatment options and patient characteristics have resulted in multiple scenarios with little or no evidence. The South East Asia Expert Panel 2019 addressed some of these challenges. METHODS: Based on evidence in the literature and expert interviews, 19 statements were formulated for key challenges in the treatment of men with castration-sensitive and -resistant prostate cancer in clinical practice. A modified Delphi process was used to reach consensus among experts in the panel and develop clinical practice recommendations. RESULTS: The majority of the panel preferred a risk-based stratification and recommended abiraterone or enzalutamide as first-line therapy for symptomatic chemotherapy naïve patients. Abiraterone is preferred over enzalutamide as a first-line treatment in these patients. However, the panel did not support the use of abiraterone in high risk lymph-node positive only (N+M0) or in non-metastatic (N0M0) patients. In select patients, low dose abiraterone with food may be used to optimize clinical outcomes. Androgen receptor gene splice variant status may be a useful guide to therapy. In addition, generic versions of approved therapies may improve access to treatment to a broader patient population. The choice of treatment, as well as sequencing are guided by both patient and disease characteristics, preferences, drug access, cost, and compliance. CONCLUSION: Expert recommendations are key to guidance for the optimal management of mPC. Appropriate choice, timing, and sequence of treatment options can help to tailor therapy to maximize outcomes in men with mPC.

Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene.

BACKGROUND: Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by absence of both hormonal receptors and human epithelial growth factor receptor 2 (HER2). TNBC accounts for 15-20% of breast cancer. TNBC is associated with more aggressive disease and worse clinical outcome. Though the underlying mechanism of TNBC is currently unclear, the heterogeneity of clinical characteristics in various population may relate to the difference in tumor mutational profile. There were studies on TNBC gene mutations in various ethnic groups but the tumor genome data on Thai TNBC patients is currently unknown. This study aims to investigate mutational profile of Thai TNBC. METHODS: The patients were Thai individuals who were diagnosed with primary breast carcinoma between 2014 and 2017. All surgically removed primary tumor tissues were carefully examined by pathologists and archived as formalin-fixed paraffin-embedded tumor. TNBC was defined by absence of hormonal receptors and HER2 by immunohistochemistry. Genomic DNA was extracted, enriched and sequenced of all exomes on the Illumina HiSeq. Genomic data were then processed through bioinformatics platform to identify genomic alterations and tumor mutational burden. RESULTS: A total of 116 TNBC patients were recruited. Genomic analysis of TNBC samples identified 81,460 variants, of which 5,906 variants were in cancer-associated genes. The result showed that Thai TNBC has higher tumor mutation burden than previously reported data. The most frequently mutated cancer-associated gene was TP53 similar to other TNBC cohorts. Meanwhile KMT2C was found to be more commonly mutated in Thai TNBC than previous studies. Mutational profile of Thai TNBC patients also revealed difference in many frequently mutated genes when compared to other Western TNBC cohorts. CONCLUSION: This result supported that TNBC breast cancer patients from various ethnic background showed diverse genome alteration pattern. Although TP53 is the most commonly mutated gene across all cohorts, Thai TNBC showed different gene mutation frequencies, especially in KMT2C. In particular, the cancer gene mutations are more prevalent in Thai TNBC patients. This result provides important insight on diverse underlying genetic and epigenetic mechanisms of TNBC that could translate to a new treatment strategy for patients with this disease.

Cooperative Effect of Oncogenic MET and PIK3CA in an HGF-Dominant Environment in Breast Cancer.

There is compelling evidence that oncogenic MET and PIK3CA signaling pathways contribute to breast cancer. However, the activity of pharmacologic targeting of either pathway is modest. Mechanisms of resistance to these monotherapies have not been clarified. Currently, commonly used mouse models are inadequate for studying the HGF-MET axis because mouse HGF does not bind human MET. We established human HGF-MET paired mouse models. In this study, we evaluated the cooperative effects of MET and PIK3CA in an environment with involvement of human HGF in vivo Oncogenic MET/PIK3CA synergistically induced aggressive behavior and resistance to each targeted therapy in an HGF-paracrine environment. Combined targeting of MET and PI3K abrogates resistance. Associated cell signaling changes were explored by functional proteomics. Consistently, combined targeting of MET and PI3K inhibited activation of associated oncogenic pathways. We also evaluated the response of tumor cells to HGF stimulation using breast cancer patient-derived xenografts (PDX). HGF stimulation induced significant phosphorylation of MET for all PDX lines detected to varying degrees. However, the levels of phosphorylated MET are not correlated with its expression, suggesting that MET expression level cannot be used as a sole criterion to recruit patients to clinical trials for MET-targeted therapy. Altogether, our data suggest that combined targeting of MET and PI3K could be a potential clinical strategy for breast cancer patients, where phosphorylated MET and PIK3CA mutation status would be biomarkers for selecting patients who are most likely to derive benefit from these cotargeted therapy.

Receptor status change from primary to residual breast cancer after neoadjuvant chemotherapy and analysis of survival outcomes.

BACKGROUND: To evaluate the frequency of receptor change from pretreatment to residual breast cancer after NCT and their correlation with outcomes. PATIENTS AND METHODS: Three hundred ninety-eight women were identified retrospectively. Estrogen receptor, progesterone receptor, and HER2 were reviewed. Patients were classified as not having receptor change versus any receptor change. Kaplan-Meier was used to estimate survival outcomes according to changes. Cox proportional hazards models were used to determine the association of receptor status changes with outcomes after adjustment for patient and tumor characteristics. RESULTS: One hundred sixty-two (40.7%) patients had a change in at least 1 of the receptors from pretreatment to residual disease. Patients who had no change in receptor status had a significantly greater triple-negative breast cancer (TNBC) rate at baseline (P = .0001). Of the 193 hormone receptor (HR)-positive tumors, 9 (4.7%) and 29 (15.1%) became HER2-positive and TNBC, respectively. Of the 72 HER2-positive tumors, 20 (27.8%) and 9 (12.5%) became HR-positive and TNBC, respectively. Of the 128 TNBC tumors, only 2 (1.6%) and 33 (25.8%) became HER2-positive and HR-positive, respectively. At a median follow up of 40 months, 5-year overall survival (OS) was 73% and 63%; and 5-year relapse-free survival (RFS) was 63% and 48% for patients with or without any receptor change (P = .07 and P = .003), respectively. Any receptor change was associated with better RFS (hazard ratio, 0.63; 95% confidence interval [CI], 0.44-0.9) but not OS. (hazard ratio, 0.79; 95% CI, 0.53-1.18). CONCLUSION: Changes in receptor status between the pretreatment and residual disease after NCT are frequent and appear to be associated with improved RFS because of the receptor stability of TNBC.

Functional consequence of the MET-T1010I polymorphism in breast cancer.

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo. A selective effect of MET-T1010I as compared to wild type MET on cell invasion both in-vitro and in-vivo suggests that the MET-T1010I SNP may alter tumor pathophysiology and should be considered as a potential biomarker when implementing MET targeted clinical trials.

cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer.

BACKGROUND: EGFR expression and pathway activation are common in triple-negative breast cancer (TNBC). However, anti-EGFR therapies have not been effective in these patients. We aimed to study the efficacy of targeting MET in overcoming resistance to EGFR therapy in TNBC cell lines. METHODS: TNBC lines (MDA-MB-468, HCC-1395, and MDA-MB-231), and a hormone receptor-positive breast cancer line (T47D) were stimulated with epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Lines were then treated with different concentrations of EGFR inhibitors (gefitinib or cetuximab), with or without a MET tyrosine kinase inhibitor (EMD 1214063). Proliferation was measured by MTS assay, in soft agar and with a matrigel assay. Synergy was measured with Calcusyn. Protein expression and signaling were examined with immunoblotting. RESULTS: There was activation of ligand-receptor-downstream signaling pathways in MDA-MB-468 and HCC-1395 upon stimulation with EGF and HGF. In these cell lines, we observed synergism when combining EGFR and MET inhibitors. These results were observed across assays. In western blotting, combination therapy resulted in abrogation of pAKT and pMAPK while monotherapy did not. CONCLUSION: Our data demonstrate that dual EGFR/MET inhibition is synergistic in TNBC. Targeting both EGFR and MET receptors may provide an effective therapeutic strategy in TNBC.

Mesothelin expression and survival outcomes in triple receptor negative breast cancer.

BACKGROUND: Mesothelin is an ideal tumor-associated marker for the development of targeted therapy due to its limited expression in normal tissues. The aim of this study was to evaluate mesothelin expression in triple-negative breast cancer (TNBC) and its correlation with survival outcomes. METHODS: Mesothelin expression was completed by using immunohistochemistry and was quantified by the H score. An H score > 10 was considered positive. Patient characteristics were compared by mesothelin expression. The Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics. RESULTS: The median age was 52 years. Of the 109 patients with TNBC, 37 (34%) were positive for mesothelin expression. There were no differences on patient and/or tumor characteristics by mesothelin expression with the exception of high frequency of lymphovascular space invasion in mesothelin-negative tumors (2P = .03). At a median follow-up of 75.8 months, 20 (18.3%) patients had experienced a recurrence, and 22 (20.2%) had died. Five-year progression-free survival was 87% and 92% in patients with mesothelin-positive and those with mesothelin-negative tumors (2P = .43). Five-year overall survival was 85% and 91% in patients with mesothelin-positive and those with mesothelin-negative tumors (2P = .57), respectively. Mesothelin expression was not an independent predictor of survival outcomes. CONCLUSION: Mesothelin expression was identified in 34% of patients with TNBC. Mesothelin expression did not correlate with survival outcomes in patients with TNBC.