Real-World Study of Adjuvant Biosimilar Trastuzumab-dkst for HER2-Positive Breast Cancer Treatment in a Brazilian Population.

INTRODUCTION: Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. METHODS: We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. RESULTS: Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9-98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. CONCLUSION: Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. GOV REGISTRATION: NCT03892655.

Selecting postoperative adjuvant systemic therapy for early-stage breast cancer: An updated assessment and systematic review of leading commercially available gene expression assays.

Gene expression assays (GEAs) can guide treatment for early-stage breast cancer. Several large prospective randomized clinical trials, and numerous additional studies, now provide new information for selecting an appropriate GEA. This systematic review builds upon prior reviews, with a focus on five widely commercialized GEAs (Breast Cancer Index®, EndoPredict®, MammaPrint®, Oncotype DX®, and Prosigna®). The comprehensive dataset available provides a contemporary opportunity to assess each GEA's utility as a prognosticator and/or predictor of adjuvant therapy benefit.

Cost-effectiveness of ribociclib for premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer: a Brazilian public health care system perspective.

Introduction: The MONALEESA-7 trial compared ribociclib plus endocrine therapy (ET) with placebo as first-line treatment of advanced luminal/HER2-negative breast cancer (ABC) in premenopausal and perimenopausal women (age <50 years) and showed significant benefits to progression-free survival and overall survival. This study aimed to compare the cost-effectiveness of ribociclib + ET versus ET alone in patients with ABC from the perspective of the Brazilian public national health system. Methods: We calculated the incremental cost-effectiveness ratio (ICER) using a Markov model with progression-free survival, post-progression survival, and death states. We expressed ICER as incremental costs per progression-free life-year (PFLY) and quality-adjusted life-year (QALY) gained in a 10-year time horizon. We used parametric survival distributions fit to MONALEESA-7 data to generate survival distributions for progression-free and post-progression survival. The largest British preference study in breast cancer served as the basis to estimate health-state utilities. We estimated direct costs (ABC treatment, follow-up, monitoring, and adverse events) using Brazilian-specific values from public sources. An expert consensus panel determined the resource patterns required. We applied annual discounts of 5% to costs and QALYs. Results: Ribociclib + ET resulted in an incremental gain of 1.03 PFLYs and 0.80 QALYs at a cost of $37,319.31. The ICER of ribociclib + ET versus ET was $36,379.41 per PFLY gained and $46,590.79 per QALY gained. In deterministic sensitivity analysis, results were primarily affected by the annual discount rate, followed by the cost of ribociclib. In probabilistic sensitivity analysis, simulations agreed with the base-case. Conclusion: Ribociclib increased PFLYs and QALYs in patients with HR+/HER2- ABC when added to ET. Because Brazil does not have a formally defined cost-effectiveness threshold, other domains need to be considered for incorporation decisions, such as disease burden and humanistic impact on this young, economically active population. These findings may be useful in discussions for incorporation of ribociclib into the Brazilian public health system.

Association Between GATA3 and Histopathological and Immunohistochemical Parameters in Early-Infiltrating Breast Carcinomas.

Objective: This study evaluated the frequency of GATA-binding protein 3 (GATA3) expression in early breast cancer and its relationship with histopathological and immunohistochemical parameters. Materials and Methods: GATA3 was analysed by immunohistochemistry in histological sections of tumors from 105 female patients, with histological diagnosis of invasive breast carcinoma (BC), at clinical stages I, II and IIIA, who underwent primary surgical treatment. GATA3 nuclear expression was determined as the percentage of positive tumor cells and further categorized as high (positive expression in more than 95% of cells) or non-high (negative or low positive expression in up to 95% of tumor cells). GATA3 expression was analysed according to the patient age, tumor and node pathological stage, histological type, histological and nuclear grade, lymphovascular invasion, and estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), human epidermal growth factor 2 (HER2) status, and Ki-67 expression. Results: GATA3 expression was positive in 103 cases (98.1%). High expression was significantly associated with low histological and nuclear grade, positive hormonal receptors, and less proliferative activity based on Ki-67 expression. A prominent feature was that 94.7% of the ER-positive/HER2-negative cases presented high-GATA3 expression, as 94.0% of the tumors showing high-GATA3 were ER-positive. In ER-negative/HER2-positive or ER-negative/HER2- negative, high-GATA3 was present in 25% while 75% were non-high-GATA3 compared with ER-positive/HER2- negative (4.1%) and ER-positive/HER2-positive (20%). Proliferative activity in triple-negative breast cancer tended to be higher among tumors with low-GATA3, irrespective of AR expression. In the group of ER-positive/HER2-negative tumors only three cases were low-GATA3 (85% and 80%), both with high proliferative activity. Conclusion: High GATA3 expression is associated with favorable histopathologic and immunohistochemical BC prognostic factors.

Cost-effectiveness analysis of Oncotype DX from a Brazilian private medicine perspective: a GBECAM multicenter retrospective study.

Background: Oncotype DX (ODX) is a validated assay for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and 1-3 positive nodes (N1), hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC). Due to limited access to genomic assays in Brazil, treatment decisions remain largely driven by traditional clinicopathologic risk factors. ODX has been reported to be cost-effective in different health system, but limited data are available considering the reality of middle-income countries such as Brazil. We aim to evaluate the cost-effectiveness of ODX across strata of clinical risk groups using data from a dataset of patients from Brazilian institutions. Methods: Clinicopathologic and ODX information were analyzed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by clinicopathologic criteria were based on binary clinical risk categorization based on the Adjuvant! Algorithm. The ODX score was correlated with the indication of CT according to TAILORx and RxPONDER data. Two decision-tree models were developed. In the first model, low and high clinical risk patients were included while in the second, only high clinical risk patients were included. The cost for ODX and CT was based on the Brazilian private medicine perspective. Results: In all, 645 patients were analyzed; 411 patients (63.7%) had low clinical risk and 234 patients (36.3%) had high clinical risk disease. The ODX indicated low (<11), intermediate (11-25), and high (>25) risk in 119 (18.4%), 415 (64.3%), and 111 (17.2%) patients, respectively. Among 645 patients analyzed in the first model, ODX was effective (5.6% reduction in CT indication) though with an incremental cost of United States Dollar (US$) 2288.87 per patient. Among 234 patients analyzed in the second model (high clinical risk only), ODX led to a 57.7% reduction in CT indication and reduced costs by US$ 4350.66 per patient. Conclusions: Our study suggests that ODX is cost-saving for patients with high clinical risk HR+/HER2- eBC and cost-attractive for the overall population in the Brazilian private medicine perspective. Its incorporation into routine practice should be strongly considered by healthcare providers.

The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker.

Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.

Immunotherapy in Breast Cancer: Current Practice and Clinical Challenges.

Immunotherapy is currently approved for a subset of patients diagnosed with advanced triple negative breast cancer (TNBC), based on the phase III randomized controlled trial, IMpassion130. The anti-programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitor atezolizumab combined with nanoparticle albumin-bound (nab)-paclitaxel is currently the standard first-line therapy in patients with metastatic TNBC who have a PD-L1-positive peritumoral immune infiltrate. Although this approval is limited to only a subset of patients, strategies to expand indications in breast cancer for this treatment modality are being extensively evaluated. A substantial need exists for the identification of patient characteristics, disease settings, immune markers, ideal partners for combination with immune checkpoint inhibitors, and the ideal sequence with traditional anticancer therapies. Additionally, in light of the results of the KEYNOTE-522 study of adjuvant pembrolizumab in TNBC, evaluation of immunotherapy in the early disease setting is a subject of great interest. This review article discusses current knowledge on immune checkpoint inhibitors in clinical practice, and provides an overview of a variety of markers evaluated to predict benefit of immunotherapy and of promising new strategies to enhance immune response and enable more patients to benefit from immunotherapy.

CDK4/6 Inhibitors in Hormone Receptor-Positive Metastatic Breast Cancer: Current Practice and Knowledge.

Treatment paradigms in advanced hormone receptor (HR)-positive breast cancer were substantially transformed with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) approval. The addition of these drugs to endocrine treatment profoundly improved progression-free and overall survival. Additionally, other important endpoints, such as the response rate, time to chemotherapy, and a delay in quality of life deterioration, were positively impacted by CDK4/6 inhibitors' addition to the treatment of advanced HR-positive breast cancer. This review article will summarize current knowledge on CDK4/6 inhibitors in clinical practice for advanced HR-positive metastatic breast cancer, as well as describe recent efforts to more precisely characterize mechanisms of sensitivity and resistance to these drugs, both on the molecular and clinical characterization level.

Impact of Delayed Neoadjuvant Systemic Chemotherapy on Overall Survival Among Patients with Breast Cancer.

BACKGROUND: Delays in the initiation of therapy among patients with early stage breast cancer (BC) can negatively affect outcomes. Patients treated with neoadjuvant systemic chemotherapy (NSC) usually display tumors with high-risk features. Considering these high-risk characteristics and the evidence supporting adverse outcomes associated with delays in adjuvant chemotherapy initiation, we sought to determine whether a delay in NSC initiation is associated with overall survival (OS). METHODS: We identified patients diagnosed between January 1995 and December 2015 with invasive primary BC (stage I-III) who received NSC at MD Anderson Cancer Center. Patients were categorized according to their time from BC diagnosis to NSC (in days) into three subgroups: 0-30, 31-60, and ≥61 days. Primary endpoint was OS. Descriptive statistics and Cox's proportional hazard models were used. RESULTS: A total of 5,137 patients were included. Median follow-up was 6.5 years. The 5-year OS estimates according to time to NSC were 87%, 85%, and 83% in patients who received NSC within 0-30, 31-60, and ≥61 days after diagnosis, respectively (p = .006). In multivariable analysis, compared with time to NSC of 0-30 days, delayed NSC ≥61 days was associated with an increased risk of death (31-60 days: hazard ratio [HR] = 1.05 [95% confidence interval (CI) 0.92-1.19]; ≥61 days, HR = 1.28 [95% CI 1.06-1.54]). In stratified analyses, the association between delay in NSC initiation and increased risk of death was statistically significant for patients with stage I and II BC (31-60 days: HR = 1.22 [95% CI 1.02-1.47]; ≥61 days, HR = 1.41 [95% CI 1.07-1.86]) and among patients with HER2-positive tumors ( ≥61 days, HR = 1.86 [95% CI 1.21-2.86]). CONCLUSION: A delay in NSC initiation of more than 61 days after BC diagnosis was associated with an increased risk of death. Early initiation of NSC should be a priority; multidisciplinary teams must focus on coordination of care and patient-centered, timely treatment planning and delivery. IMPLICATIONS FOR PRACTICE: The results of this study showed that a delay in neoadjuvant systemic chemotherapy initiation of more than 61 days after breast cancer diagnosis is associated with an increased risk of death; therefore, efforts must focus on early initiation of therapy, which should be a priority. Multidisciplinary teams must enhance coordination of care and patient-centered, timely treatment planning and delivery.

Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds.

Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another non-cytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixed-effects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR]=0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p<0.001), which was most pronounced for the association between immunotherapy combinations and longer survival. Combinations also significantlyincreased the risk of high-grade toxicities (OR=2.42, 95%CI 1.98-2.97) (most notably for immunotherapy and small molecule inhibitors) and mortality at least possibly therapy related (OR: 1.33, 95%CI 1.15-1.53) (both p<0.001) (absolute mortality = 0.90% (single agent) versus 1.31% (combinations)) compared to single agents. In conclusion, combinations of non-cytotoxic drugs versus monotherapy in randomized cancer clinical trials attenuated safety, but increased efficacy, with the balance tilting in favor of combination therapy, based on the prolongation in survival.

Return to work after breast cancer diagnosis: An observational prospective study in Brazil.

BACKGROUND: In North America and Europe, return-to-work (RTW) rates vary among breast cancer (BC) survivors, from 24% to 66% and from 53% to 82% at 6 and 36 months after diagnosis, respectively. To date, there is a lack of data on RTW rates after BC diagnosis in Latin America. Therefore, the primary objectives of this study were to define RTW rates at 12 and 24 months after BC diagnosis and to identify the factors associated with RTW in this population. METHODS: In total, 125 employed women from a single institution with newly diagnosed BC were interviewed by telephone at 6, 12, and 24 months after diagnosis. Those who had inoperable or metastatic disease were excluded. RESULTS: Overall, RTW rates were 30.3% and 60.4% at 12 and 24 months after BC diagnosis, respectively. Most women reported that they received support from their employer, but only 29.1% reported having been offered work adjustments. In multivariate analysis, the factors associated with positive RTW outcomes included higher household income (odds ratio [OR], 17.76; 95% confidence interval [CI], 3.33-94.75; P = .001), breast-conserving surgery (OR, 9.77; 95% CI, 2.03-47.05; P = .004), and work adjustments (OR, 37.62; 95% CI, 2.03-47.05; P = .004). The factors associated with negative RTW outcomes included adjuvant endocrine therapy (OR, 0.11; 95% CI, 0.02-0.74; P = .023), and depression diagnosed after BC (OR, 0.07; 95% CI, 0.01-0.63; P = .017). CONCLUSIONS: RTW rates in the current study were lower than those observed in developed countries but similar to the rates among low-income Americans. Workplace adjustments, higher income, breast-conserving surgery, endocrine therapy, and depression after BC played an important role in the RTW decision.

Lessons From the Development of the Immune Checkpoint Inhibitors in Oncology.

Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program. Hence, some of them are getting marketing approval after preliminary trials. The model continues to rely on phase I trials, designed with traditional models for dose definition, although a substantial number of patients are treated during the dose expansion cohorts. We demonstrated that efficacy and safety are reasonably predicted from the dose-finding portion of phase I trials with these agents, assuring a low treatment-related mortality for patients throughout the development process. In this article, we further discuss and summarize these findings and update some recent approval information for immune checkpoint inhibitors.

Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785-94. ©2017 AACR.

Tumor-infiltrating lymphocytes in Breast Cancer and implications for clinical practice.

Breast Cancer (BC) can be classified using pathologic features, such as grade and tumor size. It can be categorized based on the gene expression profile, which identifies the distinct molecular subtype. More recently, stromal tissue has been recognized as an important modulator of tumor cell growth, pathogenesis, and progression. Immune cells could drive important clinical characteristics that affect BC outcomes. Subgroups of patients who have tumor-infiltrating lymphocytes in the stroma may have better response to chemotherapy and favorable long-term prognosis. Accumulating evidence shows that the immune system plays a crucial role in the outcomes of some BC subgroups, especially more aggressive, proliferative ones such as triple-negative and HER2-positive BC. This review article will present data on the role of lymphocyte infiltration in BC prognosis and response to therapy. This review will also introduce the reader to the challenges of applying this promising prognostic and predictive biomarker in clinical practice.

Trends in breast cancer surgery at Brazil's public health system.

BACKGROUND AND OBJECTIVES: To analyze time trend patterns in Breast Cancer (BC) surgeries performed at Brazil's Public Health System, known as SUS from 2008 to 2014. METHODS: Ecological study of time series, based on the database system from SUS. Information on surgical procedures performed for BC treatment was collected. Analysis of the absolute number of surgeries was performed using Poisson Regression through Jointpoint Regression, and the trends were calculated through the annual percentage change (APC), with a confidence interval (CI) of 95%, and statistical significance when P < 0.05. RESULTS: Data analysis from 193.596 breast surgeries revealed a reduced number of simple mastectomies (APC -4.4%; CI -7.4 to -1.4; P < 0.05); stable trends in radical mastectomy with lymphadenectomy (APC -1.0%; CI -2.4 to 0.5; P = 0.1) and breast conserving surgery (APC 0.4%; CI -1.6 to 2.4; P = 0.6). Also, we observed a reduced number of axillary lymphadenectomy dissection (APC -16.8%; CI -26.8 to -5.4; P < 0.05); increased trends in breast reconstruction with implants after 2011 (APC 9.1%; CI 0.1-18.8; P < 0.05) and with flaps after 2012 (APC 61.3%; CI 41.3-84.0; P < 0.05). The overall rate of patients with breast reconstruction increased from 15% in 2008 to 29.2% in 2014. CONCLUSIONS: We found a significant increase in breast reconstruction in public health system in Brazil, and also a reduction in simple mastectomy and axillary lymphadenectomy.

Clinical outcomes based on multigene profiling in metastatic breast cancer patients.

BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

The Association between EGFR and cMET Expression and Phosphorylation and Its Prognostic Implication in Patients with Breast Cancer.

EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the median was selected as a cut-off after sensitivity analyses. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall survival (OS). Cox-proportional hazards models were utilized to determine associations between EGFR and cMET with outcomes. Mean age was 58 years with 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors (HER2+). HER2+ was associated with higher EGFR expression and phosphorylation, compared to HR and TN (p<0.05). High EGFR expression was associated with higher phosphorylated-cMET (p-cMET) but not cMET (ANOVA p-cMET p < 0.001; cMET p = 0.34). The same association was found with high phosphorylated-EGFR (p-EGFR) group at Tyr992 and Tyr1068 (both p < 0.001). High expressions in either of two p-EGFRs were linked with higher cMET as well (all p<0.001). For the TN subtype, high expression in EGFR and p-EGFR at Tyr992 but not at Tyr1068 was associated with higher p-cMET (p<0.00, p = 0.012, p = 0.4 respectively). Only high expression in p-EGFR at Tyr992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression in p-EGFR at Tyr1068 but not at Tyr992 was associated with higher cMET and p-cMET (cMET p = 0.023;p-cMET p<0.001). Four subgroups of patients defined by dichotomized EGFR/p-EGFR and cMET/p-cMET level demonstrated no significant differences in survival. In multivariate analyses, neither cMET nor EGFR expression/activation was found to be an independent prognostic factor in survival outcome.

An uncommon response to metronomic therapy in a heavily pretreated patient with metastatic carcinosarcoma: a case report.

BACKGROUND: Uterine carcinosarcoma is well known for its aggressive behavior. There is little evidence regarding the gold standard combination chemotherapy in metastatic or locally advanced carcinosarcoma, due to poor survival outcomes obtained with conventional scheduled chemotherapy. This case report represents the first-ever reported objective response to a metronomic chemotherapy regimen and adds to the current literature. CASE PRESENTATION: We describe a case of a Caucasian woman diagnosed with metastatic carcinosarcoma that had already been treated with multiple lines of conventional chemotherapy, with progressive disease. This patient had a surprising clinical and imaging response when treated with oral metronomic cyclophosphamide. CONCLUSIONS: We reviewed the mechanism of action implicated in metronomic chemotherapy, and correlated it with the biology of disease in carcinosarcoma. This information may add to the current literature, providing important insights to future clinical trials in this patient population.