Pathological complete response in breast cancer patients receiving neoadjuvant chemotherapy.

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Liquid Biopsy in Breast Cancer: Molecular Characterization and Support to Clinical Management

The classical paradigm of breast cancer (BC) management has been challenged by recent advances in the understanding of molecular biology, which is increasingly encouraging attempts to move away from protocol-based in favor of a personalized approach. This project aimed to test circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) to characterize the disease, and monitor patients with BC including both non-invasive and invasive cases. For this purpose, 41 patients with newly diagnosed ductal carcinoma in situ (DCIS), and 61 triple negative BC (TNBC) patients treated with neoadjuvant chemotherapy were analyzed. Primary tumor mutations identified by targeted- gene sequencing were validated, and tracked in 182 plasma samples longitudinally collected at multiple time-points by droplet-digital Polymerase Chain Reaction. In recurrent TNBC patients, plasma DNA underwent direct targeted-gene assay, and CTCs were analyzed for Copy Number Alterations (CNAs). In DCIS patients, ctDNA from baseline samples was evaluable in 71% of cases, with Variant Allele Frequency (VAF) values ranging between 0.001% and 5%, independently of clinico-pathological features, and likewise at initial diagnosis and at relapse. In TNBC patients, the number of primary tumor mutations showed a downward trend after treatment; proficient genes involved in the immune pathways were associated to response; and surgical samples of non responsive cases presented alterations in druggable pathways. ctDNA after treatment was associated with increased risk of relapse, and its prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 (HR 1.91; 95%CI 0.51-7.08). During follow-up, ctDNA was undetectable in non-recurrent cases. Conversely, ctDNA was detected in 83% of recurrent cases, and antedated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed loco-regional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling, and immune response. These findings extend the value of liquid biopsy to further clinical scenarios by reporting - unlike previous studies - the presence of ctDNA in noninvasive BC; and substantiate the development of ctDNA in invasive BC as an exploitable tool, either alone or with CTCs, for personalized TNBC management

Predictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab

CD36 expression; Breast cancer; Neoadjuvant trastuzumabExpresión CD36; Cáncer de mama; Trastuzumab neoadyuvanteExpressió CD36; Càncer de mama; Trastuzumab neoadjuvantBackground Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. Methods Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere. Results In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib–based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568). Conclusions High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.The NeoALTTO trial was sponsored by GlaxoSmithKline; the NeoSphere trial was sponsored by F. Hoffmann-La Roche. Our subanalysis of the NeoALTTO and NeoSphere trials received no funding by pharmaceutical companies

End-of-neoadjuvant treatment circulating microRNAs and HER2-positive breast cancer patient prognosis: An exploratory analysis from NeoALTTO

Cáncer de mama HER2 positivo; MicroARN circulante; Tratamiento neoadyuvanteCàncer de mama HER2-positiu; MicroARN circulant; Tractament neoadjuvantHER2-positive breast cancer; Circulating microRNA; Neoadjuvant treatmentBackground: The absence of breast cancer cells in surgical specimens, i.e., pathological complete response (pCR), is widely recognized as a favorable prognostic factor after neoadjuvant therapy. In contrast, the presence of disease at surgery characterizes a prognostically heterogeneous group of patients. Here, we challenged circulating microRNAs (miRNAs) at the end of neoadjuvant therapy as potential prognostic biomarkers in the NeoALTTO study. Methods: Patients treated within the trastuzumab arm (i.e., pre-operative weekly trastuzumab for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks; post-operative FEC for 3 cycles followed by trastuzumab up to complete 1 year of treatment) were randomized into a training (n= 54) and testing (n= 72) set. RT-PCR-based high-throughput miRNA profile was performed on plasma samples collected at the end of neoadjuvant treatment of both sets. After normalization, circulating miRNAs associated with event free survival (EFS) were identified by univariate and multivariate Cox regression model. Results: Starting from 23 circulating miRNAs associated with EFS in the training set, we generated a 3-circulating miRNA prognostic signature consisting of miR-185-5p, miR-146a-5p, miR-22-3p, which was confirmed in the testing set. The 3-circulating miRNA signature showed a C-statistic of 0.62 (95% confidence interval [95%CI] 0.53-0.71) in the entire study cohort. By resorting to a multivariate Cox regression model we found a statistical significant interaction between the expression values of miR-194-5p and pCR status (p.interaction =0.005) with an estimate Hazard Ratio (HR) of 1.83 (95%CI 1.14- 2.95) in patients with pCR, and 0.87 (95%CI 0.69-1.10) in those without pCR. Notably, the model including this interaction along with the abovementioned 3-circulating miRNA signature provided the highest discriminatory capability with a C-statistic of 0.67 (95%CI 0.58-0.76). Conclusions: Circulating miRNAs are informative to identify patients with different prognosis among those with heterogeneous response after trastuzumab-based neoadjuvant treatment, and may be an exploitable tool to select candidates for salvage adjuvant therapy.The NeoALTTO study was sponsored by GlaxoSmithKline; Lapatinib is an asset of Novartis AG as of March 2, 2015. This sub-study was supported by the Italian Ministry of Health to SC. No grant number is applicable, funds were obtained through a law that allows tax-payers to allocate the 5 × 1000 share of their payments to research

Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial

Endocrine therapy; Neutropenia; Venous thromboembolismTerapia endocrina; Neutropenia; Tromboembolismo venosoTeràpia endocrina; Neutropènia; Tromboembolisme venósBackground Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. Materials and Methods Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant–palbociclib (FP) or letrozole–palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. Results A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P < .01). Conclusion The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy.The PARSIFAL study was sponsored by Medica Scientia Innovation Research S.L. (MEDSIR) and funded by Pfizer, who had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Fulvestrant was provided by AstraZeneca

Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit

BACKGROUND: Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab. METHODS: Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data. RESULTS: Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours. CONCLUSIONS: Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes

Implication of breast cancer phenotype for patients with leptomeningeal carcinomatosis

Abstract Background We aimed to study the implications of breast cancer (BC) subtypes for the development and prognosis of leptomeningeal carcinomatosis (LC). Patients and methods Data from the breast cancer patients diagnosed with LC between 2005 and 2010 were retrieved. Patients were classified in luminal A, B, HER2 positive and triple negative (TN) and their BC diagnosis, treatment, and outcome were analyzed according to each subtype. Pearson's chi-square and Fisher's exact test were used for categorical variables. Survival analyses were performed by Kaplan–Meier method and compared with the log-rank test. Results A total of 38 BC patients were identified, with a median age of 54.8 years (range 36–79). The proportion of luminal A, B, HER2 positive and TN was 18.4%, 31.6%, 26.3% and 23.7%, respectively. LC was the first evidence of metastatic disease in 5 BC patients. Twenty patients received the systemic chemotherapy, with 16 (80%) whole brain radiotherapy (WBRT). Nine patients received only WBRT. TN patients had the shorter interval between metastatic breast cancer diagnosis and the development of LC. Median survival after the diagnosis of LC (OSLC) was 2.6 months (range 1.2–6.4), and did not differ across breast cancer subtypes. In univariate analysis, performance status (ECOG = 0–2) and chemotherapy were prognostic for OSLC, but only the treatment stood as an independent prognostic factor in multivariate analysis. Conclusions Breast cancer subtype influences the timing of LC appearance, but not OSLC. Patients with LC from breast cancer should be offered systemic treatment, as it appears to associate with the improved outcome. New therapeutic strategy, including, targeted and intrathecal therapy are deserved for BC patients with LC

HER2/neu expression and hormonal therapy in early breast cancer: can muddy waters become clear?

We have read with great interest the paper by Love et al [1] about the relationship between HER2/neu expression and response to adjuvant endocrine therapy in premenopausal women with breast cancer. Whereas HER2/neu and estrogen receptor (ER) are believed to be important cell survival and cell death factors in human breast cancer, if and how they interact to confer resistance to hormone therapy is still in debate. Several observations are consistent with a major role for c-erbB2 in the development of endocrine resistance, considering also the HER2/neu acquired expression durin

Modeling anti-IL-6 therapy using breast cancer patient-derived xenografts

The pleiotropic cytokine IL-6 accelerates the progression of breast cancer in a variety of preclinical models through the activation of the STAT3 (signal transducer and activator of transcription 3) signaling pathway. However, the proportion of breast cancers sensitive to anti-IL-6 therapies is not known. This study evaluates the efficacy of anti-IL-6 therapies using breast cancer patient derived xenografts (PDXs). During the generation of our collection of PDXs, we showed that the successful engraftment of tumor tissue in immunodeficient mice correlates with bad prognosis. Four PDXs out of six were resistant to anti-IL-6 therapies and the expression of IL-6, its receptor or the levels of phospho-STAT3 (the active form of the signal transducer) did not correlate with sensitivity. Using cell cultures established from the PDXs as well as samples from in vivo treatments, we showed that only tumors in which the activation of STAT3 depends on IL-6 respond to the blocking antibodies. Our results indicate that only a fraction of breast tumors are responsive to anti-IL-6 therapies. In order to identify responsive tumors, a functional assay to determine the dependence of STAT3 activation on IL-6 should be performed