Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer

We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; >= 50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBCPeer reviewe

A clinical evaluation of an ex vivo organ culture system to predict patient response to cancer therapy

IntroductionEx vivo organ cultures (EVOC) were recently optimized to sustain cancer tissue for 5 days with its complete microenvironment. We examined the ability of an EVOC platform to predict patient response to cancer therapy.MethodsA multicenter, prospective, single-arm observational trial. Samples were obtained from patients with newly diagnosed bladder cancer who underwent transurethral resection of bladder tumor and from core needle biopsies of patients with metastatic cancer. The tumors were cut into 250 μM slices and cultured within 24 h, then incubated for 96 h with vehicle or intended to treat drug. The cultures were then fixed and stained to analyze their morphology and cell viability. Each EVOC was given a score based on cell viability, level of damage, and Ki67 proliferation, and the scores were correlated with the patients’ clinical response assessed by pathology or Response Evaluation Criteria in Solid Tumors (RECIST).ResultsThe cancer tissue and microenvironment, including endothelial and immune cells, were preserved at high viability with continued cell division for 5 days, demonstrating active cell signaling dynamics. A total of 34 cancer samples were tested by the platform and were correlated with clinical results. A higher EVOC score was correlated with better clinical response. The EVOC system showed a predictive specificity of 77.7% (7/9, 95% CI 0.4–0.97) and a sensitivity of 96% (24/25, 95% CI 0.80–0.99).ConclusionEVOC cultured for 5 days showed high sensitivity and specificity for predicting clinical response to therapy among patients with muscle-invasive bladder cancer and other solid tumors

Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.Peer reviewe

Adjuvant systemic therapy in breast cancer: Quo vadis?

The premise that breast cancer (BC) has a tendency toward early systemic dissemination, together with empirical findings showing that drugs given after breast tumor surgery improve outcome, led to the development of systemic adjuvant therapy. This strategy, which started more than 50 years ago, revolutionized BC treatment and improved patient outcome in a substantial way. However, in recent years, several large trials that incorporated new systemic treatments in the adjuvant setting of BC failed to demonstrate a benefit. In the present review, we discuss the progress made in the adjuvant treatment of BC in the past decade, the possible reasons for the recent failures, and practical strategies that may be incorporated in the design of future trials.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Role Played by Microphthalmia Transcription Factor Phosphorylation and Its Zip Domain in Its Transcriptional Inhibition by PIAS3

Mutation of microphthalmia transcription factor (MITF) results in deafness, bone loss, small eyes, and poorly pigmented eyes and skin. A search for MITF-associated proteins, using a mast cell library that was screened with a construct that encodes the basic helix-loop-helix leucine zipper (Zip) domain of MITF, resulted in the isolation of the STAT3 inhibitor, PIAS3. PIAS3 functions in vivo as a key molecule in suppressing the transcriptional activity of MITF. Here, we report that the Zip domain is the region of MITF that is involved in the direct interaction between MITF and PIAS3. Additionally, we investigated the effect of phosphorylation of MITF on its interaction with PIAS3. We found that phosphorylation of MITF on serines in positions 73 and 409 plays an important role in its association with PIAS3. This effect was profound with phosphorylation on Ser409, which significantly reduced the inhibitory effect of PIAS3 on MITF and also modulated the transcriptional activity of MITF. Thus, phosphorylation of MITF could be considered a fine, and alternative, tuning of its transcriptional machinery

Interplay between MITF, PIAS3, and STAT3 in Mast Cells and Melanocytes

Microphthalmia transcription factor (MITF) and STAT3 are two transcription factors that play a major role in the regulation of growth and function in mast cells and melanocytes. In the present study, we explored the MITF-PIAS3-STAT3 network of interactions, how these interactions regulate gene expression, and how cytokine-mediated phosphorylation of MITF and STAT3 is involved in the in vivo interplay between these three proteins. In NIH 3T3 cells stimulated via gp130 receptor, transfected MITF was found to be phosphorylated at S409. Such phosphorylation of MITF leads to PIAS3 dissociation from MITF and its association with STAT3. Activation of mouse melanoma and mast cells through gp130 or c-Kit receptors induced the mobilization of PIAS3 from MITF to STAT3. In mast cells derived from MITF(di/di) mice, whose MITF lacks the Zip domain (PIAS3-binding domain), we found downregulation in mRNA levels of genes regulated by either MITF or STAT3. This regulatory mechanism is of considerable importance since it is likely to advance the deciphering of a role for MITF and STAT3 in mast cells and melanocytes

The History of Early Breast Cancer Treatment

“The story of cancer is the story of human ingenuity, resilience, and perseverance, but also of hubris, paternalism, and misperception” (Siddhartha Mukherjee). The present review discusses the evolution of early breast cancer (BC) treatment philosophy in the last 50 years and the shift from an emphasis on local therapy to an emphasis on systemic precision treatment options

Metastatic breast cancer: The Odyssey of personalization

Metastatic breast cancer is the most frequent cause of cancer death for women worldwide. In the last 15 years, a large number of new agents have entered clinical use, a result of the dramatic increase in our understanding of the molecular underpinnings of metastatic breast cancer. However, while these agents have led to better outcomes, they are also at the root cause of increasing financial pressure on healthcare systems. Moreover, decision making in an era where every year new agents are added to the therapeutic armamentarium has also become a significant challenge for medical oncologists. In the present article, we will provide an ample review on the most recent developments in the field of treatment of the different subtypes of metastatic breast cancer with a critical discussion on the slow progress made in identifying response biomarkers. New hopes in the form of ctDNA monitoring and functional imaging will be presented.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Is the differentiation into molecular subtypes of breast cancer important for staging, local and systemic therapy, and follow up?

Breast cancer complexity has long been known and investigated. After a first classification of the disease based on histology features, starting from the 1980s breast cancers have been distinguished on the basis of oestrogen receptor expression and later according to HER2. By 2000 the "microarray revolution" had shown that the phenotypic differences between breast cancers were a reflection of their mRNA expression profiles, while the more recent "genomic revolution" is revealing the genomic bases of breast cancer heterogeneity. However, how this huge amount of data and knowledge translate into clinically relevant practice is currently not clear. In the present review we discuss how the different breast cancer classification methods might translate into improved clinical guidelines with regard to staging, therapy, and follow up of patients with breast cancer.SCOPUS: re.jinfo:eu-repo/semantics/publishe