Rassegna della letteratura: gennaio/marzo 2020
Biologia, genetica, anatomia patologica e fattori prognostici
A 3-gene biomarker signature to predict response to taxane-based neoadjuvant chemotherapy in breast cancer.
Kallarackal J, Burger F, Bianco S et Al. – PLoS One. 2020 Mar 20;15(3):e0230313..
Breast cancer is the most common cancer in women worldwide, affecting one in eight women in their lifetime. Taxane-based chemotherapy is routinely used in the treatment of breast cancer. The purpose of this study was to develop and validate a predictive biomarker to improve the benefit/risk ratio for that cytotoxic chemotherapy. We explicitly strived for a biomarker that enables secure translation into clinical practice. We used genome-wide gene expression data of the Hatzis et al. discovery cohort of 310 patients for biomarker development and three independent cohorts with a total of 567 breast cancer patients for validation. We were able to develop a biomarker signature that consists of just the three gene products ELF5, SCUBE2 and NFIB, measured on RNA level. Compared to Hatzis et al., we achieved a significant improvement in predicting responders and non-responders in the Hatzis et al. validation cohort with an area under the receiver operating characteristics curve of 0.73 [95% CI, 69%-77%]. Moreover, we could confirm the performance of our biomarker on two further independent validation cohorts. The overall performance on all three validation cohorts expressed as area under the receiver operating characteristics curve was 0.75 [95% CI, 70%-80%]. At the clinically relevant classifier’s operation point to optimize the exclusion of non-responders, the biomarker correctly predicts three out of four patients not responding to neoadjuvant taxane-based chemotherapy, independent of the breast cancer subtype. At the same time, the response rate in the group of predicted responders increased to 42% compared to 23% response rate in all patients of the validation cohorts.
Prolactin receptor expression as a novel prognostic biomarker for triple negative breast cancer patients.
Motamedi B, Rafiee-Pour HA, Khosravi MR et Al. – Ann Diagn Pathol. 2020 Mar 13;46:151507.
Prolactin receptor (PRLR) is a novel emerging prognostic biomarker in different cancers, especially in breast cancer. However, there is limited information about the association of PRLR expression and triple-negative breast cancers (TNBC) prognosis. In this study, 80 TNBC patients were evaluated for PRLR expression by immunohistochemistry. The correlation of PRLR expression with clinicopathological features, patient recurrence, and survival was investigated. PRLR expression was considered positive if >10% of tumor cells were stained. The Fisher’s exact test was used to analyze PRLR expression relation with the clinicopathological parameters. Survival distribution was estimated by the Kaplan-Meier method. Positive immunoreactivity for PRLR was observed in 50 out of 80 (62%) specimens. Although expression of PRLR was associated with TNBC patients’ stage, no-correlation was observed between its expression and tumor size, grade, lymph node status, and Ki-67 expression. In addition, patients with positive expression of PRLR exhibited lower recurrence (P = 0.0027) and higher overall survival (P = 0.0285) in comparison with negative expression group. In multivariate analyses, positive expression of PRLR was an independent prognostic marker for lower recurrence (P < 0.001) and higher overall survival (P < 0.001). Therefore, PRLR plays a crucial role in TNBC and has to be considered as an independent prognostic biomarker for TNBC patients.
Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial.
Gennari A, Foca F, Zamarchi R et Al. – Breast Cancer Res Treat. 2020 Mar 21.
Background: To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients
Methods: CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses.
Results: Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found
Conclusions: Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies
Prospective Evaluation of Universal BRCA Testing for Women With Triple-Negative Breast Cancer.
Emborgo TS, Saporito D, Muse KI et Al. – JNCI Cancer Spectr. 2020 Jan 20;4(2)
Background: Limited published literature exists on women with triple-negative breast cancer (TNBC) diagnosed over the age of 60 years with breast cancer gene (BRCA) pathogenic variants. Our study determined whether the rate of BRCA pathogenic variants in a prospective cohort of TNBC patients outside the definition of current clinical genetic testing (GT) guidelines warrants a change in recommendations.
Methods: A prospective study of 395 women with TNBC underwent genetic counseling and 380 (96.2%) underwent clinical BRCA GT regardless of age of diagnosis beginning January 2014 to October 2015 at The University of Texas MD Anderson Cancer Center, Houston. TNBC patients older than 60 years who did not meet clinical GT guidelines had comprehensive sequencing and large rearrangement GT as part of the research protocol.
Results: Fifty-one of 380 (13.4%) women with TNBC who underwent clinical BRCA GT were BRCA positive. Of the 86 patients diagnosed at age over 60 years and underwent GT, only two (2.3%) were positive for BRCA. These two patients would have met clinical testing criteria due to family or ancestral history.
Conclusions: Our study does not support universal BRCA testing for TNBC patients diagnosed older than 60 years as their only risk factor for a BRCA pathogenic variant. Both of the positive BRCA patients older than 60 years identified would have met current National Comprehensive Cancer Network criteria for testing. Therefore, our study demonstrates that the National Comprehensive Cancer Network guidelines provide sufficient criteria for identifying BRCA pathogenic variants in women with TNBC at 60 years or younger.
Gene expression profiling identified TP53MutPIK3CAWild as a potential biomarker for patients with triple-negative breast cancer treated with immune checkpoint inhibitors.
Cheng J, Ding X, Xu S et Al – Oncol Lett. 2020 Apr;19(4):2817-2824.
Background: Triple-negative breast cancer (TNBC) accounts for 15-30% of all breast cancer cases and is clinically difficult to treat due to the lack of hormone or human epidermal growth factor receptor 2 receptors, which are usually targeted by the most successful therapeutic approaches. Immune checkpoint inhibitors (ICIs) have offered long-term survival benefits in several types of solid tumors, however with low response rates. Thus, there is an urgent need to develop feasible biomarkers for identifying patients with TNBC, who are responsive. The present study demonstrated that the immune microenvironment of TNBC has the highest expression of immunoregulatory molecules among all pathologic types. The tumor mutation burden (TMB) of TNBC was not strongly correlated with cytolytic activity and showed no significant associations with different degrees of immune cell infiltration and TMB. The machine learning method divided patients with TNBC into two groups characterized by ‘hot’ and ‘cold’ tumors, according to whether immune-associated genes were highly expressed, and different responses to immunotherapy were seen between these two groups. Furthermore, patients with a TP53MutPIK3CAWild genotype demonstrated favorable immunotherapy-responsive signatures and may have improved outcomes with ICIs. In conclusion, the present study revealed that TP53 and PIK3CA may be appropriate biomarkers to screen for patients who would benefit most from ICIs, which could guide precise immunotherapy for patients with TNBC.
Genetic alterations in the PI3K/AKT pathway and baseline AKT activity define AKT inhibitor sensitivity in breast cancer patient-derived xenografts.
Gris-Oliver A, Palafox M, Monserrat L et Al. – Clin Cancer Res. 2020 Mar 27.
Background: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.
Methods: Genetic and proteomic markers were analyzed in HER2-negative patient-derived xenografts (PDXs) and patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.
Results: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTORC1-activating alterations, e.g. in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64 to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K.
Conclusions: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer
Integrated Survival Analysis of mRNA and microRNA Signature of Patients with Breast Cancer Based on Cox Model.
Zhang W, Zhang Y. J Comput Biol. 2020 Mar 18.
Expression and clinical significance of MAPK and EGFR in triple-negative breast cancer.
Jiang W, Wang X, Zhang C, Xue L, Yang L. Oncol Lett. 2020 Mar;19(3):1842-1848.
Integrative Analyses of Multilevel Omics Reveal Preneoplastic Breast to Possess a Molecular Landscape That is Globally Shared with Invasive Basal-Like Breast Cancer (Running Title: Molecular Landscape of Basal-Like Breast CancerProgression).
Ju Z, Bhardwaj A, Embury MD, Singh H – Cancers (Basel). 2020 Mar 19;12(3).
Characteristics of sclerosing adenosis mimicking breast carcinoma.
Liu W, Li W, Li Z, Shi L, Zhao P et Al – Res Treat. 2020 Mar 29.
Molecular natural history of breast cancer: Leveraging transcriptomics to predict breast cancer progression and aggressiveness.
Cook DJ, Kallus J, Jörnsten R, Nielsen J. – Cancer Med. 2020 Mar 23