Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers

Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual’s genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence

Evaluation of adaptive and innate immune mechanisms of action of Pertuzumab plus Trastuzumab against HER2-positive breast cancer

I linfociti infiltranti il tumore (TILs) sono associati ad una maggiore efficacia terapeutica della terapia neoadiuvante basata su trastuzumab / pertuzumab in pazienti con carcinoma mammario HER2-positivo. Il trastuzumab sottocutaneo (SC) ha dimostrato un'efficacia non inferiore rispetto alla somministrazione endovenosa (EV), con un profilo di sicurezza simile. È interessante notare come il trastuzumab SC è stato osservato essere più immunogeno del trastuzumab EV e agire a diversi livelli immunologici. Pertanto, modificando la modalità di somministrazione di trastuzumab, si potrebbe interferire sul sistema immunitario a diversi livelli ed esercitare un'immunomodulazione favorevole nel tumore mammario HER2-positivo. In questo studio non comparativo, di fase II, randomizzato, nel setting neoadiuvante, erano eleggibili pazienti con diagnosi di carcinoma mammario HER2-positivo, istologicamente confermato, non precedentemente trattato, in stadio localmente avanzato, infiammatorio o iniziale. Le pazienti sono state inizialmente trattate con chemioterapia a base di 5-fluoruracile, epirubicina e ciclofosfamide (FEC) per 3 cicli. Quindi sono state assegnate in modo casuale in un rapporto 1: 1 a ricevere docetaxel + pertuzumab EV + trastuzumab EV per 4 cicli (braccio A) o docetaxel + pertuzumab EV + trastuzumab SC per 4 cicli (braccio B). Dopo l'intervento chirurgico, tutte le pazienti hanno ricevuto trastuzumab per 14 cicli utilizzando la stessa formulazione (SC o EV) della fase preoperatoria. L'endpoint primario dello studio era il tasso di TILs stromali (sTILs) nella malattia residua dopo intervento chirurgico. I campioni chirurgici della biopsia iniziale sul tumore primitivo e post-trattamento sono stati analizzati per quantificare i TILs. Sono stati inoltre raccolti dei campioni di sangue periferico, a tre punti-tempo predeterminati durante la terapia neoadiuvante, per l'analisi della concentrazione e dell'attività delle cellule linfocitarie tumore-specifiche. Fattibilità, efficacia e sicurezza dello studio sono infine state valutate. Tra novembre 2016 e settembre 2017, secondo un progetto in due fasi di Simon, abbiamo arruolato 65 pazienti, di cui due ritenute non ammissibili per lo studio. Pertanto sono state valutate complessivamente 63 pazienti (31 nel braccio A e 32 nel braccio B) per l’analisi degli endpoints primari e secondari. I tassi di risposta patologica completa ottenuti dopo trattamento neoadiuvante sono stati del 64,5% nel braccio A e del 59,4% nel braccio B, rispettivamente. Gli eventi avversi più comuni di grado 3 o superiore sono stati neutropenia (15 [48,4%] pazienti nel braccio A e 11 [34,4%] nel braccio B), neurotossicità (1 [3,2%] e 2 [6,2%], rispettivamente) e diarrea (1 [3,2%] e 1 [3,1%], rispettivamente). Non ci sono stati casi di insufficienza cardiaca congestizia. Durante l'intervento chirurgico, 11 pazienti nel braccio A e 13 pazienti nel braccio B sono risultate valutabili per l'analisi dei TILs. Come parametro di cut-off è stato utilizzato il valore mediano dei sTILs (7,5%) riscontrato nelle biopsie tumorali pre-trattamento e sono stati osservati alti livelli di sTILs nel 27,3% e nel 46,1% dei tumori residui dopo trattamento neoadiuvante nei bracci A e B, rispettivamente. È interessante notare come sia emersa una correlazione inversa significativa tra l'espressione di PD-L1 sui sTILs prima del trattamento neoadiuvante e il co-recettore CD3 delle cellule T espresso su sTILs post-trattamento (ρ = -0,70 di Pearson). Questa correlazione è risultata particolarmente evidente nel braccio B (ρ = -0,85). La terapia neoadiuvante con trastuzumab SC o EV in associazione con pertuzumab e chemioterapia ha dimostrato un effetto significativo sull'espressione di sTILs su tessuto tumorale dopo intervento chirurgico. In particolare il braccio B, a cui è stato somministrato il trastuzumab SC, ha mostrato sia un più rilevante arricchimento di sTILs nel residuo tumorale post-trattamento, sia un più significativo incremento delle cellule CD3 su sangue periferico. I risultati ottenuti suggeriscono un ruolo della somministrazione sottocutanea di anticorpi anti-HER2 nel determinare variazioni immunofenotipiche favorevoli della risposta immunitaria dell’ospite nelle pazienti affette da tumore mammario HER2-positivo in stadio iniziale con residuo di malattia dopo trattamento neoadiuvante.Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with increased therapeutic efficacy of trastuzumab/pertuzumab-based neoadjuvant therapy (NT) in patients (pts) with HER2-positive breast cancer (BC). Subcutaneous (SC) trastuzumab has non-inferior efficacy to intravenous (IV) administration, with a similar safety profile. Interestingly, SC trastuzumab has been observed to be more immunogenic than IV trastuzumab and act at different immunologic levels. Therefore, by modifying the modality of administration of trastuzumab, it could be possible to interfere with different immune pathways and exert a favorable immunomodulation in HER2-positive BC. In this non-comparative, phase II, neoadjuvant, randomized study, patients were eligible if they had previously untreated, histologically confirmed, locally advanced, inflammatory, or early-stage HER2-positive BC. Patients were treated with 5-fluoruracil, epirubicin, cyclophosphamide (FEC) chemotherapy for 3 cycles. Then they were randomly assigned in a 1:1 ratio to receive docetaxel + pertuzumab IV + trastuzumab IV for 4 cycles (arm A) or docetaxel + pertuzumab IV + trastuzumab SC for 4 cycles (arm B). Post-surgery, all patients received trastuzumab for 14 cycles using the same formulation (SC or IV) of the preoperative phase. The primary endpoint was the rate of stromal TILs (sTILs) on residual disease after surgery. Tumor biopsy and post-treatment surgical samples were centrally analyzed for TILs. Blood samples were also collected during NT for tumor-specific lymphocyte cell activity analysis. Feasibility, efficacy and safety were also evaluated. Between November 2016 and September 2017, according to an adaptive Simon's two-stage optimal design, we enrolled 65 pts, of whom two were deemed ineligible for the study. Thus, 63 patients (31 in arm A and 32 in arm B) were assessed for the primary and secondary endpoints. The pathologic complete response (pCR; no invasive tumor in breast and axilla) rates were 64.5% in arm A, and 59.4% in arm B. The most common adverse events of grade 3 or higher were neutropenia (15 [48.4%] patients in arm A, and 11 [34.4%] in arm B), neurotoxicity (1 [3.2%], and 2 [6.2%], respectively), and diarrhea (1 [3.2%], and 1 [3.1%], respectively). There were no events of congestive heart failure. At surgery, 11 patients in arm A and 13 patients in arm B were evaluable for TIL analysis. The median value of sTILs (7.5%) on pre-treatment tumor biopsies was used as the cut-off value, and high sTIL levels were observed in 27.3% and in 46.1% of residual tumors after treatment arm A and B, respectively. Interestingly, a significant inverse correlation was observed between PD-L1 expression on pretreatment sTILs and the T cell co-receptor CD3 expressed on post-treatment sTILs (Pearson’s ρ = -0.70). This finding was particularly evident in the arm B group (ρ = -0.85). NT with either SC or IV trastuzumab in combination with pertuzumab and chemotherapy had a significant effect on sTIL expression at surgery. In particular, the SC trastuzumab-based arm exerted the most relevant enrichment of sTILS in post-treatment residual tumors and a greater rise of CD3 cells on peripheral good. These findings suggest a role for the SC administration of anti-HER2 mAbs in determining favorable variations of host immune response parameters among patients with HER2-positive early BC who had residual disease after NT

Colony-stimulating factors for febrile neutropenia

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Chemotherapy in metastatic renal cell carcinoma today? A systematic review

The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20-25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed. \ua9 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens

Background: HER2-amplified breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinico-histological characteristics and prognosis of this subgroup of patients. Materials and Methods: Using a retrospective matched cohort design, we collected data from 728 women who were diagnosed with breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinical and histological characteristics of the primary tumor, time to relapse, and survival were analyzed by BRCA and HER2 status. Results: One hundred and twenty HER2-positive, BRCA mutated cases were evaluated with respect to three control groups: HER2-positive, BRCA wild-type (n=136); HER2-negative, BRCA-mutated (n=226); HER2-negative, BRCA wild-type (n=246). Breast cancers with hormone receptor-negative status or high histologic grade (odds ratio=1.7; 95% confidence interval [CI]: 1.0-2.9) were more likely HER2-positive, with no restriction by BRCA mutation status. Disease-free and overall survival for HER2-positive, BRCA mutated cases were lower than those for the other subgroups. An interaction between BRCA mutations and HER2-positive status was found for poorer overall survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Germline BRCA mutations confer worse prognosis in patients with HER2-positive breast cancer. Ongoing trials testing novel therapeutic approaches (e.g. anti-HER2 therapies combined with PARP inhibitors) are warrante

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer

Ki67 as a Predictor of Response to PARP Inhibitors in Platinum Sensitive BRCA Wild Type Ovarian Cancer: The MITO 37 Retrospective Study

Background: There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC). Methods: MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010–2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off. Results: A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0–99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5 % PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials. Conclusions: Ki67 at diagnosis did not discriminate responders to PARPi