ABSTRACT
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.
Subject(s)
Genes, BRCA2 , Ovarian Neoplasms , Female , Humans , Ovarian Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Recombinational DNA Repair , DNA Breaks, Double-Stranded , Poly(ADP-ribose) Polymerases/geneticsABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab are effective for all stages of HER2-positive breast cancer (BC). However, intrinsic or acquired resistance to these drugs may occur in a significant number of patients (pts) and, except for HER2 status, no validated predictive factors of response/resistance have been identified to date. This lack is in part due to the not yet fully elucidated mechanism of action of mAbs in vivo. Increasing evidence suggests a significant contribution of both innate and adaptive immunity to the antitumor effects of mAbs. The aim of this review was to describe the role of innate and adaptive immunity in the efficacy of anti-HER2 mAbs and to report known and novel strategies to be used for optimizing immune effects of anti-HER2 therapies for HER2-positive BC.
Subject(s)
Adaptive Immunity , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms , Receptor, ErbB-2/antagonists & inhibitors , Trastuzumab/therapeutic use , Antibodies, Monoclonal/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/immunology , Humans , Receptor, ErbB-2/chemistryABSTRACT
BACKGROUND: in the setting of metastatic malignancies, the role of concurrent stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) and immune-checkpoint inhibitors (ICI) is increasing. Few data are available about effectiveness and safety of this strategy. METHODS: we used the PRISMA guidelines to perform a systematic review. We selected only articles reporting a "real" concurrent treatment, defined as SRS/SRT performed within 30 days of ICI administration. RESULTS: Despite several limits due to the heterogeneity and retrospective nature of the studies, 1-year local control for brain lesions ranged from 42 to 100% and 1-year regional brain control ranged from 31 to 83%. An interesting rate of local and distant control was reported for concurrent SBRT-ICI on extra-cranial lesions. No relevant signals about toxicity emerged. CONCLUSIONS: Based on published evidence, concurrent SRS/SRT and ICI seems to lead intriguing outcomes, without increasing toxicity. Further investigations are warranted to obtain stronger prospective evidence.
Subject(s)
Immunotherapy , Neoplasms/therapy , Radiosurgery , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Combined Modality Therapy , Humans , Ipilimumab/therapeutic use , Neoplasm Metastasis , Neoplasms/drug therapy , Neoplasms/radiotherapy , Neoplasms/surgery , Nivolumab/therapeutic use , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND/AIMS: The aim of this study was to perform a systematic review on primary retroperitoneal cystoadenocarcinoma (PRC), which is an extremely rare disease. METHODS: According to PRISMA guidelines, all the literature about PRC from 1977 to 2015 was reviewed. Thirty articles were selected; characteristics of the patients were collected and described; time to recurrence and overall survival (OS) were investigated when available. RESULTS: Thirty seven patients were included of whom 33 were females; the median age at presentation was 43. PRC was more common in postmenopausal women. Surgery was the standard therapy; the role of chemotherapy and/or radiotherapy was uncertain. Thirty percent of the patients relapsed after 58 months from the surgery; the rupture of the cyst occurred in 13% of the cases and it was associated with poor prognosis as well as premenopausal status. At 125 months from the diagnosis, 72% of the patients were alive and the median OS was not reached. CONCLUSIONS: The present systematic review about PRC is the first performed until the date of drafting this paper. We described some clinical features of PRC and their possible prognostic value. No conclusive data can be presented due to the small population analyzed and to publication bias.
Subject(s)
Cystadenocarcinoma , Retroperitoneal Neoplasms , Cystadenocarcinoma/diagnosis , Cystadenocarcinoma/epidemiology , Cystadenocarcinoma/therapy , Humans , Neoplasm Recurrence, Local , Prognosis , Retroperitoneal Neoplasms/diagnosis , Retroperitoneal Neoplasms/epidemiology , Retroperitoneal Neoplasms/therapyABSTRACT
Although outcomes for women with breast cancers may vary by biologic subtype, patients with T1a,b N0M0 tumors have an excellent prognosis across all subgroups. HER2 overexpression occurs in 15-20% of primary breast tumors, and is associated with diminished disease-free and overall survival. The anti-HER2 monoclonal antibody trastuzumab in combination with chemotherapy is an effective treatment for all stages of HER2 positive breast cancer (bc). However, the absolute benefit decreases as the risk of recurrence lessens and no available randomized adjuvant trial has evaluated the role of trastuzumab in women with pT1a,b N0M0, HER2-positive breast tumors. These findings may explain the debate about the appropriate indication for adjuvant chemotherapy plus trastuzumab in this setting of patients. The aim of this review was to describe known and novel prognostic risk factors to be used for tailored treatment decision in pT1a,b N0M0 HER2-positive tumors. Whether patients with small HER2-positive bc may be suitable for (chemo)therapy reduction strategies, the current available data cannot exclude the need for a more aggressive treatment in a small subset of these subjects. Novel clinical prognostic factors such as interval cancer (IC) detection may help to address this clinically important controversy. A multicenter population-based cancer registry study is currently evaluating whether IC detection may identify patients with pT1a N0M0 HER2-positive tumors in whom the rate of recurrence justifies consideration for use of conventional, trastuzumab-based chemotherapy regimens.
Subject(s)
Breast Neoplasms , Neoplasm Recurrence, Local , Receptor, ErbB-2/metabolism , Trastuzumab/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/methods , Clinical Decision-Making , Disease-Free Survival , Female , Humans , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Prognosis , Risk Assessment/methods , Risk FactorsABSTRACT
Primary retroperitoneal mucinous cystoadenocarcinoma (PRMC) is an extremely rare clinical entity with about 50 cases described by the literature. Given the rarity of this pathology, the sharing of accurate available informations is important to improve its knowledge. We reported a case of a woman diagnosed with PRMC who received different lines of chemotherapy and radiotherapy and we also performed a review of the literature on the issue. (www.actabiomedica.it).
Subject(s)
Cystadenocarcinoma/diagnosis , Cystadenocarcinoma/therapy , Retroperitoneal Neoplasms/diagnosis , Retroperitoneal Neoplasms/therapy , Aged , Female , HumansABSTRACT
BACKGROUND: We present a case report of a large and deep osteolytic metastasis radiological documented involving the skull in a woman affected by advanced breast cancer during endocrine therapy.
Subject(s)
Adenocarcinoma/secondary , Breast Neoplasms/pathology , Neoplasm Staging , Skull Neoplasms/secondary , Adenocarcinoma/diagnosis , Female , Frontal Bone , Humans , Magnetic Resonance Imaging , Middle Aged , Parietal Bone , Skull Neoplasms/diagnosisABSTRACT
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.