The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved.
germline ...mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than
have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline
mutation compared to germline
and
mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that
is a high-penetrant gene with a key role in the HRR system,
mutations are predictive factors for response to treatment. Moreover, germline mutations in the
gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type
. In conclusion, sequencing of HRR-related genes other than
should be routinely offered as part of a biological characterization of pancreatic and breast cancers.
Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas ...present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.
In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in ...the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.
The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the ...impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.
Elderly patients are underrepresented in clinical study where combined endocrine strategies were compared to endocrine therapy (ET) in hormone receptors positive, HER2 negative, metastatic breast ...cancer. The role of the new endocrine approaches in elderly women is still unclear.
We performed a meta-analysis of first line phase II/III randomized trials on ET versus combined strategies considering clinical benefit and safety profile. Trials with hazard ratio (HR) for PFS in elderly patients were included.
Overall, the meta-analysis showed a PFS advantage for the experimental arms HR 0.77, p 0.016 with a significant high/moderate heterogeneity I2 65.46%, p 0.005. For patients on CDK 4/6 inhibitors and ET, HR was 0.57 (p < 0.0001), with low heterogeneity I2 0.0001%, p 0.96. Hematological adverse events, as well as diarrhea with Abemaciclib, were significantly higher in elderly population.
The magnitude of PFS benefit due to the combined strategies in elderly patients is similar to those reported in the overall clinical trial population. Adding CDK4/6 inhibitors to ET significantly prolongs PFS, even if toxicity profile have to be carefully considered. Future trials should be designed taking into account patients' age, geriatric assessment and comorbidity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article evaluates the breast cancer (BC) screening efficacy of biannual ultrasound (US) in three different risk categories. In a single‐center, prospective, nonrandomized comparison study, BRCA ...mutation carriers and women with high risk (HR) or intermediate risk (IR) received mammography (MMG), ultrasound, (US) and Magnetic Resonance Imaging (MRI), scheduled according to the risk categories. Single and combined sensitivity were evaluated in specific groups of risk and the US performance at six‐monthly interval was notably considered. Among 2,313 asymptomatic women at different risk (136 mutation carriers, 1,749 at HR and 428 at IR) 211 developed a BC, of which 193 (91.5%) were screen detected BC (SDBC) and 18 (8.5%) were interval BC (IBC). The SDBC detection rate (DR) was 11.2 per 1.000 person‐years (37.9, 8.5 and 16.1 for BRCA, HR and IR, respectively); 116 BC were detected by MMG (DR = 6.6 × 1,000 persons‐years), 62 by US (DR = 3.6 × 1,000 persons‐years) and 15 by MRI, that was applied only in 60 BRCA women (DR = 37 × 1,000 persons‐years). At the six‐monthly US, 52 BC were detected (DR = 3.0 × 1,000 persons/years), of which 8 were BRCA‐related. The most sensitive technique was MRI (93.7%) followed by MMG (55%) and US (29.4%). Combined sensitivity for MMG plus US was 100% in HR and 80.4% for IR women (p < 0.01). In BRCA mutated patients, MRI alone with annual US performed after six months, could be offered. In HR patients, MMG plus biannual US provide the most sensitive diagnosis and for IR group an annual MMG could be sufficient.
What's new?
Breast ultrasound can be a useful addition to mammogram for breast cancer screening, in certain cases. Currently, mammography is considered the most sensitive screening technique for early breast cancer detection, but dense breast tissue can make it harder for mammography to detect cancer. These authors compared mammography, ultrasound, and MRI for cancer diagnosis among various risk groups. For women with BRCA mutations, MRI gave the best results, with 94% sensitivity. In high risk patients, mammogram combined with twice‐yearly ultrasound achieved 100% sensitivity. In women considered intermediate risk, however, mammogram without ultrasound provided sufficient sensitivity.
Background:
The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by ...exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity.
Patients and methods:
This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m2 intravenously (i.v.) on day 1, docetaxel, 30 mg/m2 i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle.
Results:
Among 47 evaluable patients, there were 18 pCR 38.3%, 95% confidence interval (CI) 24.5–53.6%. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06–1.30, p = 0.11). Toxicity included grade 3–4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1–2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1–2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase.
Conclusions:
The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.
Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age ...than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades.
Approximately 5–10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors ...olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials.
The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC.
Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration.
The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology.
•Use of PARP-inhibitors in BRCA-related HER2-advanced BC has been addressed by the Italian Association of Medical Oncology.•The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach has been adopted.•HR+/HER2-and triple-negative BC subtypes have been addressed in two separate clinical questions.•Germline BRCA testing in HER2-advanced BC has a predictive value, being indicated independently from familial criteria.
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