Anthracycline-related cardiotoxicity in patients with breast cancer harboring mutational signature of homologous recombination deficiency (HRD).

BACKGROUND: The BRCA proteins play a key role in the homologous recombination (HR) pathway. Beyond BRCA1/2, other genes are involved in the HR repair (HRR). Due to the prominent role in the cellular repair process, pathogenic or likely pathogenic variants (PV/LPVs) in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. PATIENTS AND METHODS: This was a multicenter, hospital-based, retrospective cohort study to investigate the heart toxicity from anthracycline-containing regimens (ACRs) in the adjuvant setting of breast cancer (BC) patients carrying germline BRCA PV/LPVs and no-BRCA HRR pathway genes. The left ventricular ejection fraction (LVEF) was assessed using cardiac ultrasound before starting ACR therapy and at subsequent time points according to clinical indications. RESULTS: Five hundred and three BC patients were included in the study. We predefined three groups: (i) BRCA cohort; (ii) no-BRCA cohort; (iii) variant of uncertain significance (VUS)/wild-type (WT) cohort. When baseline (T0) and post-ACR (T1) LVEFs between the three cohorts were compared, pre-treatment LVEF values were not different (BRCA1/2 versus HRR-no-BRCA versus VUS/WT cohort). Notably, during monitoring (T1, median 3.4 months), patients carrying BRCA or HRR no-BRCA germline pathogenic or likely pathogenic variants showed a statistically significant reduction of LVEF compared to baseline (T0). To assess the relevance of HRR on the results, we included the analysis of the subgroup of 20 BC patients carrying PV/LPVs in other genes not involved in HRR, such as mismatch repair genes (MUTYH, PMS2, MSH6). Unlike HRR genes, no significant differences in T0-T1 were found in this subgroup of patients. CONCLUSION: Our data suggest that deleterious variants in HRR genes, leading to impaired HR, could increase the sensitivity of cardiomyocytes to ACR in early BC patients. In this subgroup of patients, other measurements, such as the global longitudinal strain, and a more in-depth assessment of risk factors may be proposed in the future to optimize cardiovascular risk management and improve long-term survival.

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA).

BACKGROUND: BRCA1/2-related metastatic breast cancers (mBC) are sensitive to DNA-damage agents and show high tumor-infiltrated lymphocytes. We hypothesized that the association between pembrolizumab and carboplatin could be active in BRCA-related mBC. PATIENTS AND METHODS: In this phase II Simon's design multicenter single-arm study, BRCA1/2-related mBC patients received carboplatin at area under the curve 6 every 3 weeks for six courses associated with 200 mg pembrolizumab every 3 weeks until disease progression or unacceptable toxicity. The primary aim at first stage was overall response rate (ORR) ≥70%. Disease control rate (DCR), time to progression (TTP), duration of response (DOR), and overall survival (OS) were the secondary aims. RESULTS: Among 22 patients enrolled at the first stage, 5 BRCA1 and 17 BRCA2, 16 (76%) were luminal tumors and 6 (24%) triple-negative BC (TNBC). In 21 patients, ORR and DCR were 43% and 76% (47% and 87% in luminal, 33% and 50% in TNBC), respectively. TTP was 7.1 months, DOR was 6.3 months, and median OS was not reached. Grade ≥3 adverse events (AEs) or serious AEs occurred in 5/22 patients (22.7%). Since the primary aim was not met, the study was terminated at the first stage. CONCLUSIONS: Although the primary aim was not reached, data on efficacy and safety of pembrolizumab plus carboplatin in first-line visceral disease BRCA-related luminal mBC were provided and they need to be further investigated.

Cancer burden in adolescents and young adults in Europe.

BACKGROUND: Cancer epidemiology is unique in adolescents and young adults (AYAs; aged 15-39 years). The European Society for Medical Oncology/European Society for Paediatric Oncology (ESMO/SIOPE) AYA Working Group aims to describe the burden of cancers in AYAs in Europe and across European Union (EU) countries. PATIENTS AND METHODS: We used data available on the Global Cancer Observatory. We retrieved crude and age-standardised (World Standard Population) incidence and mortality rates. We reported about AYA cancer burden in Europe and between 28 EU member states. We described incidence and mortality for all cancers and for the 13 cancers most relevant to the AYA population. RESULTS: Incidence and mortality varied widely between countries with the highest mortality observed in Eastern EU countries. Cancers of the female breast, thyroid and male testis were the most common cancers across countries followed by melanoma of skin and cancers of the cervix. Variations in cancer incidence rates across different populations may reflect different distribution of risk factors, variations in the implementation or uptake of screening as well as overdiagnosis. AYA cancer mortality disparities may be due to variation in early-stage diagnoses, different public education and awareness of cancer symptoms, different degrees of access or availability of treatment. CONCLUSIONS: Our results highlight the future health care needs and requirements for AYA-specialised services to ensure a homogeneous treatment across different countries as well as the urgency for preventive initiatives that can mitigate the increasing burden.

Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe.

In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician.

Two-month stop in mammographic screening significantly impacts on breast cancer stage at diagnosis and upfront treatment in the COVID era.

INTRODUCTION: The present analysis aims to evaluate the consequences of a 2-month interruption of mammographic screening on breast cancer (BC) stage at diagnosis and upfront treatments in a region of Northern Italy highly affected by the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus. METHODS: This retrospective single-institution analysis compared the clinical pathological characteristics of BC diagnosed between May 2020 and July 2020, after a 2-month screening interruption, with BC diagnosed in the same trimester of 2019 when mammographic screening was regularly carried out. RESULTS: The 2-month stop in mammographic screening produced a significant decrease in in situ BC diagnosis (-10.4%) and an increase in node-positive (+11.2%) and stage III BC (+10.3%). A major impact was on the subgroup of patients with BC at high proliferation rates. Among these, the rate of node-positive BC increased by 18.5% and stage III by 11.4%. In the subgroup of patients with low proliferation rates, a 9.3% increase in stage III tumors was observed, although node-positive tumors remained stable. Despite screening interruption, procedures to establish a definitive diagnosis and treatment start were subsequently carried out without delay. CONCLUSION: Our data showed an increase in node-positive and stage III BC after a 2-month stop in BC screening. These findings support recommendations for a quick restoration of BC screening at full capacity, with adequate prioritization strategies to mitigate harm and meet infection prevention requirements.

NUT midline carcinoma of the head and neck: current perspectives.

NUT midline carcinoma (NMC) is a rare and aggressive subtype of squamous carcinoma that typically arises from midline supradiaphragmatic structures, frequently from the head and neck area. NMC is genetically driven by a chromosomal rearrangement involving the NUT gene, which forms oncoproteins considered major pathogenic drivers of cellular transformation. Diagnosis of NMC has been made remarkably easier with the availability of a commercial antibody against NUT, and can be established through positive nuclear immunohistochemical staining. Although NMC remains an underrecognized malignancy, in recent years there has appeared to be increasing awareness of disease and frequency of diagnosis in adults. To date, a standard treatment for head and neck NMC has not been established and a multimodal approach with systemic chemotherapy, surgery and radiation therapy is currently adopted in clinical practice. Recently, BET inhibitors and histone deacetylase inhibitors have emerged as two promising classes of targeted agents, currently investigated in clinical trials for adults with head and neck NMC. At the same time, combination approaches and novel targeted agents, such as next-generation BET inhibitors and CDK9 inhibitors, have shown preclinical activity. The present review explores the clinical pathological characteristics of NMC of the head and neck and presents the current state of the art on diagnosis, prognosis, and treatment of this rare but lethal disease.

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour.

BACKGROUND: To explore the activity of pazopanib in solitary fibrous tumour (SFT). PATIENTS AND METHODS: In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm(3). Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure. RESULTS: In the xenograft model, pazopanib showed the lowest antitumour activity (21%TVI), while regorafenib was the most active (95%TVI). Sorafenib, bevacizumab, sunitinib were markedly active (78/70/65%TVI). Axitinib was marginally active (51%TVI). In the retrospective case-series, three patients carried malignant-SFT (MSFT), three DSFT. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: three stable disease (SD), all MSFT, three progressive disease (PD), all DSFT, corresponding to one partial response (PR), two SD, three PD by Choi criteria. Median-progression-free survival was 3 months (range 1-15). In one patient, sunitinib was started after pazopanib failure, with a response. CONCLUSIONS: In dedifferentiated-SFT xenograft pazopanib induced a marginal antitumour activity, while regorafenib appeared the most active and promising agent. When administered in patients, pazopanib showed a modest activity in terms of tumour growth stabilisation, observed only in non-dedifferentiated cases.

A rapid genetic counselling and testing in newly diagnosed breast cancer is associated with high rate of risk-reducing mastectomy in BRCA1/2-positive Italian women.

BACKGROUND: Risk-reducing mastectomy (RRM) decreases breast cancer (BC) risk in BRCA1/2 mutation carriers by up to 95%, but the Italian attitude towards this procedure is reluctant. PATIENTS AND METHODS: This is an observational study with retrospective design, using quantitative and qualitative research methods, aimed at evaluating the attitude towards RRM by rapid genetic counselling and testing (RGCT), at the time of BC diagnosis, compared with traditional genetic counselling and testing (TGCT), after previous BC surgery. Secondary aims were to investigate patient satisfaction after RRM and the rate of occult tumour in healthy breasts. A total of 1168 patients were evaluated: 1058 received TGCT, whereas 110 underwent RGCT. RESULTS: In TGCT, among 1058 patients, 209 (19.7%) mutation carriers were identified, with the rate of RRM being 4.7% (10 of 209). Conversely in RGCT, among 110 patients, 36 resulted positive, of which, 15 (41.7%) underwent bilateral mastectomy at the BC surgery time, showing an overall good satisfaction, measured by interpretative phenomenological analysis 12 months after the intervention. CONCLUSIONS: Our study shows that RGCT in patients with a hereditary profile is associated with a high rate of RRM at the BC surgery time, this being the pathway offered within a multidisciplinary organization.