Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication.

BACKGROUND: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. PATIENTS AND METHODS: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. RESULTS: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). CONCLUSIONS: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038.

Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.

Background: The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer. Patients and methods: Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS). Results: Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5-63.7] for combination therapy, and 60% (95% CI: 47.8-72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6-12.7) for combination therapy, and 6.5 months (95% CI: 5.4-8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4-1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3-0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months. Conclusion: Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. Clinical trial information: NCT02549430.

Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2- breast cancer: results from two prospective trials.

PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice.

Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-)) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1(+/-) mice, compared to their wild-type PINK1(+/+) littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations. Mice were exposed to a range of concentrations of rotenone (0.01-1mg/kg). Chronic treatment with concentrations of rotenone up to 0.8mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1(+/-) and PINK1(+/+) mice. Moreover, rotenone (up to 0.8mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1(+/-) striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1(+/-), a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1(+/-) mice treated with a low rotenone (0.1mg/kg) concentration. Even lower concentrations (0.01mg/kg) blocked LTP induction in heterozygous PINK1(+/-) MSNs compared to PINK1(+/+) mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations. In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but profoundly impaired the expression of long-term plasticity at corticostriatal synapses in PINK1 heterozygous knockout mice, suggesting that disruption of synaptic plasticity may represent an early feature of a pre-manifesting state of the disease, and a potential tool to test novel neuroprotective agents.

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer.

BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSIONS: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379.

Long-acting insulin analog detemir displays reduced effects on adipocyte differentiation of human subcutaneous and visceral adipose stem cells.

BACKGROUND AND AIMS: Since treatment with insulin detemir results in a lower weight gain compared to human insulin, we investigated whether detemir is associated with lower ability to promote adipogenesis and/or lipogenesis in human adipose stem cells (ASC). METHODS AND RESULTS: Human ASC isolated from both the subcutaneous and visceral adipose tissues were differentiated for 30 days in the presence of human insulin or insulin detemir. Nile Red and Oil-Red-O staining were used to quantify the rate of ASC conversion to adipocytes and lipid accumulation, respectively. mRNA expression levels of early genes, including Fos and Cebpb, as well as of lipogenic and adipogenic genes, were measured at various phases of differentiation by qRT-PCR. Activation of insulin signaling was assessed by immunoblotting. ASC isolated from subcutaneous and visceral adipose tissue were less differentiated when exposed to insulin detemir compared to human insulin, showing lower rates of adipocyte conversion, reduced triglyceride accumulation, and impaired expression of late-phase adipocyte marker genes, such as Pparg2, Slc2a4, Adipoq, and Cidec. However, no differences in activation of insulin receptor, Akt and Erk and induction of the early genes Fos and Cebpb were observed between insulin detemir and human insulin. CONCLUSION: Insulin detemir displays reduced induction of the Pparg2 adipocyte master gene and diminished effects on adipocyte differentiation and lipogenesis in human subcutaneous and visceral ASC, in spite of normal activation of proximal insulin signaling reactions. These characteristics of insulin detemir may be of potential relevance to its weight-sparing effects observed in the clinical setting.

Observational study on adjuvant trastuzumab in HER2-positive early breast cancer patients.

AIM: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates. PATIENTS & METHODS: Data on a group of HER2-positive patients collected from 13 oncology centers of northeast Italy were analyzed. RESULTS: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not-relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients. CONCLUSION: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2-positive early-stage breast cancer patients.

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole.

BACKGROUND: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. METHODS: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. RESULTS: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m(-2); 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m(-2); 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m(-2); and 43.3 (23.0-81.7, n=16) when ≥35.0 kg m(-2). No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. CONCLUSIONS: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.

Vaccination for seasonal influenza in patients with cancer: recommendations of the Italian Society of Medical Oncology (AIOM).

BACKGROUND: Influenza virus causes annual epidemics in the winter-spring season with significant morbidity in the general population and important mortality in high-risk groups, including cancer patients. Opinions on the suitability of patients with malignancies not undergoing active treatment and in different phases of antineoplastic therapy, to receive influenza vaccination, vary considerably among oncologists, sometimes even within one center. METHODS: We reviewed available data, including recommendations by national health authorities, on impact of influenza in patients with cancer and their capacity to mount protective immunological responses to vaccination, thus allowing, on behalf of Italian Association of Medical Oncology, to make suitable recommendations for the prevention and treatment of seasonal influenza. RESULTS AND DISCUSSION: Patients with cancer often have disease- or treatment-related immunosuppression, and as a consequence, they may have a suboptimal serologic response to influenza vaccination. The protective effect of the different preparations of influenza vaccines in patients with cancer has not been widely investigated, especially in adult patients harboring solid tumors. The optimal timing for administration of influenza vaccines in patients receiving chemotherapy is also not clearly defined. However, since vaccination is the most effective method, along with antiviral drugs in selected patients, for preventing influenza infection, it has to be recommended for cancer patients. Implementing vaccination of close contacts of oncology patients would be an additional tool for enhancing protection in fragile patient populations.

Liquid biopsy in triple-negative breast cancer: unlocking the potential of precision oncology.

In the era of precision oncology, the management of triple-negative breast cancer (TNBC) is rapidly changing and becoming more complicated with a variety of chemotherapy, immunotherapy, and targeted treatment options. Currently, TNBC treatment is based on prognostic and predictive factors including immunohistochemical biomarkers [e.g. programmed death-ligand 1 (PD-L1)] and germline BRCA mutations. Given the current limitation of existing biomarkers, liquid biopsies may serve as clinically useful tools to determine treatment efficacy and response in both the (neo)adjuvant and metastatic settings, for detecting early relapse, and for monitoring clonal evolution during treatment. In this review, we comprehensively summarize current and future liquid biopsy applications. Specifically, we highlight the role of circulating tumor cell characterization, circulating tumor DNA, and other preclinical liquid biopsy technologies including circulating exosomes, RNA liquid biopsy, and circulating immune-based biomarkers. In the near future, these biomarkers may serve to identify early disease relapse, therapeutic targets, and disease clonality for patients with TNBC in the clinical setting.

Neoadjuvant chemotherapy for breast cancer in Italy: A Senonetwork analysis of 37,215 patients treated from 2017 to 2022.

BACKGROUND: Adoption of neoadjuvant chemotherapy (NACT) in the "real world" has been poorly investigated. Aim of this study was to examine the rate of NACT in Italy, trends over time and determinants of therapeutic choices. METHODS: Senonetwork, the recognized network of Breast Centers in Italy, has developed a voluntary national data warehouse with the aim to monitor and improve treatments quality. A retrospective analysis was conducted among 58,661 breast cancer (BC) patients treated between 2017 and 2022 by 24 high-volume Breast Centers participating in the project. RESULTS: After subset exclusion, 37,215 primary BC patients were analysed, 32,933 underwent primary-breast-surgery and 4,282 underwent NACT. From 2017 to 2022, the overall NACT incidence increased particularly for HR-/HER2+, Triple-Negative, and HR+/HER2+ BC (p < 0.001). In cN + patients the recommendation to axillary lymph-node dissection after NACT decreased over time along with an increase of <4 lymph-nodes removed (p < 0.001). Immediate breast reconstruction and indication for nipple sparing mastectomy increased significantly over time (OR = 1.10, p = 0.011 and OR 1.14, p < 0.001, respectively). On multivariate analysis, there was a trend towards an increased adoption of conservative treatment for HR-/HER2+ (p = 0.01) and Triple Negative tumors (p = 0.06). Implementation of NACT varied significantly among Breast-Centers from 3.8 to 17.7 % (p < 0.001). CONCLUSION: The impact of NACT on the subsequent surgical management is substantial and continues to evolve over time, resulting in less-extensive surgery. Even among high-volume Centers NACT implementation rate is still highly variable. Although we registered a significant increase in its use during the study period, these results need to be further improved.

Efficacy of adjuvant chemotherapy schedules for breast cancer according to body mass index: results from the phase III GIM2 trial.

BACKGROUND: The phase III GIM2 trial showed improved disease-free survival (DFS) and overall survival (OS) with adjuvant dose-dense (DD) as compared with standard-interval (SI) chemotherapy in women with node-positive early-stage breast cancer (BC). This exploratory analysis aimed to investigate the benefit of different schedules according to body mass index (BMI) in this trial. PATIENTS AND METHODS: This analysis explored the efficacy, in terms of DFS and OS, of different chemotherapy schedules according to BMI. Univariate and multivariable Cox proportional hazard models, adjusted for relevant prognostic factors, were used. RESULTS: Out of 2091 patients enrolled, 1925 with known baseline BMI were randomized in the DD versus SI comparison and therefore included in this analysis: 31.6% were overweight and 19.3% obese. Overweight and obesity were significantly associated with postmenopausal status, pT >2, and pN >2 tumors. After a median follow-up of 15.0 years (interquartile range 8.4-16.3 years), multivariable Cox survival models demonstrated no association of different BMI categories on DFS [adjusted hazard ratio (adjHR) 0.96, 95% confidence interval (CI) 0.80-1.15 and adjHR 1.11, 95% CI 0.91-1.35 for overweight and obese patients, respectively, compared to patients with normal BMI] or OS (adjHR 0.90, 95% CI 0.71-1.14 and adjHR 1.18, 95% CI 0.92-1.52 for overweight and obese patients, respectively). No significant interaction was found between BMI and treatment schedule in terms of DFS (Pfor interaction = 0.56) or OS (Pfor interaction = 0.19). The survival benefit of DD chemotherapy was observed irrespective of different BMI categories, with a more pronounced benefit for overweight and obese patients. CONCLUSION: In node-positive BC patients, DD schedule should be considered the preferred schedule irrespective of BMI.

Characteristics and clinical outcomes of breast cancer in young BRCA carriers according to tumor histology.

BACKGROUND: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer. METHODS: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival. RESULTS: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index. CONCLUSIONS: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis.

Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole.

Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85-274) at baseline, 35 pg/mL (12-64) at 6-weeks, 29 pg/mL (17-48) at 6 months and 25 pg/mL (8-46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.

Discontinuation rate and serious adverse events of chemoimmunotherapy as neoadjuvant treatment for triple-negative breast cancer: a systematic review and meta-analysis.

BACKGROUND: The use of combination of chemotherapy with immune checkpoint inhibitors (ICIs) has shown efficacy in triple-negative breast cancer (TNBC), and chemoimmunotherapy has been introduced in clinical practice. However, limited data are available on the discontinuation rate and serious adverse events of these treatments, particularly in the neoadjuvant setting. Herein, we carried out a comprehensive systematic review and meta-analysis to assess discontinuation rate and serious adverse events of chemoimmunotherapy compared to chemotherapy alone in phase II and III neoadjuvant clinical trials in TNBC. MATERIALS AND METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, EMBASE, Cochrane Library, and PubMed/Medline were searched for articles published from June 2008 to May 2023. The outcomes of interest were the discontinuation rate, serious adverse events, and grade 3-4 adverse events. RESULTS: Four studies were included in the analysis. The pooled odds ratios (ORs) for discontinuation rate and serious adverse events were 1.26 [95% confidence interval (CI) 0.78-2.06] and 1.79 (95% CI 1.4-2.28), respectively, in patients receiving chemoimmunotherapy compared to chemotherapy alone as neoadjuvant treatment for TNBC. The chemoimmunotherapy group had a higher risk of grade 3-4 adverse events (OR 1.30, 95% CI 1.07-1.59). The analysis showed substantial heterogeneity, and the risk of discontinuation rate was heavily influenced by the KEYNOTE-522 trial. CONCLUSIONS: Our findings highlight the need for clinical trials specifically focused on safety, quality of life, and treatment adherence in TNBC patients receiving neoadjuvant treatment. Close monitoring of tolerability remains crucial in this clinical setting.

Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

BACKGROUND: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS: Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS: Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: An Italian consensus paper and critical review.

Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.