Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials.

Background: Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Methods: Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2 ≥ 0.70 were considered as indicators of a clinically relevant surrogacy. Findings: Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Interpretation: Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. Funding: This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5 × 1000 funds (years 2021-2022).

Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies.

Background: Prior exposure to adjuvant endocrine therapy (ET) and timing to recurrence are crucial factors for first-line treatment choices in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) and in clinical trial eligibility, classifying metastatic HR+/HER2- BC as endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant. However, this classification is largely based on expert opinion and no proper evidence exists to date to support its possible prognostic and clinical impact. Methods: This analysis included individual patient-level data from 4 adjuvant phase III randomized trials by the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. The impact of endocrine resistance/sensitivity classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models. Findings: Between November 1992 and July 2012, 9058 patients were randomized in 4 trials, of whom 6612 had HR+/HER2- BC. Median follow-up was 9.1 years (interquartile range [IQR] 5.6-15.0). In the whole cohort, disease-free survival and OS were 90.4% and 96.6% at 5 years, and 79.1% and 89.4% at 10 years, respectively. The estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less pronounced after year 7. Among the 493 patients with a distant relapse as first disease-free survival event and available date on ET completion, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Median follow-up from diagnosis of a distant relapse was 3.8 years (IQR 1.6-7.5). Patients with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumours and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups (p = 0.005). In patients with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p = 0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1 ER (adjusted Hazard Ratio [aHR] 1.54; 95% CI 1.03-2.30) and 2ER (aHR 1.17; 95% CI 0.87-1.56) (p = 0.11). Interpretation: This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted endocrine resistance/sensitivity classification in patients with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future ET trials in the metastatic setting. Funding: AIRC.

Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2-3 years of letrozole in postmenopausal patients with breast cancer who have already received 2-3 years of tamoxifen. METHODS: This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I-III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2-3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635. FINDINGS: Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2-3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5-13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57-66) in the control group and 67% (62-71) in the extended group (hazard ratio 0·78, 95% CI 0·65-0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed. INTERPRETATION: In postmenopausal patients with breast cancer who received 2-3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2-3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2-3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer. FUNDING: Novartis and the Italian Ministry of Health. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.

Clinical outcomes of patients with breast cancer relapsing after (neo)adjuvant trastuzumab and receiving trastuzumab rechallenge or lapatinib-based therapy: a multicentre retrospective cohort study.

BACKGROUND: In the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab. MATERIALS AND METHODS: In this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics. RESULTS: Out of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval <1 month (37% vs 13.9%; p=0.017) and brain metastasis as first site of relapse (38.2% vs 9.4%; p<0.001). Among the 128 patients who relapsed after prior (neo)adjuvant trastuzumab, 101 (78.9%) received first-line trastuzumab and 27 (21.1%) first-line lapatinib. The following outcomes were observed with first-line lapatinib or trastuzumab, respectively: overall response rate 45.5% vs 61.3% (p=0.184), clinical benefit rate 68.2% vs 72.5% (p=0.691), median progression-free survival (PFS) 11.4 vs 12.0 months (p=0.814) and median overall survival (OS) 34.7 vs 48.2 months (p=0.722). In patients with brain metastasis as first site of relapse, median PFS was 12.2 vs 9.9 months (p=0.093) and median OS 33.7 vs 28.5 months (p=0.280), respectively. CONCLUSIONS: In patients with HER2-positive breast cancer relapsing after prior (neo)adjuvant trastuzumab, first-line treatment with trastuzumab or lapatinib was not associated with a significant difference in the clinical outcomes. A non-significant trend favouring the use of lapatinib was observed in patients with brain metastasis as the first site of relapse.

T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study.

BACKGROUND: T-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy. PATIENTS AND METHODS: Eligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. RESULTS: Of 445 patients with HER2+ metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%. CONCLUSIONS: Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control.

Prevalence and Determinants of Peripheral Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients: A Multicenter Cross-Sectional Study.

OBJECTIVES: To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events. MATERIALS AND METHODS: Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis-ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED. RESULTS: Peripheral microvascular ED was documented in one-third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218-2.396), p < 0.01 and OR (95% CI) = 1.005 (1.002-1.009), p < 0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values. CONCLUSIONS: This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration.

Impact of body mass index on the clinical outcomes of patients with HER2-positive metastatic breast cancer.

BACKGROUND: Overweight and obesity are associated with an increased risk of developing many types of cancer, including breast cancer. Moreover, increased body mass index (BMI) seems to be associated with a worse prognosis in patients with HER2-positive early breast cancer. However, little is known about the impact of BMI on the clinical outcomes of HER2-positive metastatic breast cancer (MBC). METHODS: This was a multicenter retrospective cohort study including 329 consecutive patients with HER2-positive MBC treated with first-line trastuzumab-based regimens. BMI at the time of MBC diagnosis was collected. World Health Organization BMI categories were used: underweight <18.5, normal 18.5-24.9 Kg/m2, overweight 25-29.9 Kg/m2, and obese ≥30 Kg/m2. The analyses were conducted using two categories: BMI < 25.0 (normal/underweight) and BMI ≥ 25 (overweight/obese). Progression-free survival (PFS) and overall survival (OS) rates were estimated using Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Cox's proportional hazards model. Disease response to therapy was analyzed using univariate and multivariate logistic regression. RESULTS: Overall, 176 (53.5%) patients were normal/underweight and 153 (46.5%) overweight/obese. Median PFS was 14.8 months in BMI < 25 group and 15.7 months in BMI ≥ 25 group (adjusted-HR 0.88; 95% CI 0.66-1.17; p = 0.387). Median OS was 58.6 months in BMI < 25 group and 52.6 in BMI ≥ 25 group (adjusted-HR 0.88; 95% CI 0.59-1.31; p = 0.525). Overall response rate was 71.7% and 65.9% (p = 0.296) and clinical benefit rate was 82.1% and 83.3% (p = 0.781) in BMI < 25 and BMI ≥ 25 groups, respectively. CONCLUSIONS: BMI does not seem to be associated with clinical outcomes in HER2-positive MBC patients.

Asymmetric dimethylarginine and arterial stiffness in patients with rheumatoid arthritis: A case-control study.

OBJECTIVE: To investigate whether levels of asymmetric dimethylarginine (ADMA), as a measure of endothelial dysfunction, are higher in patients with rheumatoid arthritis compared with healthy control subjects. The relationships between ADMA and surrogate measures of arterial stiffness were evaluated. METHODS: Patients with rheumatoid arthritis and healthy control subjects were recruited. ADMA was quantified via enzyme-linked immunosorbent assay. Arterial stiffness was evaluated using pulse wave analysis. RESULTS: There was no significant difference in plasma ADMA concentration between patients with rheumatoid arthritis (n = 30) and healthy controls (n = 30). Aortic augmentation pressure was significantly higher in patients than in controls. C-reactive protein and Health Assessment Questionnaire score were independent predictors of arterial stiffness in patients. There was no relationship between ADMA concentration and aortic augmentation pressure in the study population as a whole. CONCLUSIONS: Arterial stiffness appears to be increased in rheumatoid arthritis and independently associated with systemic inflammation and physical disability. ADMA concentration was not increased in this small group of patients with rheumatoid arthritis compared with healthy controls; nor was it associated with arterial stiffness.

Patterns of Care and Clinical Outcomes of First-Line Trastuzumab-Based Therapy in HER2-Positive Metastatic Breast Cancer Patients Relapsing After (Neo)Adjuvant Trastuzumab: An Italian Multicenter Retrospective Cohort Study.

BACKGROUND: We evaluated the patterns of care and clinical outcomes of metastatic breast cancer patients treated with first-line trastuzumab-based therapy after previous (neo)adjuvant trastuzumab. MATERIALS AND METHODS: A total of 416 consecutive, HER2-positive metastatic breast cancer patients who had received first-line trastuzumab-based therapy were identified at 14 Italian centers. A total of 113 patients had presented with de novo stage IV disease and were analyzed separately. Dichotomous clinical outcomes were analyzed using logistic regression and time-to-event outcomes using Cox proportional hazards models. RESULTS: In the 202 trastuzumab-naïve patients and 101 patients with previous trastuzumab exposure, we observed the following outcomes, respectively: overall response rate, 69.9% versus 61.3% (adjusted odds ratio [OR], 0.62; p = .131), clinical benefit rate, 79.1% versus 72.5% (adjusted OR, 0.73; p = .370), median progression-free survival (PFS), 16.1 months versus 12.0 months (adjusted hazards ratio [HR], 1.33; p = .045), and median overall survival (OS), 52.2 months versus 48.2 months (adjusted HR, 1.18; p = .404). Patients with a trastuzumab-free interval (TFI) <6 months, visceral involvement, and hormone receptor-negative disease showed a worse OS compared with patients with a TFI of ≥6 months (29.5 vs. 48.3 months; p = .331), nonvisceral involvement (48.0 vs. 60.3 months; p = .270), and hormone receptor-positive disease (39.8 vs. 58.6 months; p = .003), respectively. CONCLUSION: Despite the inferior median PFS, trastuzumab-based therapy was an effective first-line treatment for patients relapsing after (neo)adjuvant trastuzumab. Previous trastuzumab exposure and the respective TFI, type of first site of disease relapse, and hormone receptor status should be considered in the choice of the best first-line treatment option for HER2-positive metastatic breast cancer patients.

Risk of Adverse Pregnancy Outcomes in Women with CKD.

CKD is increasingly prevalent in pregnancy. In the Torino-Cagliari Observational Study (TOCOS), we assessed whether the risk for adverse pregnancy outcomes is associated with CKD by comparing pregnancy outcomes of 504 pregnancies in women with CKD to outcomes of 836 low-risk pregnancies in women without CKD. The presence of hypertension, proteinuria (>1 g/d), systemic disease, and CKD stage (at referral) were assessed at baseline. The following outcomes were studied: cesarean section, preterm delivery, and early preterm delivery; small for gestational age (SGA); need for neonatal intensive care unit (NICU); new onset of hypertension; new onset/doubling of proteinuria; CKD stage shift; "general" combined outcome (preterm delivery, NICU, SGA); and "severe" combined outcome (early preterm delivery, NICU, SGA). The risk for adverse outcomes increased across stages (for stage 1 versus stages 4-5: "general" combined outcome, 34.1% versus 90.0%; "severe" combined outcome, 21.4% versus 80.0%; P<0.001). In women with stage 1 CKD, preterm delivery was associated with baseline hypertension (odds ratio [OR], 3.42; 95% confidence interval [95% CI], 1.87 to 6.21), systemic disease (OR, 3.13; 95% CI, 1.51 to 6.50), and proteinuria (OR, 3.69; 95% CI, 1.63 to 8.36). However, stage 1 CKD remained associated with adverse pregnancy outcomes (general combined outcome) in women without baseline hypertension, proteinuria, or systemic disease (OR, 1.88; 95% CI, 1.27 to 2.79). The risk of intrauterine death did not differ between patients and controls. Findings from this prospective study suggest a "baseline risk" for adverse pregnancy-related outcomes linked to CKD.

Sentinel node biopsy in early breast cancer: lessons learned from more than 1000 cases at a single institution.

AIMS: The aims of this paper are to report the development of sentinel node biopsy (SNB) in breast cancer at a single institution and to discuss the relevant issues on SNB still to be elucidated. PATIENTS AND METHODS: From 1998 to 2010, 1021 SNBs with frozen section examination were carried out in patients with breast cancer. In the early period (1998-2002) SNB was always combined with axillary lymph node dissection (ALND). From 2002 onwards, only patients with a positive SNB result underwent ALND (late period). The characteristics of patients with infiltrating carcinoma (IC) and ductal carcinoma in situ (DCIS) and the histological status of the sentinel nodes were examined. The survival outcomes of node-negative patients were compared between patients submitted to SNB and ALND (ALND group) during the early period and patients who underwent only SNB during the late period (SNB group). RESULTS: The sentinel node was identified intraoperatively in 98.3% of cases. During the early period the overall accuracy of SNB was 97.0%. During the late period, 700 patients with IC and 140 with DCIS underwent SNB. In the IC group, 149 patients (21.3%) had sentinel node macrometastases and 36 (5.1%) micrometastases; of that subgroup, 21 underwent ALND and no other metastatic lymph nodes were found, and 15 underwent SNB only. Axillary recurrences were observed in 4 patients (0.77%) with negative SNB; none of these were among the patients with micrometastatic SNB. Two patients (1.4%) with DCIS had a positive SNB. In node-negative patients the 5-year overall survival was 96.7% in the ALND group and 96.5% in the SNB group (P = 0.63). The 5-year disease-free survival was 93.8% and 93.2% in the ALND and SNB groups, respectively (P = 0.77). CONCLUSIONS: Overall and disease-free survival in patients with a negative SNB result and no further axillary surgery were equal to those in patients with negative ALND. Intraoperative assessment of the sentinel node in expert hands has a low false-negative rate and allows immediate ALND in patients with sentinel node metastases, avoiding the need for a second operation. ALND for sentinel node micrometastases may be safely omitted in most patients with early stage breast cancer.

HELP LDL-apheresis in two cases of familial hypercholesterolemic pregnant women.

We report our experience with selective LDL-apheresis in two women affected by autosomal recessive hypercholesterolemia and heterozygous familial hypercholesterolemia respectively, during pregnancy. To date only a few cases have been reported, because of the rarity of pregnancy in these patients and a hesitation of physicians to perform extracorporeal treatment. One of the patients had severe coronary artery disease, an absolute contraindication for pregnancy. Both patients had extremely elevated lipoprotein values because of their primary dyslipidemia, pregnancy-related modification of their lipid profile, and mandatory discontinuation of lipid-lowering drugs. In both cases the use of the Heparin-induced Extracorporeal Lipoprotein Precipitation (HELP) therapy improved the clinical situation and resulted in a good outcome for both mother and fetus.