Adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive early breast cancer: evidence evaluation and GRADE recommendations by the Italian Association of Medical Oncology (AIOM)

Premenopausal women with hormone receptor-positive early breast cancer are candidates for adjuvant endocrine therapy, as recommended by the major international guidelines. To date, adjuvant endocrine options for premenopausal women include tamoxifen with or without ovarian function suppression (OFS) or an aromatase inhibitor with OFS. Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed, and the results of randomised clinical trials have been reported over the last years. Despite this evidence, the optimal algorithm for endocrine therapy for premenopausal women with hormone receptor-positive early stage invasive breast cancer shows open questions regarding the role of OFS in addition to tamoxifen and the optimal use of hormonal agents. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer applied the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology on three critical questions on the choice of the adjuvant hormonal therapy in premenopausal breast cancer patients to summarise available evidence and to create recommendations to help physicians in their clinical practice.

Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Although in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Relevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016. The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). RESULTS: A total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643). No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). CONCLUSION: Our pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.

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.

Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes.

BACKGROUND: Feasibility and accuracy of sentinel node biopsy (SLNB) after the delivery of neo-adjuvant chemotherapy (NAC) is controversial. We here report our experience in NAC-treated patients with locally advanced breast cancer and clinically positive axillary nodes, and compare it with the results from our previous randomized trial assessing SLNB in early-stage breast cancer patients. PATIENTS AND METHODS: Sixty-four consecutive patients with large infiltrating tumor and clinically positive axillary nodes received NAC and subsequent lymphatic mapping, SLNB and complete axillary lymph node dissection (ALND). The status of the sentinel lymph node (SLN) was compared to that of the axilla. RESULTS: At least one SLN was identified in 60 of the 64 patients (93.8%). Among those 60 patients, 37 (61.7%) had one or more positive SLN(s) and 23 (38.3%) did not. Two of the patients with negative SLN(s) presented metastases in other non-sentinel nodes. SLNB thus had a false-negative rate, a negative predictive value and an overall accuracy of 5.1%, 91.3% and 96.7%, respectively. All these values were similar to those we reported for SLNB in the settings of early-stage breast cancer. CONCLUSION: SLNB after NAC is safe and feasible in patients with locally advanced breast cancer and clinically positive nodes, and accurately predicts the status of the axilla.

Pathological and molecular characteristics distinguishing contralateral metastatic from new primary breast cancer.

BACKGROUND: Breast cancer patients have a cumulative lifetime risk of 2%-15% of developing a contralateral metastatic or ex novo primary cancer. From prognostic and therapeutic viewpoints, it is important to differentiate metastatic from second primary. To distinguish these entities, we investigated whether the pattern of X chromosome inactivation could determine whether the two tumors derived from different progenitor cells. MATERIALS AND METHODS: The clonality of bilateral breast cancer was evaluated through the X-inactivation analysis using the human androgen receptor gene (HUMARA) polymorphism and the histopathologic and molecular results were compared. A different or an identical pattern of X inactivation was considered as indicator of a second primary cancer or not informative, respectively. We considered morphological indicators of a new primary cancer the absence of concordance in the histological type or a better histological differentiation. RESULTS: Ten patients with bilateral breast cancer were evaluated. Morphological criteria indicated that eight were second primary, a conclusion confirmed by the X-inactivation analysis. Two cases classified as recurrence according to morphological criteria were classified as second tumor by molecular analysis. CONCLUSION: Our results show that the HUMARA clonality assay can improve the histological parameters in differentiating metastatic cancer from second primary cancer.