Treating advanced breast cancer with metronomic chemotherapy: What is known, what is new and what is the future?

The prognosis for patients with locally advanced or metastatic breast cancer (mBC) remains poor, with a median survival of 2-4 years. About 10% of newly diagnosed breast cancer patients present with metastatic disease, and 30%-50% of those diagnosed at earlier stages will subsequently progress to mBC. In terms o f ongoing management for advanced/metastatic breast cancer after failure of hormonal therapy, there is a high medical need for new treatment options that prolong the interval to the start of intensive cytotoxic therapy, which is often associated with potentially serious side effects and reduced quality of life. Oral chemotherapeutic agents such as capecitabine and vinorelbine have demonstrated efficacy in patients with mBC, with prolonged disease control and good tolerability. Use of oral chemotherapy reduces the time and cost associated with treatment and is often more acceptable to patients than intravenous drug delivery. Metronomic administration of oral chemotherapy is therefore a promising treatment strategy for some patients with mBC and inhibits tumor progression via multiple mechanisms of action. Ongoing clinical trials are investigating metronomic chemotherapy regimens as a strategy to prolong disease control with favorable tolerability. This article provides an overview of metronomic chemotherapy treatment options in mBC, with perspectives on this therapy from a panel of experts

Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments

Incidence of breast cancer in Italy: mastectomies and quadrantectomies performed between 2000 and 2005.

Objectives. We aimed to determine the incidence of women's breast cancer in Italy without using statistical approximations. Methods. We analyzed the national hospitalizations database at the Ministry of Health to calculate the number of major surgeries in Italian women (mastectomies and quadrantectomies) due to breast cancer between 2000 and 2005, overall and by age groups (<44, 4564, 6574 and 75 years old). Results. Over the six years examined, an overall number of 100,745 mastectomies and 168,147 quadrantectomies were performed. A total of 41,608 major surgeries due to breast cancer were performed in the year 2000 and this number rose to 47,200 in 2005, with a 13.4% increase over six years. Conclusion. by analyzing the hospitalizations database concerning major breast surgery, incidence of breast cancer in Italy was found to be 26.5% higher than the official estimations which have been computed using statistical models (namely 47,200 vs. 37,300 cases in year 2005)

Immune infiltrate composition across intrinsic subtypes in hormone receptor (HR)+/HER2- early breast cancer (BC) enrolled in the prospective LETLOB trial.

Background In HR+/HER2- early BC, high tumour infiltrating lymphocytes (TIL) levels predict higher pathological complete response to neoadjuvant chemotherapy, but are associated with shorter overall survival (Denkert, Lancet Oncol 2018). HR+/HER2- BC is a biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes, with different clinical behaviour (Cejalvo, CTR 2018). Little is known concerning the distribution of TIL levels and immune infiltrate composition across intrinsic subtypes in HR+/HER2- BC. Methods Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 postmenopausal patients with HR+/HER2- early BC from the LETLOB trial (neoadjuvant letrozole+/-lapatinib) (Guarneri, JCO 2014). Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. Relative leukocyte fractions were calculated using CIBERSORT (Newman, Nature Methods 2015), a deconvolution method based on RNA gene-expression signatures. Pre-treatment stromal TILs were assessed on centralized HES slides according to recommendations (Salgado, Ann Oncol 2015). Results Intrinsic subtype distribution was as follows: basal 18% (N = 12), HER2-enriched 8% (N = 5), Luminal A 39% (N = 25), Luminal B 36% (N = 24). Non-luminal subtypes (HER2-enriched and Basal) had significantly higher baseline TIL levels than luminal subtypes (median (range): 7 (0-100) and 2 (0-35), respectively; p = 0.038). Non-luminal subtypes also presented higher fractions of CD4 memory activated T-cells (p = 0.018), γδ T-cells (p = 0.010) and M1 macrophages (p = 0.001) and lower fractions of T-regulatory cells (p = 0.002) than luminal subtypes. Conclusions In HR+/HER2- early BC, non-luminal subtypes show higher TIL levels and a more pro-inflammatory anti-tumour immune infiltrate composition. This immune heterogeneity across intrinsic subtypes should be considered when analysing the complex prognostic role of TILs in HR+/HER2- early BC

Oncoplastic and reconstructive surgery in SENONETWORK Italian breast centers: lights and shadows

Highlights: • Despite the significance of oncoplastic procedure, an italian database is lacking. • Senonetwork established a multidisciplinary survey to assess their safety and efficacy. • Reconstructive outcomes were positive across low and high-volume centers. • After mastectomy, implant-based techniques are common. DTI reconstruction is advantageuos. • This contributes to the global understanding of effective strategies against breast cancer

Breast cancer "tailored follow-up" in Italian oncology units: a web-based survey

urpose: Breast cancer follow-up procedures after primary treatment are still a controversial issue. Aim of this study was to investigate, through a web-based survey, surveillance methodologies selected by Italian oncologists in everyday clinical practice. Methods: Referents of Italian medical oncology units were invited to participate to the study via e-mail through the SurveyMonkey website. Participants were asked how, in their institution, exams of disease staging and follow-up are planned in asymptomatic women and if surveillance continues beyond the 5th year. Results: Between February and May 2013, 125 out of 233 (53.6%) invited referents of Italian medical oncology units agreed to participate in the survey. Ninety-seven (77.6%) referents state that modalities of breast cancer follow-up are planned according to the risk of disease progression at diagnosis and only 12 (9.6%) oncology units apply the minimal follow-up procedures according to international guidelines. Minimal follow-up is never applied in high risk asymptomatic women. Ninety-eight (78.4%) oncology units continue follow-up in all patients beyond 5 years. Conclusions: Our survey shows that 90.4% of participating Italian oncology units declare they do not apply the minimal breast cancer follow-up procedures after primary treatment in asymptomatic women, as suggested by national and international guidelines. Interestingly, about 80.0% of interviewed referents performs the so called "tailored follow-up", high intensity for high risk, low intensity for low risk patients. There is an urgent need of randomized clinical trials able to determine the effectiveness of risk-based follow-up modalities, their ideal frequency and persistence in time

Safety and Activity Report of a Randomized Phase II Trial of Preoperative Anthracycline-Based Chemotherapy Plus Lapatinib, Trastuzumab or Both in HER2 Positive Breast Cancer: CHERLOB Trial.

Introduction: We have designed a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or both trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage of pathological complete response (pCR) as defined as complete disappearance of invasive tumor in both breast and axillary nodes.Methods: chemotherapy (CT) consists of paclitaxel 80 mg/m2 weekly x 12 weeks followed by FE75C x 4 cycles administered every 3 weeks. Patients randomized to arm A receive CT plus weekly trastuzumab; in arm B patients receive CT plus lapatinib 1500 mg po daily; in arm C patients receive CT plus weekly trastuzumab and lapatinib 1000 mg po daily. Trastuzumab and lapatinib are administered throughout the entire CT plan. The study sample size has been calculated according to the two steps Simon's design. The overall planned accrual is 120 patients. Following the second safety report from the Independent Data Monitoring Committee on the first 30 evaluable patients, due to the occurrence of grade 3 diarrhea in 20% and in 41% of the patients randomized to arm B and C respectively, lapatinib doses have been reduced to 1250 mg in arm B and 750 mg in arm C.Results: 66 patients have been randomized: 20 in arm A, 20 in arm B, and 26 in arm C. Median age is 50 years (range 27-66). The overall non hematologic toxicity of grade (G) >1, as reported as maximum toxicity per patient, is as follows: diarrhea G2 29%, G3 22%; skin rash G2 29%, G3 7%; hepatobiliary events G2 10%, G3 5%, G4 3%.Left ventricular ejection fraction (LVEF) has been evaluated at baseline, after 12-13 weeks, and at the end of therapy. Mean LVEF% (range) was 62% (52%-77%), 61% (44%-78%) and 61% (53%-74%) respectively. No patient had symptomatic cardiac events. Forty-five patients underwent surgery, and are evaluable for response: 67% of the patients received breast conserving surgery. A pCR in breast and axillary nodes has been observed in 39% of the cases.Conclusions: The study accrual is ongoing. The safety of patients randomized following the amendment reducing lapatinib dosage will be presented at the Meeting

Safety and Activity Report of a Randomized Phase II Trial of Preoperative Anthracycline-Based Chemotherapy Plus Lapatinib, Trastuzumab or Both in HER2 Positive Breast Cancer: CHERLOB Trial.

Introduction: We have designed a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or both trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage of pathological complete response (pCR) as defined as complete disappearance of invasive tumor in both breast and axillary nodes. Methods: chemotherapy (CT) consists of paclitaxel 80 mg/m2 weekly x 12 weeks followed by FE75C x 4 cycles administered every 3 weeks. Patients randomized to arm A receive CT plus weekly trastuzumab; in arm B patients receive CT plus lapatinib 1500 mg po daily; in arm C patients receive CT plus weekly trastuzumab and lapatinib 1000 mg po daily. Trastuzumab and lapatinib are administered throughout the entire CT plan. The study sample size has been calculated according to the two steps Simon's design. The overall planned accrual is 120 patients. Following the second safety report from the Independent Data Monitoring Committee on the first 30 evaluable patients, due to the occurrence of grade 3 diarrhea in 20% and in 41% of the patients randomized to arm B and C respectively, lapatinib doses have been reduced to 1250 mg in arm B and 750 mg in arm C. Results: 66 patients have been randomized: 20 in arm A, 20 in arm B, and 26 in arm C. Median age is 50 years (range 27-66). The overall non hematologic toxicity of grade (G) >1, as reported as maximum toxicity per patient, is as follows: diarrhea G2 29%, G3 22%; skin rash G2 29%, G3 7%; hepatobiliary events G2 10%, G3 5%, G4 3%. Left ventricular ejection fraction (LVEF) has been evaluated at baseline, after 12-13 weeks, and at the end of therapy. Mean LVEF% (range) was 62% (52%-77%), 61% (44%-78%) and 61% (53%-74%) respectively. No patient had symptomatic cardiac events. Forty-five patients underwent surgery, and are evaluable for response: 67% of the patients received breast conserving surgery. A pCR in breast and axillary nodes has been observed in 39% of the cases. Conclusions: The study accrual is ongoing. The safety of patients randomized following the amendment reducing lapatinib dosage will be presented at the Meeting. Supported by GlaxoSmithKlin