Francesco Schettini

Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: Where we are now and where we are going

Near 75% of all breast cancers (BC) express estrogen receptors (ER) and/or progesterone receptors (PgR), while up to 20% of BC show an overexpression/amplification of Human Epidermal Growth Factor Receptor 2 (HER2). Around 50% of all HER2-overexpressing BC show the coexistence of both HER2 overexpression/amplification and ER and/or PgR overexpression. Numerous in vitro and in vivo studies suggest the existence of a cross-talk between their downstream pathways, which seem to affect the natural history, response to therapy and outcome of patients affected by this subset of BC. Meta-analyses or subgroup analysis of numerous neo-/adjuvant trials demonstrated significant clinical implications deriving from ER/HER2 co-existence, consisting in a different pattern of relapse and dissimilar outcome in response to anti-HER2 therapy. However, only two randomized trials in early disease and three in advanced disease specifically addressed the issue whether a combined approach with both hormonal and anti-HER2 therapy would have a better therapeutic impact in this subset of BC compared to the lone anti-HER2 or hormonal therapies (HT). None of these trials demonstrated improvements in overall survival, even though several efficacy end-points such as progression free survival, in advanced setting, or pCR rates in neoadjuvant setting, often favored the combined hormonal and anti-HER2 therapeutic approach. In the next few years, a certain number of ongoing randomized trials, both in neoadjuvant and advanced setting, will evaluate the efficacy of new anti-HER2 drugs, T-DM1 and pertuzumab, in combination with HT, helping to improve the therapeutic strategy for this specific subtype of breast tumors.

Fractional microablative CO2 laser for vulvovaginal atrophy in women treated with chemotherapy and/or hormonal therapy for breast cancer: a retrospective study.

Objectives:Breast cancer is one of the most common malignancies in women. Hormonal treatment and chemotherapy induce a transient or permanent menopause status. Vulvovaginal atrophy (VVA) is a frequent debilitating symptom of menopause that is best treated with local or systemic estrogen formulations. Because estrogens drive the growth of the majority of breast cancers, most effective VVA therapies are precluded. The aim of this study was to evaluate the effects of fractional microablative CO2 laser on sexual function and in relieving symptoms in women with breast cancer and VVA induced or exacerbated by iatrogenic menopause. Methods:This retrospective study included 26 women affected by hormone-receptor positive breast tumors and treated for VVA symptoms with the fractional microablative CO2 laser system. Every 30 to 40 days, women underwent a cycle of treatment for a total of three cycles. During each cycle, women underwent a gynecological examination and completed visual analog scale questionnaires designed to assess (1) the degree of symptoms and (2) procedure-related discomfort. Results:Treatment resulted in a significant regression of VVA symptoms and procedure-related discomfort versus baseline (P < 0.001 in almost all cases). No adverse reactions were observed nor reported by women. Conclusions:Fractional microablative CO2 laser treatment is associated with a significant improvement of VVA symptoms in women affected by hormone-driven breast cancer. This procedure has the advantage of relieving iatrogenic/physiological VVA symptoms without resorting to contraindicated estrogen preparations, which have been the most effective therapy thus far.

Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives

Triple-negative breast cancer (TNBC) accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Despite an increasing understanding of the molecular heterogeneity of TNBC, clinical trials of targeted agents have thus far been disappointing; chemotherapy, in particular with anthracycline and taxanes, remains the backbone medical management for both early and metastatic TNBC. Nab-paclitaxel is a solvent-free, albumin-bound, nanoparticle formulation of paclitaxel and represents a novel formulation of an established, effective chemotherapeutic agent. Nab-paclitaxel has been specifically designed to overcome the limitations of conventional taxane formulations, including the barriers to effective drug delivery of highly lipophilic agents. It has shown significant efficacy and better tolerability than conventional taxanes in metastatic breast cancer and is approved for use in this setting. Increasing evidence suggests that nab-paclitaxel is effective in patients with more aggressive tumours, as seen in TNBC. Indeed, results of Phase II/III studies indicate that nab-paclitaxel may be effective as neoadjuvant treatment of TNBC. This article reviews the rationale and evidence supporting a role for nab-paclitaxel in the treatment of TNBC, including ongoing studies such as ADAPT-TN and tnAcity. In addition, the article reviews ongoing research into targeted therapies and immuno-oncology for the treatment of TNBC, and explores the potential role, current evidence and ongoing studies of nab-paclitaxel as the chemotherapy partner in combination with immunotherapy, where the unique properties of this taxane, including the lack of requirement for steroid pre-medication, may present an advantage.

Combined effect of obesity and diabetes on early breast cancer outcome: a prospective observational study

Background Previous studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients. Materials and Methods Overall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi-square test and survival data by the log-rank test. Results At diagnosis, obese and diabetic patients were more likely to be older (p < 0.0001) and post-menopausal (p < 0.0001) and to have a tumor larger than 2 cm (p < 0.0001) than patients in groups 1–3. At univariate analyses, obese and diabetic patients had a worse disease-free survival (p = 0.01) and overall survival (p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for disease-free survival (hazard ratio=2.62, 95% CI 1.23–5.60) but not for overall survival. Conclusions At diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cancer.

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom?

Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in luminal breast cancer (BC). Despite the efficacy of endocrine agents, many patients with luminal BC do not respond to endocrine therapy and many others develop endocrine resistance over time, due to the activation of escape pathways such as the PI3K/AKT/mTOR signaling. Several clinical trials have demonstrated the efficacy of mTOR and PI3K inhibitors in overcoming endocrine resistance in hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic BC (MBC) patients. Nevertheless, to date, everolimus is the only agent targeting the PI3K/mTOR pathway that has been approved for clinical use. Recently, the introduction of CDK 4/6 inhibitors into clinical practice has significantly changed the therapeutic scenarios in luminal MBC. In the absence of direct comparisons among the new treatment combinations and predictive biomarkers of response, the choice of optimal therapeutic algorithms is very challenging. Future trials should focus on identifying more effective and safe combination therapies and defining the best treatment sequences in luminal BC.

Luminal-like HER2-negative stage IA breast cancer: A multicenter retrospective study on long-term outcome with propensity score analysis

The benefit of adding chemotherapy (CT) to adjuvant hormone therapy (HT) in stage IA luminal-like HER2-negative breast cancer (BC) is unclear. We retrospectively evaluated predictive factors and clinical outcome of 1,222 patients from 4 oncologic centers. Three hundred and eighty patients received CT and HT (CT-cohort) and 842 received HT alone (HT-cohort). Disease-free survival (DFS) and overall survival (OS) were evaluated with univariate and multivariate analyses. We also applied the propensity score methodology. Compared with the HT-cohort, patients in the CT-cohort were more likely to be younger, have larger tumors of a higher histological grade that were Ki67-positive, and lower estrogen and progesterone receptor expression. At univariate analysis, a higher histological grade and Ki67 were significantly associated to a lower DFS. At multivariable analysis, only histological grade was predictive of DFS. The CT-cohort had a worse outcome than the HT-cohort in terms of DFS and OS, but differences disappeared when matched according to propensity score. In summary, patients with stage IA luminal-like BC had an excellent prognosis, however relapse and mortality were higher in the CT-cohort than in the HT-cohort. Longer use of adjuvant HT or other therapeutic strategies may be needed to improve outcome.