Elisabetta Landucci

Eribulin Mesylate in Pretreated Breast Cancer Patients: A Multicenter Retrospective Observational Study

Background: Eribulin was recently approved in patients progressing after being treated with anthracyclines and taxanes and after two or more chemotherapy lines for advanced disease. Objectives: This multicenter observational retrospective study was performed in order to evaluate activity and tolerability of eribulin in real-world patient population. Methods: 133 advanced breast cancer patients pretreated with ≥ 2 chemotherapy lines for metastatic disease were retrospectively enrolled in the observational trial in 11 italian cancer centres. Results: A median of 5 cycles of eribulin (range, 1-15) were administered. Twenty-eight partial responses were observed, for an overall response rate of 21.1% (95%CI,14.1-28.0). A stable disease was recorded in 57 patients (42.8%), and a clinical benefit (response or stable disease lasting ≥ six months) was observed in 51 patients (38.3%, 95%CI, 30.1-46.6). The subgroup analysis showed that a significant improvement in term of partial response and clinical benefit was achieved when eribulin was administered in HER-2 negative tumors (p=0.01 and p=0.004, respectively) and when it is given as third-line (p=0.09 and p=0.02, respectively). Toxicity was manageable; fatigue is the most common side effect observed, usually of low-grade, and clearly cumulative-dose related. Conclusions: In this retrospective, observational analysis eribulin confirmed its efficacy and manageable tolerability even in real-world population and in heavily pretreated patients.

Activity of first-line epirubicin and paclitaxel in metastatic breast cancer is independent of type of adjuvant therapy

To evaluate the impact of prior adjuvant chemotherapy on response rate (RR), progression-free (PFS) and overall survival (OS) of metastatic breast cancer patients treated with epirubicin/paclitaxel (ET) regimens. In all, 291 patients enrolled in five studies in metastatic breast cancer were analysed: 101 (35%) were chemonaive, 109 (37%) had received adjuvant CMF and 81 (28%) adjuvant anthracyclines. Response rate to ET was 66%. Response rate was 63% for cyclophosphamide plus methotrexate plus 5-fluorouracil (CMF), 67% for prior anthracyclines and 68% in chemonaive patients (P=0.5). By multivariate analysis, adjusted odds ratio for response was 0.81 (95% CI: 0.37–1.79) for CMF and 0.92 (95% CI 0.43–2.01) for anthracyclines (P=0.86). The CR rates were 14% for both CMF and anthracyclines and 22% for chemonaive patients (P=0.2). By multivariate analysis, the relative odds of CR for CMF or anthracyclines were 0.40 and 0.39 as compared to chemonaive patients (P=0.036). The median PFS was 11.0 months for prior CMF, 10.2 months for anthracyclines and 12.5 months in chemonaive patients (P=0.33). In multivariate Coxs model, a nonsignificant increase in the risk of progression was seen in patients treated with adjuvant CMF or anthracyclines. The median OS was 23.8 months for CMF, 20.2 months for anthracyclines and 27.5 months in chemonaive patients (P=0.61). The same, nonsignificant, association was seen in multivariate analysis. The ET regimens provide satisfactory results in metastatic breast cancer, regardless of previous adjuvant chemotherapy.

Gemcitabine, epirubicin, and paclitaxel combinations in advanced breast cancer.

Strategies to improve outcome in metastatic breast cancer include the first-line use of combinations of optimal doses of active agents, with the goal being to improve complete response rates and thus long-term survival. Although prior studies of anthracycline/taxane combinations generally have shown improved response rates and progression-free survival in comparison with single-agent regimens or anthracycline/cyclophosphamide-containing combinations, the data have not consistently demonstrated improved overall survival; indeed, they have yielded generally disappointing complete response rates. We evaluated the combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), epirubicin, and paclitaxel (GET) based on the hypothesis that epirubicin/paclitaxel is best suited for achieving delivery of optimal doses, and the addition of gemcitabine (which exhibits good single-agent activity with a favorable toxicity profile) will increase activity. In a phase II trial of 36 patients, the GET regimen produced reasonable toxicity and was associated with a 92% response rate, including complete responses in 31% of patients. The overall response rate increased to 97%, including complete responses in 41% of patients, with high-dose consolidation chemotherapy in 25 patients. A trial comparing GET with epirubicin/paclitaxel as first-line treatment in more than 600 patients with metastatic breast cancer has been initiated, with survival as the primary end point. Another large-scale trial is being planned to compare the GET regimen with an anthracycline/cyclophosphamide/paclitaxel combination in patients with early stage high-risk breast cancer. Semin Oncol 28 (suppl 7):15-17.

Body Mass Index and Treatment Outcomes in Metastatic Breast Cancer Patients Treated With Eribulin

Eribulin has shown survival advantage and manageable toxicity in heavily pre‐treated metastatic breast cancer (mBC). We assessed whether body mass index (BMI) impacts treatment outcomes in 101 patients treated with eribulin at six Italian Oncologic Centers. BMI was addressed as a categorical variable (18.5–24.9 vs. at least 25). Clinical benefit rate (CBR) was assessed overall and in subgroups defined by BMI, line of therapy (LOT), and hormone receptor (HR) status. Analysis of CBR by LOT and HR status were further stratified by BMI. Survival curves were compared using the Kaplan–Meier method and log‐rank test. Predictors of survival were tested in Cox models. Patients treated with eribulin as third line showed greater CBR when their BMI was in the lowest category (77.8 vs. 58.1%, P = 0.03). Median progression free survival (PFS) and overall survival (OS) in normal and overweight patients were 4 (95% CI, 3–5) versus 3 (2.1–4) months, P = 0.02 and 13 (11–15) versus 12 (6–18) months, P = 0.96, respectively. Median PFS and OS in estrogen receptor (ER) positive and negative tumours were 4 (3–5) versus 3 (2–4) months, P = 0.005 and 14 (10–18) versus 7 (4–10), P = 0.02, respectively. In multivariate analyses, BMI impacted PFS at a nearly significant extent (P = 0.05), while ER expression significantly affected PFS and OS (P = 0.01 and 0.02, respectively). No relevant findings emerged concerning toxicity. We found evidence of greater efficacy of eribulin in leaner mBC patients, particularly if given as third line and in ER positive tumors. Further studies are warranted to confirm our findings. J. Cell. Physiol. 231: 986–991, 2016.

Neoadjuvant chemotherapy in triple-negative breast cancer: A multicentric retrospective observational study in real-life setting

We aimed to assess the efficacy of neoadjuvant chemotherapy (NACT) in a cohort of 213 triple‐negative breast cancer (TNBC) patients treated in real‐world practice at eight Italian cancer centers. We computed descriptive statistics for all the variable of interest. Factors testing significant in univariate analysis were included in multivariate models. Survival data were compared by Kaplan–Meier curves and log‐rank test. The median follow‐up was 45 months. We observed 60 (28.2%) pathological complete response (pCR). The sequential anthracyclines‐taxanes‐based regimens produced the highest rate of pCR (42.6%), followed by concomitant anthracycline‐taxane (24.2%), and other regimens (15.6%) (p = 0.008). When analyzing the role of baseline Ki‐67, a 50% cut‐off was the optimal threshold value for pCR prediction (p = 0.0005). The 5‐year disease‐free survival (DFS) was 57.3% and the 5‐year overall survival (OS) was 70.8%. In patients not achieving pCR, the optimal Ki‐67 variation between biopsy and surgical specimen with prognostic relevance on long‐term outcomes was 13% (p = 0.04). Patients with a Ki‐67 reduction (rKi‐67)<13% had worse outcomes compared to those who experienced pCR or a rKi‐67≥13%. The number of NACT cycles also affected long‐term outcomes (5‐year DFS 65.7% vs 51.6% in patients having received >6 cycles compared with their counterparts, p = 0.02). In multivariate analysis, node status, grading, and bio‐pathological treatment response (including pCR and rKi‐67) impacted DFS and OS. Our results confirmed the advantage conferred by more than 6 cycles of a sequential antracycline‐taxane‐based NACT. Higher baseline Ki‐67 values shows greater predictive significance on pathogical response, while the rKi‐67 plays a prognostic role on long‐term outcomes.

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.

Germline Mutations in DNA Repair Genes May Predict Neoadjuvant Therapy Response in Triple Negative Breast Patients

Triple negative breast cancers (TNBCs) represent about 15–20% of all breast cancer cases and are characterized by a complex molecular heterogeneity. Some TNBCs exhibit clinical and pathological properties similar to BRCA‐mutated tumors, without actually bearing a mutation in BRCA genes. This “BRCAness” phenotype may be explained by germline mutations in other genes involved in DNA repair. Although respond to chemotherapy with alkylating agents, they have a high risk of recurrence and progression. Some studies have shown the efficacy of neoadjuvant therapy in TNBC patients with DNA repair defects, but proper biomarkers of DNA repair deficiency are still needed. Here, we investigated if mutations in DNA repair genes may be correlated with anthracyclines/taxanes neoadjuvant therapy response. DNA from 19 TNBC patients undergoing neoadjuvant therapy were subjected to next generation sequencing of a panel of 24 genes in DNA repair and breast cancer predisposition. In this study, 5 of 19 patients (26%) carried a pathogenic mutation in BRCA1, PALB2, RAD51C and two patients carried a probable pathogenic missense variant. Moreover, VUS (Variants of Unknown Significance) in other genes, predicted to be deleterious by in silico tools, were detected in five patients. Germline mutations in DNA repair genes were found to be associated with the group of TNBC patients who responded to therapy. We conclude that a subgroup of TNBC patients have defects in DNA repair genes, other than BRCA1, and such patients respond favourably to neoadjuvant anthracyclines/taxanes therapy.

Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

In this study, we determined if BRCA1 partners involved in DNA double-strand break (DSB) and mismatch repair (MMR) may contribute to breast and ovarian cancer development. Taking advantage the functional conservation of DNA repair pathways between yeast and human, we expressed several BRCA1 missense variants in DNA repair yeast mutants to identify functional interaction between BRCA1 and DNA repair in BRCA1-induced genome instability. The pathogenic p.C61G, pA1708E, p.M775R, and p.I1766S, and the neutral pS1512I BRCA1 variants increased intra-chromosomal recombination in the DNA-repair proficient strain RSY6. In the mre11, rad50, rad51, and msh6 deletion strains, the BRCA1 variants p.C61G, pA1708E, p.M775R, p.I1766S, and pS1215I did not increase intra-chromosomal recombination suggesting that a functional DNA repair pathway is necessary for BRCA1 variants to determine genome instability. The pathogenic p.C61G and p.I1766S and the neutral p.N132K, p.Y179C, and p.N550H variants induced a significant increase of reversion in the msh2Δ strain; the neutral p.Y179C and the pathogenic p.I1766S variant induced gene reversion also, in the msh6Δ strain. These results imply a functional interaction between MMR and BRCA1 in modulating genome instability. We also performed a somatic mutational screening of MSH6, RAD50, MRE11A, and RAD51 genes in tumor samples from 34 patients and identified eight pathogenic or predicted pathogenic rare missense variants: four in MSH6, one in RAD50, one in MRE11A, and two in RAD51. Although we found no correlation between BRCA1 status and these somatic DNA repair variants, this study suggests that somatic missense variants in DNA repair genes may contribute to breast and ovarian tumor development.

Evaluation of safety and activity of everolimus plus exemestane in metastatic breast cancer: A single institution experience.

e14554Background: Everolimus (EV) is an oral inhibitor of mammalian target of rapamicin (mTOR), recently approved in combination with exemestane (EX) for the treatment of hormonal positive metastat...

A41Evaluation of safety and activity of everolimus plus exemestane in metastatic breast cancer: a single institution experience

e14554Background: Everolimus (EV) is an oral inhibitor of mammalian target of rapamicin (mTOR), recently approved in combination with exemestane (EX) for the treatment of hormonal positive metastat...