Ilaria Bertolini

Triple positive early breast cancer: An observational multicenter retrospective analysis of outcome

We recently found that trastuzumab benefit may be lower in a small subset of early breast cancer (BC) patients (pts) with tumors expressing high levels of both hormonal receptors (HRs), i.e. triple positive (TP). To better investigate the role of HRs in HER2 positive BC, we retrospectively identified 872 TP BC pts treated with adjuvant chemotherapy alone (cohort A-366 pts), or plus trastuzumab (cohort B-506 pts). Relapse-free-survival (RFS) and breast-cancer-specific-survival (BCSS) were evaluated. Trastuzumab improved RFS and BCSS in all the subsets analyzed, but the effect on BCSS in tumors expressing both HRs in >30% of cells (TP30), and even on RFS in tumors with both HRs expressed in >50% of cells (TP50) was not significant. Distinct patterns of relapse were observed in TP50 and no-TP50 tumors, the former showing low and constant risk in the first 5 years, a late increase beyond 5 years and modest trastuzumab effect. Trastuzumab effect tended to disappear in pts whose tumors expressed ER in >50% of cells. Multivariate analysis of RFS confirmed a significant interaction between trastuzumab and ER expression, with benefit confined to pts whose tumors expressed ER in ≤50% of cells. Our data suggest that the pattern of relapse of TP tumors with high HRs is similar to that of “luminal”, HER2 negative tumors, without clear benefit from adjuvant trastuzumab, which remains the standard treatment even in TP tumors. Confirmatory findings on the extent to which quantitative expression of HRs may impact clinical behavior of HER2 positive BC are warranted.

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.

A Real‐World Multicentre Retrospective Study of Paclitaxel‐Bevacizumab and Maintenance Therapy as First‐Line for HER2‐Negative Metastatic Breast Cancer

Bevacizumab in combination with taxanes in HER2‐negative metastatic breast cancer (MBC) patients has shown improved progression‐free survival (PFS), despite the lack of clear overall survival (OS) benefit. We performed a retrospective analysis to evaluate the impact of paclitaxel‐bevacizumab and of maintenance therapy with bevacizumab (BM) and endocrine therapy (ET) in the real‐world practice. We identified 314 HER2‐negative MBC patients treated in 12 cancer centers. Overall, the median PFS and OS were 14 and 40 months, respectively. Among the 254 patients potentially eligible for BM, 183 received BM after paclitaxel discontinuation until progression/toxicity. PFS and OS were improved in patients who had received BM in comparison with those potentially eligible but who did not receive BM (P< 0.0001 and P = 0.001, respectively). Results were confirmed when adjusting for propensity score. Among the 216 hormone‐receptor positive patients eligible for BM, a more favorable PFS and OS were observed when maintenance ET was administered (P < 0.0001). Multivariate analysis showed that PS, BM, number of disease sites and maintenance ET were related to PFS, while response and maintenance ET were related to OS. In hormone‐receptor positive patients, BM produced a significant PFS and a trend towards OS benefit only in absence of maintenance ET (P = 0.0007 and P = 0.06, respectively). In the triple‐negative subgroup, we observed a trend towards a better OS for patients who received BM (P = 0.06), without differences in PFS (P = 0.21). Our results confirmed the efficacy of first‐line paclitaxel‐bevacizumab in real‐world practice; both BM and maintenance ET significantly improved PFS and OS compared to no maintenance therapies. J. Cell. Physiol. 232: 1571–1578, 2017.

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.

Body mass index in HER2-negative metastatic breast cancer treated with first-line paclitaxel and bevacizumab

ABSTRACT The evidence emerged from the TOURANDOT trial encourages evaluating the role of anthropometric determinants on treatment outcomes in HER2-negative metastatic breast cancer patients treated with bevacizumab-including regimens. We thus analyzed data from a subgroup of these patients from a larger cohort previously assessed for treatment outcomes. Patients were included in the present analysis if body mass index values had been recorded at baseline. Clinical benefit rates, progression free survival and overall survival were assessed for the overall study population and subgroups defined upon molecular subtype. One hundred ninety six patients were included (N:196). Body mass index showed no impact on clinical benefit rates in the overall study sample and in the luminal cancer subset (p = 0.12 and p = 0.79, respectively), but did so in the triple negative subgroup, with higher rates in patients with body mass index ≥25 (p = 0.03). In the overall study sample, body mass index did no impact progression free or overall survival (p = 0.33 and p = 0.67, respectively). Conversely, in triple negative patients, progression free survival was significantly longer with body mass index ≥25 (6 vs 14 months, p = 0.04). In this subset, overall survival was more favorable (25 vs 19 months, p = 0.02). The impact of the molecular subtype was confirmed in multivariate models including the length of progression free survival, and number of metastatic sites (p < 0.0001). Further studies are warranted to confirm our findings in more adequately sized, ad hoc, prospective studies.

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...

Abstract P1-08-31: Putative role of genetic variants of eNOS in survival and toxicity of patients given antiangiogenic therapy

Background: The development of tumor angiogensis is mainly driven by vascular endothelial growth factor (VEGF), which is strongly overexpressed in many cancers. VEGF induces the expression of the endothelial nitric oxide (NO) synthase (eNOS) and the resultant overproduction of NO may be associated with recruitment of inflammatory cells, disruption of endothelial barrier, edema and impaired drug delivery within tumors (1). Functional polymorphisms in the eNOS gene, including -786C>T and 894G>T, have been associated with impaired production of NO and higher incidence of hypertension (HT) (2), diabetic nephropathy (3) and glaucoma (4). Since suppression of VEGF-eNOS signal transduction by antiangiogenic drugs may normalize tumor vasculature by restoring interstitial fluid pressure and drug distribution in tumors, but may induce HT in patients, the purpose of this study was to examine the association between the major eNOS variants -786C>T and 894G>T with treatment outcome and risk of HT in metastatic breast cancer (MBC) patients given bevacizumab. Methods: Sixty-five MBC patients given bevacizumab as per approved indication were enrolled. Main characteristics were: mean age 49.5 years (range 29-73) at first diagnosis, 53 years (range 34-74) at metastatic progression and PS 0-1. Four subjects with HT and 1 patient with compensated cardiovascular disease were also included. First-line chemotherapy for metastatic disease was taxol plus bevacizumab. Germline DNA was extracted from peripheral blood with the Qiamp Mini Kit (Qiagen, Milano, Italy) and examined for eNOS -786C>T and 894G>T variants by Real Time PCR (Life Sciences 7900HT platform) and automatic sequencing (Life Sciences 3100 Avant). The study was approved by the local Ethics Committee. Results: Genotype frequencies are reported below (Table 1). The presence of -786TT genotype was associated with longer PFS compared with the other genotypes (median PFS 95%CI, CC/CT = 9 vs TT = 12 months, Log-rank [Mantel Cox] test p = 0.0066), but not with any grade of HT. Also the 894GT/TT was associated with longer PFS compaed with the GG homozygous wild-type genotype (median PFS 95%CI, GG = 7,5 vs GT/TT = 10 months, Log-rank [Mantel-Cox] test p = 0,0497). The incidence and severity of HT did not vary among genotypes. Conclusion: Patients bearing deficient eNOS variant did not experience higher risk or severity of HT with respect to the wild-type allele but enjoied a longer PFS. View this table: Table 1. Genotype frequencies References 1. Goel S et al. Physiol Rev 2011;91:1071 2. Niu W, Qi Y. PLoS One 2011;6:e24266 3. Rahimi Z et al. Dis Markers 2013;34:437 4. Awadalla MS et al. Invest Ophtalmol Vis Sci 2013;54:2108. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-31.

Abstract P5-17-06: The deficient eNOS c.894G>T genotype is not associated with increased severity of hypertension and proteinuria in breast cancer patients receiving bevacizumab

Background. Tumor angiogenesis is a complex process involving a wide array of effector molecules and stromal cells. In tumor tissue, vasculature is structurally and functionally abnormal, causing elevated interstitial pressure and irregular perfusion. The expression of vascular endothelial growth factor (VEGF), the most important angiogenic factor, is enhanced in many tumors. VEGF may induce nitric oxide (NO) production via up-regulation of the endothelial NO synthase (eNOS, NOS3) and the resultant overproduction of NO is associated with vasodilation and edema within tumors (Goel S et al. Physiol Rev 2011;91:1071). eNOS plays an important physiologic role in maintaining blood pressure homeostasis and vascular integrity by providing constitutive release of NO in endothelial cells. Functional variants of the eNOS gene, including the single-nucleotide polymorphism rs1799983 (c.894G>T, p. Asp298Glu) at codon 298, have been associated with reduced function of eNOS and higher incidence of hypertension (HT) (Niu W, Qi Y. PLoS One 2011;6:e24266). Purpose. Since suppression of VEGF-eNOS axis by anti-angiogenic therapies is considered a causative factor of HT in patients, the purpose of this study was to examine whether the major eNOS non-synonymous variant c.894G>T may be associated with increased risk of developing hypertension (HT) and proteinuria (PU) in breast cancer patients treated with bevacizumab. Patients and methods. Forty-one metastatic breast cancer patients given bevacizumab as per standard of care were enrolled. Main characteristics were: median age 49.5 years (range 29–73) at first diagnosis, 53 years (range 34–74) at metastatic disease; PS 0–1 in all patients; 4 subjects with hypertension and 1 patient with compensated cardiovascular disease at diagnosis. Twenty-six subjects had received neoadjuvant or adjuvant chemotherapy based on anthracycline and taxane; first-line chemotherapy for metastatic disease was paclitaxel plus bevacizumab for all patients; 14 subjects received hormone-therapy for metastatic disease (range 1–5 lines). Germline DNA was extracted from peripheral blood and used to screen patients for eNOS c.894G>T variant by automatic sequencing. The study was approved by the local Ethics Committee. Results. Three patients (7.3%) were homozygous variant c.894TT, 12 (29.3%) homozygous wild-type c.894GG and the remaining 26 (63.4%) were heterozygous c.894GT. The c.894TT patients had no HT or PU at baseline and developed grade (G) 1, 2, 2 HT, respectively, and in one case PU during treatment. G1, 2 and 3 HT developed in 4, 5 and 2 c.894GG subjects, respectively, while PU was observed in 7/12 (58%) patients. The full range of HT grades and PU were observed in heterozygous subjects. Thirty-seven patients achieved one of the following: partial remission, minimal response or stable disease upon treatment with bevacizumab in combination with chemotherapy; 3 subjects had progressive disease and 1 was not evaluable. Conclusions. The presence of the mutant T allele of c.894G>T is not associated with increased severity of HT and PU; therefore, bevacizumab can be administered at no increased risk in TT patients with respect to the wild-type GG population. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-06.