Long-Term Outcomes With Pharmacological Ovarian Suppression During Chemotherapy in Premenopausal Early Breast Cancer Patients.

BACKGROUND: Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available, raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential. METHODS: The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6 (PROMISE-GIM6) trial is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomly assigned to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). The primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency. Post hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Of 281 randomly assigned patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in the GnRHa arm vs 69.2% [95% CI = 60.3% to 76.5%] in the control arm; HR = 1.16, 95% CI = 0.76 to 1.77) or in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in the GnRHa arm vs 81.3% [95% CI = 73.1% to 87.2%] in the control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the hazard ratio was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a posttreatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92). CONCLUSIONS: Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease.

EFFECT: a randomized phase II study of efficacy and impact on function of two doses of nab-paclitaxel as first-line treatment in older women with advanced breast cancer.

BACKGROUND: Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. METHODS: EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m2 (arm A) or 125 mg/m2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9-8.9; p = 0.188) in arm A vs 8.3 months (90% CI, 6.2-9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2-3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2-3 arm A vs B, 19% and 38%, respectively). CONCLUSION: Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. TRIAL REGISTRATION: EudraCT, 2012-002707-18 . Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222 . Retrospectively registered on May 26, 2016.

Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting.

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs-negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment-related outcomes of HER2-positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2-positive (mbc) patients.

A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study.

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.

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

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.

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.

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. © 2016 Wiley Periodicals, Inc.

Symptom improvement as prognostic factor for survival in cancer patients undergoing palliative care: a pilot study.

BACKGROUND: The Edmonton Symptom Assessment Scale (ESAS) is a validated tool for physical symptom assessment in palliative care practice which evaluates symptoms through a numeric scale from 0 to 10. The use of symptom improvement as a prognostic factor is controversial. To this purpose, a pilot study in advanced cancer patients now undergoing only palliative care was conducted. METHODS: Patients were considered eligible if no longer able to receive any anticancer treatment; they were scheduled to undergo ESAS assessment at the hospitalization and hospital discharge time points. Symptoms' scores were divided into three severity classes: mild, moderate and severe. Differences across symptoms' classes between hospitalization and hospital discharge time points were analysed with the paired-data McNemar test, according to tumour types. RESULTS: ESAS assessment was administered to 68 patients with gastrointestinal (39 patients) and non-small cell lung cancer (29 patients); median age was 69 years; Karnofsky Performance Status was 50 in 27 (39.7%) patients and >50 in 41 (60.3%) patients. Palliative Prognostic Score was A for 26 (38.2%) patients, B for 37 (54.4%) patients and C for 5 (7.4%) patients. A statistically significant reduction of severe severity class rates was observed. Symptom improvement correlates with survival improvement: Palliative Prognostic Score (hazard ratio (HR) 2.95, 95% CI 1.35-6.41, p = 0.006) and anorexia (HR 3.21, 95% 1.33-7.72, p = 0.009) appear to be prognostic factors for survival at the multivariate analysis for gastrointestinal cancer patients; asthenia is the only significant variable (HR 5.11, 95% CI 1.86-14.03, p = 0.002) for non-small cell lung cancer patients. CONCLUSIONS: Symptom improvement according to ESAS after palliative care treatment represents an important prognostic for survival in patients no longer suitable to receive any anticancer active therapies.

Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.

CONTEXT: Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available. OBJECTIVE: To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. DESIGN, SETTING, AND PATIENTS: The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data. INTERVENTIONS: Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy. MAIN OUTCOME MEASURE: Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy). RESULTS: The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001). CONCLUSION: The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00311636.

Time to first tumor progression as outcome predictor of a second trasuzumab-based therapy beyond progression in HER-2 positive metastatic breast cancer.

In a previous analysis performed on a cohort of 37 HER-2 positive metastatic breast cancer (MBC) patients treated with trastuzumab beyond progression, we found that a second trastuzumab-based therapy is associated with a considerable response rate and preserved time to progression as compared with a first trastuzumab-based therapy. In the present study, we extended the analysis to a total of 69 patients treated in four different italian Institutions, also trying to identify clinical predictors of sensitivity to a second trastuzumab-based therapy beyond progression. Efficacy results on the overall population confirmed that a second trastuzumab-based therapy beyond progression is an active regimen (27.5% of responses and 6.5 months of time to progression, respectively). Median time to progression to the first trastuzumab therapy (TTP1) identified two groups of patients with different sensitivity to trastuzumab beyond progression (group A, TTP1 >or= 8 months and group B, TTP1 < 8 months) in terms of time to second progression and post-progression survival (group A versus group B showed respectively a time to second progression of 7.6 versus 4.7 months, p = 0.05, and a post-progression survival of 31.7 months versus 21.8 months, p = 0.04). In the multivariate analysis, only TTP1 was a predictor of time to second progression and post-progression survival. Despite the recent approval of lapatinib plus capecitabine for trastuzumab-progressing patients, it is still reasonable to offer trastuzumab beyond progression to HER-2 positive MBC patients, because these data confirm the potential utility of such a conduct. In the clinic, time to first tumor progression may represent a useful tool to identify patients who are more likely to benefit from trastuzumab beyond progression.

Gemcitabine as single agent chemotherapy in elderly patients with stages III-IV non-small cell lung cancer (NSCLC): a phase II study.

INTRODUCTION: In the past the unfavourable profile of toxicity of antineoplastic drugs employed (i.e. cisplatinum) weakened the role of chemotherapy in aged patients with non-small cell lung cancer (NSCLC). Recently, new active drugs with lesser toxicity have became widely used in this setting. In this prospective study we evaluated the efficacy and tolerability of gemcitabine in elderly patients with stages III-IV NSCLC. MATERIALS AND METHODS: From December 1996 to April 1999, we enrolled 52 previously untreated elderly patients with advanced/metastatic NSCLC. Gemcitabine was administered at 1000 mg/mq i.v. over 30 minutes weekly for three consecutive weeks every 28 days. The planned number of cycles was three while responding or stable patients received chemotherapy until disease progression or the ninth cycle. A total of 291 cycles were delivered with a median number of 6 cycles (range: 3-9). An evaluation of the quality of life was performed every three courses of gemcitabine. RESULTS: After three cycles of treatment, a complete response was seen in four patients (7.7%), partial response in 16 patients (30.8%) with an overall response rate of 38.5%. Nineteen patients (36.5%) showed stable disease, while thirteen patients (25%) progressed. Median progression-free survival was 22 weeks, median duration of response 26 weeks, median overall survival 34 weeks and 1-year overall survival 46.1%. A statistically significant improvement in the quality of life was registered only after the first three cycles of gemcitabine (p = 0.045). Toxicity was extremely mild. CONCLUSION: In elderly patients with stages III-IV NSCLC gemcitabine showed good activity with a mild toxicity and could be considered a valid therapeutic option in this setting.