Barbara Pistilli

Prognostic Impact of Pregnancy After Breast Cancer According to Estrogen Receptor Status: A Multicenter Retrospective Study

PURPOSE We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status. PATIENTS AND METHODS A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1:3) to patients with BC with similar ER, nodal status, adjuvant therapy, age, and year of diagnosis. To adjust for guaranteed time bias, each nonpregnant patient had to have a disease-free interval at least equal to the time elapsing between BC diagnosis and date of conception of the matched pregnant one. The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC-pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER-positive patients were required to detect a hazard ratio (HR) = 0.65. RESULTS A total of 333 pregnant patients and 874 matched nonpregnant patients were analyzed, of whom 686 patients had an ER-positive disease. No difference in DFS was observed between pregnant and nonpregnant patients in the ER-positive (HR = 0.91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC-pregnancy interval did not seem to impact the risk of relapse. CONCLUSION Pregnancy after ER-positive BC does not seem to reduce the risk of BC recurrence.

Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. METHODS The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. FINDINGS Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. INTERPRETATION The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. FUNDING Novartis Pharmaceuticals Corporation.

Abstract S6-01: PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial

Background: PI3K pathway activation is a hallmark of hormone receptor-positive (HR+) BC cells resistant to endocrine therapy (ET). Preclinical and early clinical data suggest that combining the pan-PI3K inhibitor BUP (BKM120) with ET may provide clinical benefits in this setting. BELLE-2 (NCT01610284) is the first randomized Phase III trial to assess the efficacy and safety of a PI3K inhibitor combined with FULV in HR+ advanced BC, including a prospective analysis of whether PI3K pathway activation status measured in archival tumor tissue and ctDNA is predictive of clinical benefit. Methods: Postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to aromatase inhibitor therapy were enrolled. After a 14-day run-in with FULV (500 mg), patients (pts) were randomized (1:1) to receive oral BUP (100 mg/day) or placebo (PBO) with FULV (500 mg per standard of care). Randomization of all pts was stratified by PI3K pathway status measured in archival tumor tissue (PIK3CA mutation or PTEN loss; activated, non-activated, unknown) and visceral disease status (present, absent). Baseline PIK3CA mutation status in ctDNA was assessed in a subset of 587 pts at trial entry. The primary endpoint was locally-assessed progression-free survival (PFS; RECIST v1.1) in the full population and PI3K pathway-activated group. Secondary endpoints included overall survival, safety, overall response rate (ORR), and clinical benefit rate (CBR). Results: 1147 pts received FULV with BUP or PBO, with 187 (16%) ongoing at data cut-off. Baseline characteristics were well balanced between the two arms: median age was 62 years, 98% had ECOG performance status of 0/1, 61% had visceral disease, 69% were sensitive to prior ET, 28% had received prior chemotherapy for metastatic BC. BELLE-2 met its primary endpoint in the full population (Table). In pts with PI3K pathway-activated tumor tissue, PFS increase for BUP+FULV vs PBO+FULV did not meet the planned endpoint. Among pts with PIK3CA status measured in ctDNA, median PFS, ORR, and CBR were significantly improved for BUP+FULV vs PBO+FULV in pts with PIK3CA-mutant tumors but not pts without. The most common Grade 3/4 adverse events (AEs; ≥5% of pts; BUP+FULV vs PBO+FULV) in all pts were increased alanine aminotransferase (26 vs 1%), increased aspartate aminotransferase (18 vs 3%), hyperglycemia (15 vs 0.2%), and rash (8 vs 0%). The most common reasons for treatment discontinuation were disease progression (54 vs 73%) and AEs (13 vs 2%). Conclusions: BELLE-2 met its primary endpoint in the full population. Prespecified analyses showed that characterizing PIK3CA mutation in ctDNA at trial entry identifies pts with endocrine- resistant HR+/HER2–advanced BC, for whom BUP+FULV results in meaningful clinical benefits. Citation Format: Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortes J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Hachemi S, Le Mouhaer S, Di Tomaso E, Urban P, Massacesi C, Campone M. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2– advanced breast cancer (BC): First results from the randomized, phase III BELLE-2 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-01.

Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: Subgroup analysis from the BOLERO-2 study

BACKGROUND Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). METHODS Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. FINDINGS At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). INTERPRETATION Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases.

Pregnancy following breast cancer using assisted reproduction and its effect on long-term outcome.

INTRODUCTION AND AIMS We have previously shown that pregnancy is safe following breast cancer, even in endocrine sensitive disease. Yet infertility remains common following systemic treatment. To date, no study has evaluated the safety of assisted reproductive technology (ART) after breast cancer treatment. In this study, we evaluated the impact of ART on pregnancy and long-term outcomes of young breast cancer survivors. METHODS This is a multi-centre retrospective study in which women who were diagnosed with breast cancer between 2000 and 2009, and had a pregnancy following breast cancer diagnosis were eligible. Patients were divided into two groups according to whether ART following primary systemic therapy was performed to achieve pregnancy. We evaluated the association between ART use and clinic-pathological characteristics, pregnancy outcome and long-term breast cancer outcome. RESULTS A total of 198 patients were evaluated; of whom 25 underwent ART. No significant differences in tumour characteristics were observed between both groups, except for histological grade 3 tumours, which were fewer in the ART group (36% versus 59%, p=0.033). Around 90% of patients received primary adjuvant chemotherapy and more than 50% had an endocrine sensitive disease. Patients in the ART group were older at diagnosis (31.4 versus 33.7 years, p=0.009), at conception (38 versus 35 years, p<0.001), and experienced more miscarriages (23.5 versus 12.6%, p=0.082). Full term pregnancies were achieved in 77% and 76% of the spontaneous and ART groups, respectively. Mean follow-up between conception and last follow-up was 63 and 50 months in the spontaneous and ART groups, respectively with no difference in breast cancer outcome observed between the two groups (p=0.54). CONCLUSION Pregnancy using ART in women with history of breast cancer is feasible and does not seem to be detrimental to cancer outcome. Larger studies are needed to further confirm this observation.

Predictors of short-term survival and progression to chemotherapy in patients with advanced colorectal cancer treated with 5-fluorouracil-based regimens.

The aim of this study was to assess in patients with advanced colorectal cancer which factors were associated with short-term survival (6 months or less) and progression to first-line 5-fluorouracil (5-FU) chemotherapy. Three hundred twenty-one consecutive nonselected patients with advanced colorectal cancer were treated with conventional 5-FU-based regimens as first-line treatment from 1988 to 1999. Factors related to patient, tumor, or treatment were analyzed by univariate and multivariate logistic regression analysis by comparing short survivors (SS, those who survived ≤6 months) with those who survived longer than 6 months. The same statistical methods were used to analyze 200 patients, all treated with bolus 5-FU regimens, by comparing who progressed to treatment with those who did not. Sixty-two patients (19.3%) were SS, the remaining 259 patients survived more than 6 months. First-line chemotherapy included 5-FU in all patients; 112 (35%) and 27 (8.4%) patients were offered, after disease progression, second and third-line chemotherapy, respectively. The overall response rate to first-line chemotherapy was 12.9%. No SS patient achieved an objective response. To investigate factors associated with progression to first-line chemotherapy, we considered only those patients treated with bolus 5-FU regimens, to eliminate the variable of regimen used. Ninety-six of them progressed to treatment and 104 did not. At multivariate analysis, SS patients were characterized by the following: right and transverse colon primary (p = 0.006), younger age (p = 0.043), poor performance status (Eastern Cooperative Oncology Group ≥ 2) (p = 0.015), elevated (≥5 &mgr;g/l) serum carcinoembryonic antigen (CEA) (p = 0.015), and more than one site of metastatic disease (p < 0.001). Progression to first-line chemotherapy (p < 0.001) was also a strong factor associated with short survival in multivariate analysis; factors predictive of progression were elevated CEA (p = 0.027) and diffuse metastatic disease (p = 0.029). Our data indicate the relevance of some clinical prognostic factors (younger age, poor performance status, elevated CEA, site of primary, number of metastatic sites, resistance to chemotherapy) as independent factors associated with poor survival and progression to first-line chemotherapy in patients with metastatic colorectal cancer treated with conventional 5-FU regimens. Patients identified by these factors as having a poor prognosis and low probability of response to treatment should be considered either for more aggressive regimens or supportive care only: conventional 5-FU treatments do not impact on response or survival.

Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: How should we counsel cancer patients about breastfeeding?

An increasing number of women are diagnosed with cancer during pregnancy and lactation. Women are usually advised to interrupt breastfeeding during systemic anticancer treatment for fear of serious adverse effects to the nursed infant. However, the issue is poorly addressed in the literature and very few studies have evaluated the safety of breastfeeding during or after cytotoxic drugs or target agents administration. In this review we will analyze the available evidence that addresses the issue of anticancer drugs, targeted agents, antiemetics and growth-factors excretion in human milk. This could serve as a unique resource that may aid physicians in the management of breastfeeding cancer patients interested in maintaining lactation during treatment.

“The only thing I know is that I know nothing”: 5-fluorouracil in human milk

Women are usually advised to interrupt breastfeeding during chemotherapy for concerns of serious side-effects to the infant. However, the passage of cytotoxic drugs in human milk has been poorly studied. A 36-year-old woman was diagnosed with rectal cancer while she was still breastfeeding her 9-month-old son. The tumor was staged as cT3N1M0 and neoadjuvant 5-flourouracil (5-FU)-based chemoradiotherapy (CRT) was planned. She was advised to stop nursing, however, she expressed her desire to resume breastfeeding after treatment. After a multidisciplinary discussion, the patient was advised to pump her breasts twice daily during CRT in order to maintain milk production. To decide when breastfeeding could be safely resumed, we evaluated the pharmacokinetics of 5-FU in milk. The patient received standard CRT with 5-FU 200 mg/m/day as i.v. continuous infusion concurrently with pelvic radiotherapy. Samples of peripheral blood were taken before the start of 5-FU and after 1, 2 and 5 weeks. Milk samples were obtained before, during and up to 10 days following the completion of therapy. 5-FU concentrations were measured using an highperformance liquid chromatography (HPLC) method [1] modified and optimized for plasma and milk samples. Four plasma samples were collected and analyzed. The concentration of 5-FU in plasma ranged between 11.14 and 114.95 lM (Figure 1A and B). Thirty-three milk samples were collected and tested. 5-FU levels were undetectable in milk at any time during and after CRT treatment. To validate the HPLC methodology used, we carried out parallel analyses on human milk spiked with different concentrations of 5-FU, which were stored, extracted and measured in the same conditions. 5-FU was detected in the validation samples with a limit of detection at 0.5 lM (Figure1C and D). The patient completed the planned treatment and eventually underwent radical surgery without complications. Ten days after surgery, when pharmacokinetics results were available, the patient tried to resume breastfeeding, but her infant refused to latch. Breastfeeding is an essential physiologic process that provides nutrition and protects the child against infection, immunologic disorders and some types of cancer during adulthood [2, 3]. Nevertheless and despite the lack of evidence, breastfeeding is usually not recommended during maternal chemotherapy because of the potential toxic effects to the infant. In this case, we report for the first time that 5-FU was undetectable at any time during and following CRT, although maternal plasma concentrations reflected normal pharmacokinetics. The amount of a drug or its metabolites excreted into milk is dependent upon several factors: lipid solubility, molecular size, ionization, protein binding and halflife in maternal plasma [4]. 5-FU has a short half-life and a high protein bound in serum [5]; these factors probably accounted for the undetectable levels of 5-FU in milk. Our results are reassuring, but genetic background and plasma levels variability might influence 5-FU distribution into milk. Collecting breast milk for drug assays during and after chemotherapy, as impractical as this approach may seem, could provide valuable information to counsel patients receiving chemotherapy who are willing to resume breastfeeding after the end of treatment.

BOLERO-2: Efficacy and safety of first-line everolimus plus exemestane in advanced breast cancer.

152 Background: In the BOLERO-2 study, progression-free survival (PFS) was significantly longer with the combination of everolimus and exemestane (EVE + EXE) compared with placebo and exemestane (PBO + EXE; hazard ratio = 0.45; p < .0001). Consistent efficacy results were observed in all subgroup analyses, such as in patients with visceral metastases and patients with disease recurrence during/after adjuvant therapy. This analysis of BOLERO-2 examines the efficacy of EVE + EXE in the subgroup of patients who received treatment immediately after recurrence during adjuvant therapy (i.e., as first-line therapy in the advanced setting). METHODS BOLERO-2 enrolled patients with hormone receptor-positive (HR+) advanced breast cancer with disease recurrence or progression after prior nonsteroidal aromatase inhibitors and compared EVE (10 mg/d) + EXE (25 mg/d) vs PBO + EXE. The primary end point was PFS by local investigator review. RESULTS A total of 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37) in the advanced setting. Of these patients, 74% of the EVE + EXE arm and 76% of the PBO + EXE arm had recurred after adjuvant endocrine therapy plus chemotherapy; 26% and 24%, respectively, had recurred after adjuvant endocrine therapy alone. Also, approximately 20% of patients entered the trial after recurring during or within 12 months of adjuvant therapy (21% EVE + EXE vs 16% PBO + EXE). The EVE + EXE group had significantly longer PFS compared with the PBO + EXE group (11.50 vs 4.07 months, respectively; hazard ratio = 0.39; 95% confidence interval, 0.25-0.62). Median PFS remained longer with EVE + EXE versus PBO + EXE, regardless of whether chemotherapy was included with the prior adjuvant hormonal therapy. Similar results were obtained from the analyses based on central review. The safety profile was consistent with the known profiles of each agent. CONCLUSIONS EVE + EXE prolonged PFS in patients with HR+ advanced breast cancer who received treatment as first-line therapy. These results support the combination of EVE + EXE in patients with recurrence after adjuvant therapy. The recently initiated BOLERO-4 study is also evaluating the efficacy of EVE as a first-line therapy in patients with HR+ advanced breast cancer. CLINICAL TRIAL INFORMATION NCT00863655.

Retinal metastasis regression with eribulin in a heavily pretreated breast cancer patient

The authors present the case of a heavily pretreated young woman with retinal and brain metastases from breast cancer who was successfully treated with eribulin. Eribulin was given at 1.1 mg/m(2) on day 1 and 8, every 3 weeks for a total of 12 courses. A significant reduction in the size of brain and retinal lesions was achieved after three cycles. The treatment was continued for 12 cycles, with a good profile of tolerability. In this clinical case, eribulin demonstrated to be active on brain and retinal metastases from breast cancer, although preclinical data showed limited ability to cross the blood-brain barrier.