Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial.

Importance: Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events. Objective: To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor-positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of -6%. Design, Setting, and Participants: This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor-positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021. Interventions: Exemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery. Main Outcomes and Measures: Serum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography-tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry. Results: A total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was -89%, -85%, and -60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was -3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, -5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of -7.5%, -5.0%, and -4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and -17.0%, -9.0%, and -7.0% for progesterone receptor, respectively. Sex hormone-binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms. Conclusions and Relevance: In this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16.

Predictors of poor seroconversion and adverse events to SARS-CoV-2 mRNA BNT162b2 vaccine in cancer patients on active treatment.

PURPOSE: Initial findings in patients with cancer suggest a lower seroconversion to SARS-CoV-2 vaccination possibly related to myelo-immunosuppressive therapies. We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunisation (AEFI) to the BNT162b2 vaccine in patients on active treatment. PATIENTS AND METHODS: Cancer patients, candidates to two doses of BNT162b2 SARS-CoV-2 vaccination, were enrolled. Patients on active surveillance served as controls. The primary endpoint was poor seroconversion (anti S1/S2 IgG < 25 AU/mL) after 21 days from the second dose. RESULTS: Between March and July 2021, 320 subjects were recruited, and 291 were assessable. The lack of seroconversion at 21 days from the second dose was 1.6% (95% CI, 0.4-8.7) on active surveillance, 13.9% (8.2-21.6) on chemotherapy, 11.4% (5.1-21.3) on hormone therapy, 21.7% (7.5-43.7) on targeted therapy and 4.8% (0.12-23.8) on immune-checkpoint-inhibitors (ICI). Compared to controls, the risk of no IgG response was greater for chemotherapy (p = 0.033), targeted therapy (0.005) and hormonotherapy (p = 0.051). Lymphocyte count < 1 × 109/L (p = 0.04) and older age (p = 0.03) also significantly predicted poor seroconversion. Overall, 43 patients (14.8%) complained of AEFI, mostly of mild grade. Risk of AEFI was greater in females (p = 0.001) and younger patients (p = 0.009). CONCLUSION: Chemotherapy, targeted therapy, hormone therapy, lymphocyte count < 1 × 109/L, and increasing age predict poor seroconversion after two doses of BNT162b2 in up to 20% of patients, indicating the need for a third dose and long-term serological testing in non-responders. AEFI occur much more frequently in women and younger subjects who may benefit from preventive medications. CLINICALTRIALS. GOV IDENTIFIER: NCT04932863.

Home Se-Cure: A Home Care Service for Cancer Patients during the COVID-19 Pandemic.

Cancer patients are exposed to a greater risk of COVID-19 infection, resulting in treatment delays and unnecessary hospitalizations. International authorities have suggested reducing visits to hospitals and guarantee continuity of care. We developed a home care project called Home Se-Cure (HSC) to guarantee the continuity of oral, intramuscular, and subcutaneous cancer therapy during COVID-19. The Home Se-Cure project included cancer patients living near Galliera Hospital. Patients received home visits by registered nurses (RNs), whoperformed blood tests and delivered cancer therapies. Patients were instructed to take drugs after blood test results and therapy confirmation by oncologists. Sixty-six patients decided to participate and 38 declined the service. A customer satisfaction questionnaire was administered to a subgroup of patients participating in the project. The most prevalent disease in the HSC group was prostate cancer. The mean age of the patients in HSC was 78.4 years and 68.9 in the decliner group. The majority of the HSC participants appreciated the project because they could stay at home (71%) and reduce the risk of COVID-19 contagion (67.7%). Compared to decliners, the time the study group saved was 2033 hours. HSC guaranteed the continuity of care during the COVID-19 pandemic by reducing the number of patients in the hospital and avoiding crowds in the waiting room.

Patient- versus physician-reported outcomes in a low-dose tamoxifen trial in noninvasive breast cancer.

BACKGROUND: We recently conducted a de-escalation trial of low-dose tamoxifen 5 mg/day ("babytam", BT) or placebo given for 3 years in 500 women with noninvasive breast cancer. Women on babytam had a 52% reduction of recurrence (invasive breast cancer or DCIS) after 5 years. Since menopausal symptoms are major reasons for treatment withdrawal during tamoxifen preventive therapy, we compared and analyzed the patient-reported outcomes (PROs) with the physician-reported adverse events and studied their association with recurrence. METHODS: Menopausal symptoms recorded by physicians using the Common Terminology Criteria (CTCAEs) were compared with a patient self-reported validated questionnaire reviewed by a research nurse at baseline and every 6 months up to 36 months. Hot flashes (HF), the main outcome measure, were detected through a self-report 7-day diary for frequency and intensity. Treatment adherence and efficacy were assessed by the Kaplan-Meier curves and the Cox model. RESULTS: The number of HF events at 12, 24, and 36 months for PROs versus CTCAEs was 246 versus 12, 238 versus 8, and 210 versus 4, respectively. The majority of events were grade 1. There was no difference in PROs between babytam and placebo except for HF daily frequency, which increased by 1.5 events (95% CI, 1.1-1.8) on placebo to 2.1 on babytam (95% CI, 1.7-2.5, p = 0.05). The presence of HF at baseline was a favorable prognostic factor for recurrence and a predictive factor for response to babytam. Adherence was similar between babytam and placebo. CONCLUSIONS: The use of PROs is effective for identifying frequent mild grade menopausal symptoms which are underestimated by physicians but important prognostic and predictive factors. Research nurse can use these results as a tool to reassure patients about symptoms, improve adherence to treatment, and limit dropouts.

Alternative dosing of exemestane in postmenopausal women with ER-positive breast cancer. Design and methods of a randomized presurgical trial.

INTRODUCTION: Aromatase inhibitors are effective in lowering breast cancer incidence among postmenopausal women, but adverse events represent a barrier to their acceptability and adherence as a preventive treatment. This study aims to assess whether lowering exemestane schedule may retain biological activity while improving tolerability in breast cancer patients. METHODS/DESIGN: We are conducting a, pre-surgical, non-inferiority phase IIb study in postmenopausal women with newly diagnosed estrogen receptor-positive breast cancer. Participants are randomized to receive either exemestane 25 mg/day or 25 mg/three times-week or once a week for 4 to 6 weeks prior to surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery comparing the three arms. Sample size of 180 women was calculated assuming a 6% non-inferiority of the percent change of estradiol in the lower dose arms compared with the 80% decrease predicted in the full dose arm, with 80% power and using a one-sided 5% significance level and a two-sample t-test. Main secondary outcomes are: safety; change in Ki-67 in cancer and adjacent pre-cancer tissue, circulating sex hormones, adipokines, lipid profile, insulin and glucose changes, in correlation with drug and metabolites concentrations. RESULTS AND DISCUSSION: The present paper is focused on methodology and operational aspects of the study. A total of 180 participants have ben enrolled. The trial is still blinded, and the analyses are ongoing. Despite the short term duration, results may have relevant implications for clinical management of women at increased risk of developing a ER positive breast cancer.

Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial.

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9-16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3-11.4) in patients who recurred vs 7.5 (5.1-10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14-16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772 .

Estimating the magnitude of clinical benefit of systemic therapy in patients with DCIS or pre-invasive disease of the breast.

The challenge of effective management of ductal carcinoma in situ (DCIS) and other pre-malignant disorders of the breast is to select patients who will not progress to invasive carcinoma from those at the highest risk who require radiotherapy and/or endocrine therapy to minimize the risk of a subsequent invasive recurrence. Although IBIS-II and NSABP-B35 DCIS phase III trials proved that tamoxifen 20 mg/day and anastrozole reduce the risk of ipsilateral and contralateral events, the toxicities of both drugs have hampered the drug uptake by high-risk women. We recently reported results of a 3-year placebo-controlled trial of low-dose (5 mg/d) tamoxifen in 500 women with intraepithelial neoplasia (70% DCIS). At a median follow-up of 5 years, women randomly assigned to low-dose tamoxifen had half the number of subsequent diagnoses of DCIS or invasive cancer compared with those randomly assigned to placebo but no increase in thromboembolic events or endometrial cancers. The 5-year number needed to treat was 22 (95% CI, 20-27). Our attention is now focused on prognostic and predictive markers to identify patients who can derive the greatest benefits from low dose tamoxifen, such as for instance the expression of 23 genes involved in cell cycle progression (CCP). In conclusion, we endorse an active treatment of DCIS as the standard of care.

Association of Biomarkers with Serious Cardiac Adverse Events during Abiraterone Acetate Treatment in Castration Resistant Prostate Cancer.

BACKGROUND: Abiraterone acetate is an effective drug for castration-resistant prostate cancer, but cardiac serious adverse events (SAEs) may occur. We studied their association with N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T (TnT) during abiraterone therapy. PATIENTS AND METHODS: In a single institution, 17 patients were treated with abiraterone acetate 1 g daily with concomitant prednisone and then switched to dexametasone plus canrenone. Blood samples for PSA, NT-proBNP, and TnT were obtained at baseline and after 1, 3, and 6 months. RESULTS: Five patients (29.4%) experienced G3 to 4 cardiac SAEs after a median of 13 weeks (range, 9-32), including pulmonary edema, heart failure, acute coronary syndrome, sinus bradycardia with syncope, and pulmonary edema. At baseline, 4 weeks, and 3 months, median NT-proBNP and TnT levels were higher in patients with subsequent cardiac SAEs (P= .03 and P= .04 for NT-proBNP and TnT at 3 months, respectively). After switching to dexametasone and introducing canrenone, no additional cardiac SAEs were noted. Overall response rate was 67%. CONCLUSIONS: Our study suggests a higher than expected risk of cardiac SAEs during abiraterone treatment which may well be due to the small sample size and the unrestricted entry criteria. However, baseline and frequent NT-proBNP and TnT monitoring predicted a higher risk for cardiac SAE. Larger studies should confirm our findings.

Dual Block with Lapatinib and Trastuzumab Versus Single-Agent Trastuzumab Combined with Chemotherapy as Neoadjuvant Treatment of HER2-Positive Breast Cancer: A Meta-analysis of Randomized Trials.

PURPOSE: (Neo)adjuvant treatment with chemotherapy plus trastuzumab reduces recurrence and death risk in HER2-positive (HER2(+)) breast cancer. Randomized trials assessed HER2 dual block by adding lapatinib to trastuzumab and chemotherapy in the neoadjuvant setting using pathologic complete response (pCR) as the outcome measure. We conducted a meta-analysis of randomized trials testing neoadjuvant dual block with lapatinib and trastuzumab versus trastuzumab alone in HER2(+) breast cancer. EXPERIMENTAL DESIGN: Trials were identified by Medline (PubMed), ISI Web of Science (Science Citation Index Expanded), Embase, Cochrane library, and reference lists of published studies, review articles, editorials, and by hand-searched reports from major cancer meeting reports. RESULTS: Six randomized trials including 1,155 patients were identified, of whom 483 (41.8%) were hormone receptor-negative, 672 (58.2%) hormone receptor-positive, 534 (46.2%) received taxanes alone, and 621 (53.8%) anthracyclines plus taxanes or the docetaxel-carboplatin regimen. Overall, the dual block was associated with a significant 13% absolute improvement in pCR rate compared with single-agent trastuzumab (summary risk difference, SRD 0.13; 95% CI, 0.08-0.19). The activity was greater in hormone receptor-negative patients who received chemotherapy with taxanes alone (SRD 0.25; 95% CI, 0.13-0.37), compared to hormone receptor-positive or hormone receptor-negative disease treated with anthracyclines plus taxanes or the docetaxel-carboplatin regimen (SRD 0.09; 95% CI, 0.02-0.15; Pinteraction = 0.05). CONCLUSIONS: On the basis of ΔpCR data, the dual block with trastuzumab and lapatinib plus chemotherapy is a very active treatment only in HER2(+) and hormone receptor-negative breast cancer treated with taxane monochemotherapy. Clin Cancer Res; 22(18); 4594-603. ©2016 AACR.

FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.

BACKGROUND: In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups. METHODS: TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min, a 400 mg/m(2) intravenous bolus of fluorouracil, and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min, followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797. FINDINGS: Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52). INTERPRETATION: FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status.

An observational study of nasal cavity toxicity in cancer patients treated with bevacizumab.

BACKGROUND: The nasal cavity is a vulnerable zone which may be damaged by vascular disorders. We systematically assessed the frequency and severity of nasal cavity alterations during bevacizumab treatment, to determine its clinical relevance and factors contributing to its onset. PATIENTS AND METHODS: We conducted a hospital-based cohort study in 47 consecutive patients with advanced cancers who were on treatment with chemotherapy and bevacizumab at different doses. All patients underwent otolaryngology (ENT) examination at the time of study initiation. RESULTS: The mean number of cycles at first ENT examination was 16 (standard deviation = 14). A total of 45 patients (96%) showed nose mucosal lesions, of whom 30% had erosions and 62% had grade 1 - 2 epistaxis. One patient had septal perforation. Grades 1 - 4 sinus disorders were noted in 60%. There was a significant trend to a higher risk of grade ≥ 2 nasal events for bevacizumab doses > 7.5 mg/kg, concomitant taxane use and digital nasal self-manipulation. CONCLUSIONS: We found a high incidence of nasal cavity lesions in patients receiving bevacizumab, with evidence for a dose-related effect. Most cases were low grade and manageable without drug interruption, but severe toxicity may rarely occur. Oncologists should be aware of this unusual event.

A case series of low dose bevacizumab and chemotherapy in heavily pretreated patients with epithelial ovarian cancer.

BACKGROUND: The addition of bevacizumab to standard chemotherapy prolongs progression free survival in the first line treatment of epithelial ovarian cancer (EOC), but its cost/effectiveness is debated. We assessed the safety and activity of a lower dose of bevacizumab in pretreated advanced stage EOC. METHODS: We treated 15 patients, mostly with platinum resistant EOC, who had received a median of four prior cytotoxic regimens, with bevacizumab 5-7.5 mg/kg q21 days in combination with either carboplatin (n = 8), oral cyclofosfamide (n = 5) or weekly paclitaxel (n = 2). Bevacizumab was administered until disease progression. Tumor response was assessed by CA125 and fusion 18 F-FDG PET/contrast enhanced CT. RESULTS: The median number of bevacizumab cycles was 21 (range 3-59). The median baseline CA125 was 272 U/ml and decreased to 15.2 U/ml at nadir. Tumor response was 4 complete response (CR) (26.7%) and 7 partial response (PR) (46.7%) by chemotherapy (CT), with an overall response rate of 73.4% (95% CI, 51.0 - 95.8) according to Response Evaluation Criteria In Solid Tumors (RECIST), and 6 CR (40%) and 4 PR (26.7%) by PET, for an overall metabolic response rate of 67% (95%CI, 42.8 - 90.6) according to PET Response Criteria in Solid Tumors (PERCIST). Median progression free survival (PFS) was 21 months and median overall survival (OS) was 24 months. Grade 3 adverse events related to bevacizumab were hypertension (n = 2), proteinuria (n = 1) and epistaxis (n = 5). Treatment was delayed in five patients for nasal bleeding or uncontrolled hypertension. CONCLUSIONS: Low-dose bevacizumab and chemotherapy was well tolerated and active in a heavily pretreated population of advanced EOC. Further studies should assess the activity of low dose bevacizumab in EOC.

Extending the duration of first-line chemotherapy in metastatic breast cancer: a perspective review.

The treatment of metastatic breast cancer is mainly palliative, but optimal management might result in survival improvement as well. For this reason, many trials have attempted to optimize the therapeutic approach in this disease setting. Among the possible options, chemotherapy represents the backbone of the treatment and survival improvements that have been shown by the use of modern chemotherapeutic agents. Whereas the type of chemotherapy is generally dictated by patient characteristics and those of their disease, substantial controversy still remains on how long chemotherapy should be administered after disease control is achieved. In this review, we have analysed all available evidence on the duration of first-line chemotherapy in advanced breast cancer.

Severe fluoropyrimidine-related toxicity: clinical implications of DPYD analysis and UH2/U ratio evaluation.

The fluoropyrimidines are commonly used in chemotherapeutic cancer medicine, but many patients still experience severe adverse side effects from these drugs. We observed a severe toxicity in a 50-year-old woman treated with capecitabine and docetaxel for a metastatic breast cancer. Since dihydropyrimidine dehydrogenase (DPD) is the main candidate for pharmacogenetic studies on 5-FU toxicity, the entire coding sequence and exon-flanking intronic regions of the DPYD gene were sequenced in the patient. None of the previously described deleterious variants were detected. Also, the haplotype-based analysis failed to reveal DPYD variations associated with 5-FU toxicity. We also evaluated the UH2/U ratio in plasma as an index of 5-FU pharmacokinetics. The UH2/U value did not demonstrate low DPD activity in the patient. We discuss the advantages and limitations of this approach, particularly concerning the clinical applications of 5-FU pharmacogenetics in the family setting.

Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of randomized clinical trials.

PURPOSE: To evaluate the effect of different first-line chemotherapy durations in patients with metastatic breast cancer (MBC) on overall survival (OS) and progression-free survival (PFS). METHODS: We searched literature databases to identify randomized controlled trials that compared different chemotherapy durations in the first-line treatment of MBC. Only trials with unconfounded comparisons of additional cycles of chemotherapy were included. The main outcome measures for this analysis were OS and PFS. Published data from retrieved studies were analyzed according to standard meta-analytic techniques. RESULTS: We found 11 randomized clinical trials including 2,269 patients. Longer first-line chemotherapy duration resulted into a significantly improved OS (hazard ratio [HR], 0.91; 95% CI, 0.84 to 0.99; P = .046) and PFS (HR, 0.64; 95% CI, 0.55 to 0.76; P < .001). There were no differences in effects on either OS or PFS between subgroups defined by time of random assignment, study design, number of chemotherapy cycles in the control arm or concomitant endocrine therapy. CONCLUSION: Longer first-line chemotherapy duration is associated with marginally longer OS and a substantially longer PFS.