PREDICT underestimates survival of patients with HER2-positive early-stage breast cancer.

The prognostic performance of PREDICT in patients with HER2-positive early breast cancer (EBC) treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies is unclear. Therefore, we investigated its prognostic performance using data extracted from ALTTO, a phase III trial evaluating adjuvant lapatinib ± trastuzumab vs. trastuzumab alone in patients with HER2-positive EBC. Our analysis included 2794 patients. After a median follow-up of 6.0 years (IQR, 5.8-6.7), 182 deaths were observed. Overall, PREDICT underestimated 5-year OS by 6.7% (95% CI, 5.8-7.6): observed 5-year OS was 94.7% vs. predicted 88.0%. The underestimation was consistent across all subgroups, including those according to the type of anti HER2-therapy. The highest absolute differences were observed for patients with hormone receptor negative-disease, nodal involvement, and large tumor size (13.0%, 15.8%, and 15.3%, respectively). AUC under the ROC curve was 73.7% (95% CI 69.7-77.8) in the overall population, ranging between 61.7% and 77.7% across the analyzed subgroups. In conclusion, our analysis showed that PREDICT highly underestimated OS in HER2-positive EBC. Hence, it should be used with caution to give prognostic estimation to HER2-positive EBC patients treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies.

Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial.

BACKGROUND: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. METHODS: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. RESULTS: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48-0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30-0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46-0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. CONCLUSIONS: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.

Body Mass Index and Weight Change in Patients With HER2-Positive Early Breast Cancer: Exploratory Analysis of the ALTTO BIG 2-06 Trial.

BACKGROUND: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. METHODS: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, <18.5 kg/m2; normal weight, 18.5 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. RESULTS: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04-1.50) and OS (aHR, 1.27; 95% CI, 1.01-1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97-1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05-1.71), DDFS (aHR, 1.46; 95% CI, 1.07-1.98), and OS (aHR, 1.83; 95% CI, 1.18-2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. CONCLUSIONS: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

Endocrine therapy-based treatments in hormone receptor-positive/HER2-negative advanced breast cancer: systematic review and network meta-analysis.

BACKGROUND: Several endocrine therapy (ET)-based treatments are available for patients with advanced breast cancer. We assessed the efficacy of different ET-based treatments in patients with hormone receptor-positive/HER2-negative advanced breast cancer with endocrine-sensitive or endocrine-resistant disease. METHODS: We searched Medline and Cochrane Central Register of Controlled Trials up to 15 October 2019 and abstracts from major conferences from 2016 to October 2019. We included phase II/III randomised trials, comparing ≥2 ET-based treatments. Progression-free survival (PFS) and overall survival (OS) were analysed by network meta-analyses using MTC Bayesian models based on both fixed-effect and random-effect models; relative treatment effects were measured as HRs and 95% credibility intervals (CrI). All statistical tests were two-sided. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and this systematic review is registered in the PROSPERO database. RESULTS: 55 publications reporting on 32 trials (n=12 293 patients) were included. Regarding PFS in the endocrine sensitive setting (n=5200; 12 trials), the combination of cyclin-dependent kinases (CDK)4/6-inhibitors (CDK4/6i)+fulvestrant 500 mg (F500) was likely the most effective treatment (surface under the cumulative ranking curve (SUCRA)=97.3%), followed by CDK4/6i+aromatase inhibitor ±goserelin; there was no significant difference between them (HR 0.82; 95% CrI 0.54-1.25). Regarding OS (n=2157; five trials), the most effective treatment was probably CDK4/6i+F500 (SUCRA=97.3%); comparing CDK4/6i+F500 versus F500 held a HR of 0.77 (95% CrI 0.63-0.95). Regarding PFS in the endocrine-resistant setting (n=6635; 20 trials), CDK4/6i+F500 was likely the most effective treatment (SUCRA=95.7%), followed by capivasertib+F500, without significant difference between them (HR 0.91; 95% CrI 0.60-1.36). For OS (n=4377; 11 trials), the most effective treatments were capivasertib+F500 (SUCRA=84.7%) and CDK4/6i+F500 (SUCRA=69.9%). Comparing CDK4/6i+F500 versus F500 held a HR of 0.77 (95% CrI 0.67-0.89). CONCLUSIONS: CDK4/6i+F500 is likely the best treatment option in both endocrine-sensitive and endocrine-resistant diseases for PFS, and in endocrine-sensitive patients for OS. Concerning OS in endocrine-resistant patients, capivasertib+F500 and CDK4/6i+F500 are likely the best treatments. PROSPERO REGISTRATION NUMBER: CRD42018104628.

Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: Analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.

BACKGROUND: Limited data exist on the safety of using anti-human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2-positive patients. METHODS: The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2-positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease-free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time-varying covariates to account for a guarantee-time bias. RESULTS: Ninety-two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52-2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307). CONCLUSIONS: For patients with HER2-positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.

Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis.

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer.

Endocrine therapy and palbociclib within a compassionate use program in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer.

This is a single center retrospective analysis of patients with hormone receptor-positive, HER2-negative metastatic breast cancer progressing after ≥ 4 treatment lines treated with palbociclib in combination with endocrine therapy within a compassionate use program. Thirty-four patients were included between 10/2015 and 02/2017, the majority (82.4%) being previously treated with mTOR inhibitors. Disease control rate was 52.9% and 24.4% at week 12 and 24. Overall progression-free survival was 3.1 months with no difference between mTOR inhibitor-pretreated (3.5 months) and -naïve patients (2.7 months; hazard ratio, 0.83). Toxicity profile in this population was comparable to that seen in previous trials.

Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis.

BACKGROUND: Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS: A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models. RESULTS: Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95). CONCLUSIONS: Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used.

Impact of body mass index on the clinical outcomes of patients with HER2-positive metastatic breast cancer.

BACKGROUND: Overweight and obesity are associated with an increased risk of developing many types of cancer, including breast cancer. Moreover, increased body mass index (BMI) seems to be associated with a worse prognosis in patients with HER2-positive early breast cancer. However, little is known about the impact of BMI on the clinical outcomes of HER2-positive metastatic breast cancer (MBC). METHODS: This was a multicenter retrospective cohort study including 329 consecutive patients with HER2-positive MBC treated with first-line trastuzumab-based regimens. BMI at the time of MBC diagnosis was collected. World Health Organization BMI categories were used: underweight <18.5, normal 18.5-24.9 Kg/m2, overweight 25-29.9 Kg/m2, and obese ≥30 Kg/m2. The analyses were conducted using two categories: BMI < 25.0 (normal/underweight) and BMI ≥ 25 (overweight/obese). Progression-free survival (PFS) and overall survival (OS) rates were estimated using Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Cox's proportional hazards model. Disease response to therapy was analyzed using univariate and multivariate logistic regression. RESULTS: Overall, 176 (53.5%) patients were normal/underweight and 153 (46.5%) overweight/obese. Median PFS was 14.8 months in BMI < 25 group and 15.7 months in BMI ≥ 25 group (adjusted-HR 0.88; 95% CI 0.66-1.17; p = 0.387). Median OS was 58.6 months in BMI < 25 group and 52.6 in BMI ≥ 25 group (adjusted-HR 0.88; 95% CI 0.59-1.31; p = 0.525). Overall response rate was 71.7% and 65.9% (p = 0.296) and clinical benefit rate was 82.1% and 83.3% (p = 0.781) in BMI < 25 and BMI ≥ 25 groups, respectively. CONCLUSIONS: BMI does not seem to be associated with clinical outcomes in HER2-positive MBC patients.

Breast cancer treatment-induced cardiotoxicity.

INTRODUCTION: Breast cancer is the most frequent cancer affecting women worldwide. In every setting, the majority of women are treated with an evergrowing arsenal of therapeutic agents that have greatly improved their outcomes. However, these therapies can also be associated with significant adverse events. Areas covered: This review aims to thoroughly describe the current state of the evidence regarding the potential cardiotoxicity of agents commonly used in the treatment of breast cancer. These include chemotherapeutic agents, anti-HER2 therapies and CDK4/6 and mTOR inhibitors. Furthermore, issues related to the risk stratification and monitoring tools are explored. Expert opinion: Anthracycline- and trastuzumab-related cardiac toxicities have been extensively studied. Substantial evidence is now available concerning additional anti-HER2 agents such as pertuzumab, T-DM1 and tyrosine kinase inhibitors; overall, the cardiotoxicity profile is reassuring. Cardiac events due to endocrine therapy are mostly ischemic and, in the context of prolonged therapy, need specific attention. Novel agents implicated in the treatment of hormone receptor-positive disease are potentially arrhythmogenic and the exact risk will need to be further refined. As for today, assessment of baseline risk factors prior to treatment initiation and cardiac imaging before and during treatment remains the optimal way to prevent cardiac dysfunction. Cardioprotective therapy in primary prevention is still a matter of debate.

New agents for endocrine resistance in breast cancer.

Estrogen receptor positive (ER+) and HER2-negative (HER2-) breast cancer (BC) is the most common BC subtype, defined by expression of the ER and absence of HER2 amplification. Endocrine treatment (ET), aiming at therapeutic blockade of ER signaling, represents the therapeutic mainstay for patients with both early and advanced disease. Despite its wide therapeutic efficacy, ET fails for a proportion of ER+, HER2- BC patients with early disease who develop endocrine resistance, resulting in disease recurrence. Endocrine resistance occurs almost invariably in patients with metastatic disease. Recently, increasing understanding of the molecular mediators of endocrine resistance has been achieved. This review focuses on the molecular mechanisms mediating endocrine resistance, on molecularly targeted agents to overcome or delay it, and potential predictive biomarkers for accurate patient stratification.