Many patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) are candidates for trastuzumab emtansine (T-DM1) treatment sometime in their disease history. KAMILLA evaluated safety of T-DM1 in patients with previously treated HER2-positive locally advanced or metastatic BC (advanced BC). KAMILLA (NCT01702571) is a single-arm, open-label, international, phase IIIb safety study of patients with HER2-positive advanced BC with progression after prior treatment with chemotherapy and a HER2-directed agent for MBC or within 6 months of completing adjuvant therapy. Patients received T-DM1 (3.6 mg/kg every 3 weeks) until unacceptable toxicity, withdrawal or disease progression. Among 2002 treated patients, median age was 55 years (range, 26-88; 373 [18.6%] aged ≥65 years), 1321 (66.0%) received ≥2 prior metastatic treatment lines and 398 (19.9%) had baseline central nervous system metastases. Adverse events (AEs) and serious AEs occurred in 1862 (93.0%) and 427 (21.3%) patients, respectively. Grade ≥3 AEs occurred in 751 (37.5%) patients; the three most common (individual Medical Dictionary for Regulatory Activity terms) were anaemia (3.0%), thrombocytopaenia (2.7%) and fatigue (2.5%). Median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI], 6.0-7.6). Median overall survival (OS) was 27.2 months (95% CI, 25.5-28.7). With increasing lines of prior advanced therapy (0-1 versus 4+), median PFS and OS decreased numerically from 8.3 to 5.6 months and from 31.3 to 22.5 months, respectively. KAMILLA is the largest cohort of T-DM1-treated patients studied to date. Results are consistent with prior randomised studies, thereby supporting T-DM1 as safe, tolerable and efficacious treatment for patients with previously treated HER2-positive advanced BC.

Introduction: Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. Methods: We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003–02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. Results: Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. Conclusions: Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

Purpose: In hormone receptor–positive (HR+)/HER2− metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed. Experimental Design: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2− MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor–positive (ER+)/HER2− breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2− cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusions: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.

Purpose: Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy. Experimental Design: Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model. Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms. Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor–positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.

Background: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. Objective: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman’s life on development of breast cancer (BC). Methods: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women’s lifetime. Results: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. Conclusions: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk.

Purpose: We assessed the 27-gene RT-qPCR–based DetermaIO assay and the same score calculated from RNA sequencing (RNA-seq) data as predictors of sensitivity to immune checkpoint therapy in the neoTRIPaPDL1 randomized trial that compared neoadjuvant carboplatin/nab-paclitaxel chemotherapy (CT) plus atezolizumab with CT alone in stage II/III triple-negative breast cancer. We also assessed the predictive function of the immuno-oncology (IO) score in expression data of patients treated with pembrolizumab plus paclitaxel (N = 29) or CT alone (N = 56) in the I-SPY2 trial. Experimental Design: RNA-seq data were obtained from pretreatment core biopsies from 242 (93.8%) of the 258 patients in the per-protocol-population. The DetermaIO RT-qPCR test, performed in the CAP/CLIA-accredited laboratory of Oncocyte Corp., was available for 220 patients (85.3%). A previously established threshold was used to assign DetermaIO-positive versus DetermaIO-negative status. Publicly available microarray data were used from I-SPY2. Results: IO scores calculated from RNA-seq and RT-qPCR data were highly concordant. In neoTRIPaPDL1, DetermaIO-positive cancers (N = 92, 41.8%) had pathologic complete response (pCR) rates of 69.8% and 46.9% in the CT + atezolizumab and CT arms, respectively. In DetermaIO-negative cases, pCR rates were similar in both arms (44.6% vs. 49.2%; interaction test P = 0.04). PDL1 protein expression and stromal tumor–infiltrating lymphocyte count were not predictive of differential benefit from atezolizumab. In I-SPY2, IO-positive cancers (45.9%) had pCR rates of 85.7% and 16%, with and without immunotherapy, respectively. In IO-negative cancers, pCR rates were 46.7% versus 16.1%. Conclusions: DetermaIO identified patients who benefited from neoadjuvant immunotherapy resulting in improved pCR rate, independently of PDL1.