Background: This hypothesis-generating trial evaluated neoadjuvant ipatasertib-paclitaxel for early triple-negative breast cancer (TNBC).Patients and methods: In this randomized phase II trial, patients with early TNBC (T ! 1.5 cm, N0-2) were randomized 1 : 1 to receive weekly paclitaxel 80 mg/m 2 with ipatasertib 400 mg or placebo (days 1-21 every 28 days) for 12 weeks before surgery. Co-primary end points were pathologic complete response (pCR) rate (ypT0/TisN0) in the intention-to-treat (ITT) and immunohistochemistry phosphatase and tensin homolog (PTEN)-low populations. Secondary end points included pCR rate in patients with PIK3CA/AKT1/PTEN-altered tumors and pre-surgery response rates by magnetic resonance imaging (MRI).Results: pCR rates with ipatasertib versus placebo were 17% versus 13%, respectively, in the ITT population (N ¼ 151), 16% versus 13% in the immunohistochemistry PTEN-low population (N ¼ 35), and 18% versus 12% in the PIK3CA/AKT1/PTEN-altered subgroup (N ¼ 62). Rates of overall and complete response (CR) by MRI favored ipatasertib in all three populations (CR rate 39% versus 9% in the PIK3CA/AKT1/PTEN-altered subgroup). Ipatasertib was associated with more grade !3 adverse events (32% versus 16% with placebo), especially diarrhea (17% versus 1%). Higher cycle 1 day 8 (C1D8) immune score was significantly associated with better response only in placebo-treated patients. All ipatasertib-treated patients with low immune scores and a CR had PIK3CA/AKT1/PTEN-altered tumors.Conclusions: Adding ipatasertib to 12 weeks of paclitaxel for early TNBC did not clinically or statistically significantly increase pCR rate, although overall response rate by MRI was numerically higher with ipatasertib. The antitumor effect of ipatasertib was most pronounced in biomarker-selected patients. Safety was consistent with prior experience of ipatasertib-paclitaxel. A T-cellrich environment at C1D8 had a stronger association with improved outcomes in paclitaxel-treated patients than seen for baseline tumor-infiltrating lymphocytes. This dependency may be overcome with the addition of AKT inhibition, especially in patients with PIK3CA/AKT1/PTEN-altered tumors. ClinicalTrials.gov: NCT02301988.

Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a wholeexome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy.Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes.Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4 Ã 20 allele) and a novel missense variant (CYP3A4 Ã 25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4 Ã 20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4 Ã 8 and the novel CYP3A4 Ã 27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2-and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P ¼ 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7-and 3-fold higher risk for loss-of-function and missense variants, respectively, P ¼ 5.9 Â 10 À5 ).Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization.

Purpose-Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that mutations in these genes might be responsible for this event. Given the contradictory results reported in the literature, we tested whether other parameters, such as chemotherapy, could be modifying telomere-length.Methods-We performed a cross-sectional study measuring leukocyte telomere-length of 266 sporadic breasts cancer patients treated with first-line chemotherapy, with a median follow up of 240 days.Additionally, we performed both cross-sectional and longitudinal studies in a series of 236 familial breast cancer patients that included affected and non-affected BRCA1/2 mutation carriers. We Ethical standards:The authors declare that this work complies with current Spanish laws. Conflict of interest:The authors declare that they have no conflicts of interest. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts have measured in leukocytes from peripheral blood: The telomere-length, percentage of short telomeres (<3Kb), telomerase activity levels and the annual telomere shortening speed.Results-In sporadic cases we found that chemotherapy exerts a transient telomere shortening effect (around 2 years) that varies depending on the drug combination.In familial cases, only patients receiving treatment were associated with telomere shortening but they recovered normal telomere-length after a period of two years.Conclusion-Chemotherapy affects telomere-length and should be considered in the studies that correlate telomere-length with disease susceptibility.

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18 F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-ofopportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/ changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB ¼ 3 (P ¼ 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P ¼ 0.09). In Arm B, 18F-FMISO-PET lacked predictive/ prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib.