Haplotype inference constrained by plausible haplotype data

The haplotype inference problem (HIP) asks to find a set of haplotypes which resolve a given set of genotypes. This problem is of enormous importance in many practical fields, such as the investigation of diseases, or other types of genetic mutations. In order to find the haplotypes that are as close as possible to the real set of haplotypes that comprise the genotypes, two models have been suggested which by now have become widely accepted: The perfect phylogeny model and the pure parsimony model. All known algorithms up till now for the above problem may find haplotypes that are not necessarily plausible, i.e. very rare haplotypes or haplotypes that were never observed in the population. In order to overcome this disadvantage we study in this paper, for the first time, a new constrained version of HIP under the above mentioned models. In this new version, a pool of plausible haplotypes Ĥ is given together with the set of genotypes G, and the goal is to find a subset H ⊆ Ĥ that resolves G. For the constrained perfect phylogeny haplotyping (CPPH) problem we provide initial insights and polynomial-time algorithms for some restricted cases that help understanding the complexity of that problem. We also prove that the constrained parsimony haplotyping (CPH) problem is fixed parameter tractable by providing a parameterized algorithm that applies an interesting dynamic programming technique for solving the problem

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial

PubMed ID: 26822398Background: Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. Methods: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m 2 per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. Findings: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). Interpretation: Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.Novartis AstraZeneca Boehringer Ingelheim Eisai KoreaWe showed that afatinib plus vinorelbine did not improve progression-free survival or objective response and was also associated with shorter overall survival compared with trastuzumab plus vinorelbine. Afatinib was also less well tolerated than was trastuzumab. Cross-signalling by other members of the ErbB family is thought to be an important mechanism through which HER2 can remain activated, despite HER2-targeted therapy. We therefore expected that broader inhibition of the ErbB family with afatinib might improve efficacy compared with trastuzumab in patients who were anticipated to have trastuzumab resistance (based on progression during or shortly after trastuzumab treatment). However, the results show that continuation of trastuzumab beyond progression conferred better outcomes than did switching to an ErbB family blocker. Our findings also suggest that the definition of trastuzumab resistance remains challenging. Despite progressing on or shortly after trastuzumab treatment, a proportion of patients may retain some sensitivity to this drug, which could have implications for future studies in this area. Our findings accord with those from studies of tyrosine kinase inhibitors for HER2-overexpressing metastatic breast cancer. In the MA.31 trial, 23 a taxane (paclitaxel or docetaxel) plus lapatinib was associated with shorter median progression-free survival than was a taxane plus trastuzumab for first-line treatment of metastatic breast cancer (9·0 months vs 11·3 months; HR 1·37 [95% CI 1·13–1·65]; p=0·001), resulting in early closure of the trial. Overall survival did not significantly differ between lapatinib plus taxane and trastuzumab plus taxane in the intention-to-treat group (HR 1·28 [95% CI 0·95–1·72]; p=0·11); however, overall survival was worse with lapatinib than with trastuzumab in patients with centrally confirmed HER2-positive disease (HR 1·47 [95% CI 1·03–2·09]; p=0·03). 23 In the CEREBEL trial, 24 median progression-free survival and overall survival were shorter with lapatinib plus capecitabine than with trastuzumab plus capecitabine in patients with HER2-positive metastatic breast cancer, although the difference was not significant for overall survival (progression-free survival was 6·6 months vs 8·1 months; HR 1·30 [95% CI 1·04–1·64]; p=0·021; overall survival was 22·7 months vs 27·3 months; HR 1·34 [95% CI 0·95–1·90]; p=0·095). In MA.31, roughly 40% of patients had a primary diagnosis of metastatic breast cancer and thus had not received any previous anti-HER2 treatment. By contrast, to our knowledge, our study is the first to compare trastuzumab-based treatment in multiple lines versus switching to an alternative treatment on progression. Furthermore, although MA.31 and CEREBEL assessed lapatinib (an EGFR and HER2 inhibitor), we used a second-generation irreversible ErbB family inhibitor to provide broader inhibition. By contrast with the CEREBEL trial, which included patients without brain metastases at baseline, our study enrolled those with inactive, asymptomatic brain metastases. In this small subgroup of patients, there was no evidence that switching to irreversible ErbB family inhibition was beneficial compared with remaining on trastuzumab-based therapy. Similarly, a retrospective subgroup analysis of EMILIA 25 showed that the rate of CNS progression was similar for patients receiving trastuzumab emtansine and those receiving lapatinib plus capecitabine. In the present study, the incidence of drug-related adverse events was consistent with the safety profiles of each drug; however afatinib plus vinorelbine was less well tolerated than was trastuzumab plus vinorelbine. More patients in the afatinib group than in the trastuzumab group had adverse events leading to treatment discontinuation, serious adverse events, and fatal adverse events. The incidence and severity of haematological adverse events (including neutropenia) were generally similar between treatment groups; however, more patients in the afatinib group had fatal infections than did those in the trastuzumab group. One potential explanation for poorer tolerability could be a negative pharmacological interaction between afatinib and vinorelbine. However, extensive investigation of the combination in phase 1 studies, 26,27 based on plasma exposure, did not suggest any pharmacokinetic interaction between these two compounds. LUX-Breast 1 was a large randomised multicentre trial; nevertheless, there were some limitations. First, recruitment was terminated early and patients receiving afatinib were required to switch to alternative treatments, which only enables an adequate comparison of efficacy and safety results between the randomised treatment groups up to the point of the treatment switch. The findings for overall survival could be affected by subsequent treatments, the data for which are still being collected, and many patients have still not had an overall survival event, which could render the findings immature. Additionally, second-generation antibodies, such as pertuzumab and trastuzumab emtansine (not available at the time of study design), are now standard treatments in many countries. As such, use of trastuzumab across multiple lines or trastuzumab plus vinorelbine as first-line treatment is limited in clinical practice. However, trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer failing on trastuzumab. Contributors NH, C-SH, ZS, R-GG, MU-F, BX, and MP-G designed the study. NH, C-SH, SH, D-CY, KHJ, KS, JR, Y-HI, MW, QS, and BX recruited patients. NH, C-SH, SH, D-CY, ZS, S-AI, KHJ, KS, JR, JJ, QZ, Y-HI, MW, QS, S-CC, MU-F, BX, and MP-G collected data. NH, C-SH, SH, S-AI, KHJ, JR, JJ, QZ, Y-HI, S-CC, R-GG, MU-F, and BX analysed and interpreted data. MU-F provided administrative and technical support. All authors drafted and reviewed the report, and approved the final version for submission. Declaration of interests NH has received research fees to her institution for conducting studies from Boehringer Ingelheim; and personal fees from Roche and Novartis. C-SH has received grants from Boehringer Ingelheim and Roche. SH has received research funds to her institution from Boehringer Ingelheim, Genentech/Roche, Novartis, Lilly, OBI Pharmaceuticals, Merrimack, PUMA, Biomarin, GlaxoSmithKline, and Amgen; personal fees for reimbursement for travel to meetings from Boehringer Ingelheim, Genentech/Roche, Novartis, Lilly, OBI Pharmaceuticals, and Merrimack; honoraria for leading an advisory board from Boehringer Ingelheim; and honoraria for speaking at a conference from Genentech/Roche. S-AI has received research funding from AstraZeneca and has participated in advisory boards for AstraZeneca, Novartis, and Roche. KHJ has received a grant from Eisai Korea. JJ has held an advisory role with Boehringer Ingelheim. R-GG and MU-F are employees of Boehringer Ingelheim. The other authors declare no competing interests. Acknowledgments This study was supported by Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. We thank the patients, their families, and all of the investigators who participated in this study. Additionally, we thank the Boehringer Ingelheim trial manager Annick Lahogue for her excellent support throughout the trial. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Caroline Allinson of GeoMed, an Ashfield company, part of UDG Healthcare, during the preparation of this Article. -