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Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8–10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0–14·7) in the BRCA mutant subgroup, 5·7 months (5·3–7·6) in the LOH high subgroup, and 5·2 months (3·6–5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16–0·44, p<0·0001) and LOH high (0·62, 0·42–0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer—Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR–Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, ‘Shieldin’ (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance. Through CRISPR–Cas9 screen, Dev et al. identified that SHLD1/2 inhibition contributes to PARP-inhibitor resistance. Mechanistically, SHLDs promote non-homologous end-joining and antagonize homologous recombination.

Rubin and colleagues discuss the origin and evolution of poorly differentiated neuroendocrine tumors, and highlight potential new therapeutic strategies. Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo , they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

A proof of principle study shows that by exome sequencing of cell-free circulating DNA from cancer patient plasma samples, the genomic evolution of metastatic cancers and the acquisition of resistance in response to therapy can be tracked over time. Plasma screening tracks tumour evolution This proof-of-principle study shows that by sequencing cancer exomes from patient plasma samples, it is possible to track genomic evolution of metastatic cancers and acquisition of resistance in response to therapy. In six patients with advanced breast, lung and ovarian cancers, sequences were derived from two to five plasma samples taken during multiple courses of treatment. Mutations associated with the emergence of resistance to drugs including cisplatin, tamoxifen and gefitinib were identified. Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection 1 , 2 . Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity 3 , 4 . Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy 5 , 6 , 7 . Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1–2 years. For each case, exome sequencing was performed on 2–5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel 8 ; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin 9 ; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab 10 , 11 , and following subsequent treatment with lapatinib 12 , 13 , a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib 14 . These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses. POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing. Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported. POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical–pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies. Cancer Research UK.

Epithelial‐mesenchymal transition (EMT) is a reversible and dynamic process hypothesized to be co‐opted by carcinoma during invasion and metastasis. Yet, there is still no quantitative measure to assess the interplay between EMT and cancer progression. Here, we derived a method for universal EMT scoring from cancer‐specific transcriptomic EMT signatures of ovarian, breast, bladder, lung, colorectal and gastric cancers. We show that EMT scoring exhibits good correlation with previously published, cancer‐specific EMT signatures. This universal and quantitative EMT scoring was used to establish an EMT spectrum across various cancers, with good correlation noted between cell lines and tumours. We show correlations between EMT and poorer disease‐free survival in ovarian and colorectal, but not breast, carcinomas, despite previous notions. Importantly, we found distinct responses between epithelial‐ and mesenchymal‐like ovarian cancers to therapeutic regimes administered with or without paclitaxel in vivo and demonstrated that mesenchymal‐like tumours do not always show resistance to chemotherapy. EMT scoring is thus a promising, versatile tool for the objective and systematic investigation of EMT roles and dynamics in cancer progression, treatment response and survival. Synopsis A novel EMT scoring method reveals that EMT status does not unanimously correlate with poorer overall and disease‐free survival. Different EMTed tumours show distinct responses to certain chemotherapeutics, with the potential to stratify patients by EMT status. A novel scoring method was developed based on transcriptomics to universally estimate and compare the Epithelial‐Mesenchymal Transition (EMT) phenotype across cancer types. A spectrum of EMT was established across more than 15 cancers using this EMT scoring method. Correlations of EMT status with poorer overall‐ and disease‐free survival were not unanimously observed in all cancers. Differential and preferential responses of EMTed tumours to certain chemotherapeutics were observed, suggesting the potential to stratify patients by EMT status. Graphical Abstract A novel EMT scoring method reveals that EMT status does not unanimously correlate with poorer overall and disease‐free survival. Different EMTed tumours show distinct responses to certain chemotherapeutics, with the potential to stratify patients by EMT status.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer ( r g  = 0.57, p  = 4.6 × 10 −8 ), breast and ovarian cancer ( r g  = 0.24, p  = 7 × 10 −5 ), breast and lung cancer ( r g  = 0.18, p  =1.5 × 10 −6 ) and breast and colorectal cancer ( r g  = 0.15, p  = 1.1 × 10 −4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis. Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.