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Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies 1 , 2 . While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response ( n  = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo ( n  = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders ( P  < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Some patients, however, achieve lasting responses, emphasizing the need to understand how tumor microenvironment and molecular characteristics influence ICI response. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated stage IV HGSOC patients, who were scheduled for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation using multiplexed immunofluorescence and immune-related gene expression. Our findings show immune activation, evidenced by an increase in CD3 + , CD8 + , CD8 + /FOXP3+ ratio, TNF-α and interferon-γ signaling. Treatment was well-tolerated. We observed major pathologic responses in 9/33 patients (27%, 95%CI 14-46), with pathologic response strongly associated with immune activation and OS. At a median follow-up of 52.8 months, 8/9 major responders were alive, with 6 patients recurrence-free. In contrast, 4/24 minor responders survived, including one recurrence-free. ctDNA clearance was observed in all major responders and was associated with prolonged PFS and OS. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as biomarkers, warranting further exploration. These results suggest major responders may benefit from neo-adjuvant pembro. While the emergence of immune checkpoint inhibitors has improved cancer patient outcomes, efficacy in high-grade serous ovarian cancer (HGSOC) is limited. Here, the authors report a phase 2 clinical trial investigating immune activation and efficacy of neoadjuvant pembrolizumab administered after one cycle of neo-adjuvant chemotherapy in patients with untreated stage IV HGSOC.

IntroductionImmune checkpoint inhibition (ICI) has improved patients’ outcomes in advanced melanoma, often resulting in durable response. However, not all patients have durable responses and the patients with dissociated response are a valuable subgroup to identify mechanisms of ICI resistance.MethodsStage IV melanoma patients treated with ICI and dissociated response were retrospectively screened for available samples containing sufficient tumor at least at two time-points. Included were one patient with metachronous regressive and progressive lesions at the same site, two patients with regressive and novel lesion at different sites, and three patients with regressive and progressive lesions at different sites. In addition, four patients with acquired resistant tumor samples without a matched second sample were included.ResultsIn the majority of patients, the progressive tumor lesion contained higher CD8+ T cell counts/mm2 and interferon-gamma (IFNγ) signature level, but similar tumor PD-L1 expression. The tumor mutational burden levels were in 2 out 3 lesions higher compared to the corresponding regressive tumors lesion.In the acquired tumor lesions, high CD8+/mm2 and relatively high IFNγ signature levels were observed. In one patient in both the B2M and PTEN gene a stop gaining mutation and in another patient a pathogenic POLE mutation were found.ConclusionIntrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140 ), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8 + PD-1 + T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data. Results from the NICHE study show remarkable pathological responses to neoadjuvant combination immunotherapy in patients with early-stage colon cancer and uncover potential biomarkers of response.

Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3 ; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P= 0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2 .

Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients 1 , 2 . In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy 3 . Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy 4 . To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg −1 and nivolumab 1 mg kg −1 , as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity. Neoadjuvant combination immunotherapy in patients with advanced melanoma shows favorable activity over adjuvant treatment and warrants future evaluation with modified dosing schedules to reduce treatment-related adverse events.

Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha ( PIK3CA ) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95–0.99, P =4.6 × 10 −3 ), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96–1.01, P =0.139). Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer

To understand how genotype determines the phenotype of the animal Caenorhabditis elegans, one ideally needs to know the complete sequence of the genome and the contribution of genes to phenotype, which requires an efficient strategy for reverse genetics. We here report that the Tc1 transposon induces frequent deletions of flanking DNA, apparently resulting from Tc1 excision followed by imprecise DNA repair. We use this to inactivate genes in two steps. (i) We established a frozen library of 5000 nematode lines mutagenized by Tc1 insertion, from which insertion mutants of genes of interest can be recovered. Their address within the library is determined by PCR. (ii) Animals are then screened, again by PCR, to detect derivatives in which Tc1 and 1000-2000 base pairs of flanking DNA are deleted, and thus a gene of interest is inactivated. We have thus far isolated Tc1 insertions in 16 different genes and obtained deletion derivatives of 6 of those.

Germline mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia‐telangiectasia (A‐T). In our study, we have determined the ATM mutation spectrum in 19 classical A‐T patients, including some immigrant populations, as well as 12 of Dutch ethnic origin. Both the protein truncation test (PTT) and the restriction endonuclease fingerprinting (REF) method were used and compared for their detection efficiency, identifying 76% and 60% of the mutations, respectively. Most patients were found to be compound heterozygote. Seventeen mutations were distinct, of which 10 were not reported previously. Mutations are small deletions or point mutations frequently affecting splice sites. Moreover, a 16.7‐kb genomic deletion of the 3′ end of the gene, most likely a result of recombination between two LINE elements, was identified. The most frequently found mutation, identified in three unrelated Turkish A‐T individuals, was previously described to be a Turkish A‐T founder mutation. The presence of a founder mutation among relatively small ethnic population groups in Western Europe could indicate a high carrier frequency in such communities. In patients of Dutch ethnic origin, however, no significant founder effect could be identified. The observed genetic heterogeneity including the relative high percentage of splice‐site mutations had no reflection on the phenotype. All patients manifested classical A‐T and increased cellular radioresistant DNA synthesis. Hum Mutat 12:330–337, 1998.© 1998 Wiley‐Liss, Inc.

BackgroundBefore adjuvant checkpoint inhibition the 5-year overall survival (OS) rate was poor (<50%) in high-risk stage III melanoma patients. Adjuvant CTLA-4 (ipilimumab, IPI) and PD-1 (nivolumab, NIVO, or pembrolizumab) blockade have been shown to improve relapse-free survival (RFS) and OS (latter only for IPI so far). Due to a broader immune activation neoadjuvant therapy with checkpoint inhibitors might be more effective than adjuvant, as suggested in preclinical experiments. The OpACIN trial compared neoadjuvant versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO without adjuvant therapy. High pathologic response rates of 74–78% were induced by neoadjuvant IPI plus NIVO. Here, we present the 36- and 24-months RFS of the OpACIN and OpACIN-neo trial, respectively.Materials and MethodsThe phase 1b OpACIN trial included 20 stage IIIB/IIIC melanoma patients, which were randomized to receive IPI 3 mg/kg plus NIVO 1 mg/kg either adjuvant 4 cycles or split 2 cycles neoadjuvant and 2 adjuvant. In the phase 2 OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant treatment, either in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), or arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as <50% viable tumor cells and in both trials centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method.ResultsOnly 1 of 71 (1.4%) patients with a pathologic response on neoadjuvant therapy had relapsed, versus 16 of 23 patients (69.6%) without a pathologic response, after a median follow-up of 36 months for the OpACIN and 24 months for the OpACIN-neo trial. In the OpACIN trial, the estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm. Median RFS was not reached for any of the arms within the OpACIN-neo trial. Estimated 24-months RFS rate was 84% for all patients (95% CI: 76%-92%); 90% for arm A (95% CI: 80%-100%), 78% for arm B (95% CI: 63%-96%) and 83% for arm C (95% CI: 70%-100%). Baseline interferon-γ gene expression score and tumor mutational burden predict response.ConclusionsOpACIN for the first time showed a potential benefit of neoadjuvant IPI plus NIVO versus adjuvant immunotherapy, whereas the OpACIN-neo trial confirmed the high pathologic response rates that can be achieved by neoadjuvant IPI plus NIVO. Both trials show that pathologic response can function as a surrogate markers for RFS.Clinical trial informationNCT02437279, NCT02977052Disclosure InformationJ.M. Versluis: None. E.A. Rozeman: None. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Roche, Pierre-Fabre. I.L.M. Reijers: None. O. Krijgsman: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS. E.P. Hoefsmit: None. B.A. van de Wiel: None. K. Sikorska: None. C. Bierman: None. P. Dimitriadis: None. M. Gonzalez: None. A. Broeks: None. R.M. Kerkhoven: None. A.J. Spillane: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, MSD, Neon Therapeutics, Novartis. F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Pfizer, AZ/MedImmune, Rocher/Genentech, Ipsen, Bayer, Immunocore, SeattleGenetics, Neon Therapeutics, Celsius Therapeutics, Gadet, GSK. W.J. van Houdt: None. R.P.M. Saw: None. H. Eriksson: None. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD Merck, Merck-Pfizer, 4SC. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. T.N. Schumacher: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; MSD, BMS, Merck. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neogene Therapeutics, Neon Therapeutics. F. Consultant/Advisory Board; Modest; Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech. Other; Modest; Third Rock Ventures. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, NanoString. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Uniti Cars, Neon Therapeutics, Forty Seven. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre-Fabre.