SummarySalmonella enterica serovar Paratyphi C causes enteric (paratyphoid) fever in humans. Its presentation can range from asymptomatic infections of the blood stream to gastrointestinal or urinary tract infection or even a fatal septicemia [1]. Paratyphi C is very rare in Europe and North America except for occasional travelers from South and East Asia or Africa, where the disease is more common [2, 3]. However, early 20th-century observations in Eastern Europe [3, 4] suggest that Paratyphi C enteric fever may once have had a wide-ranging impact on human societies. Here, we describe a draft Paratyphi C genome (Ragna) recovered from the 800-year-old skeleton (SK152) of a young woman in Trondheim, Norway. Paratyphi C sequences were recovered from her teeth and bones, suggesting that she died of enteric fever and demonstrating that these bacteria have long caused invasive salmonellosis in Europeans. Comparative analyses against modern Salmonella genome sequences revealed that Paratyphi C is a clade within the Para C lineage, which also includes serovars Choleraesuis, Typhisuis, and Lomita. Although Paratyphi C only infects humans, Choleraesuis causes septicemia in pigs and boar [5] (and occasionally humans), and Typhisuis causes epidemic swine salmonellosis (chronic paratyphoid) in domestic pigs [2, 3]. These different host specificities likely evolved in Europe over the last ∼4,000 years since the time of their most recent common ancestor (tMRCA) and are possibly associated with the differential acquisitions of two genomic islands, SPI-6 and SPI-7. The tMRCAs of these bacterial clades coincide with the timing of pig domestication in Europe [6].

Together with plague, smallpox and typhus, epidemics of dysentery have been a major scourge of human populations for centuries(1). A previous genomic study concluded that Shigella dysenteriae type 1 (Sd1), the epidemic dysentery bacillus, emerged and spread worldwide after the First World War, with no clear pattern of transmission(2). This is not consistent with the massive cyclic dysentery epidemics reported in Europe during the eighteenth and nineteenth centuries(1,3,4) and the first isolation of Sd1 in Japan in 1897(5). Here, we report a whole-genome analysis of 331 Sd1 isolates from around the world, collected between 1915 and 2011, providing us with unprecedented insight into the historical spread of this pathogen. We show here that Sd1 has existed since at least the eighteenth century and that it swept the globe at the end of the nineteenth century, diversifying into distinct lineages associated with the First World War, Second World War and various conflicts or natural disasters across Africa, Asia and Central America. We also provide a unique historical perspective on the evolution of antibiotic resistance over a 100-year period, beginning decades before the antibiotic era, and identify a prevalent multiple antibiotic-resistant lineage in South Asia that was transmitted in several waves to Africa, where it caused severe outbreaks of disease.

Bloodstream infections caused by nontyphoidal Salmonella are a major public health concern in Africa, causing ~49,600 deaths every year. The most common Salmonella enterica pathovariant associated with invasive nontyphoidal Salmonella disease is Salmonella Typhimurium sequence type (ST)313. It has been proposed that antimicrobial resistance and genome degradation has contributed to the success of ST313 lineages in Africa, but the evolutionary trajectory of such changes was unclear. Here, to define the evolutionary dynamics of ST313, we sub-sampled from two comprehensive collections of Salmonella isolates from African patients with bloodstream infections, spanning 1966 to 2018. The resulting 680 genome sequences led to the discovery of a pan-susceptible ST313 lineage (ST313 L3), which emerged in Malawi in 2016 and is closely related to ST313 variants that cause gastrointestinal disease in the United Kingdom and Brazil. Genomic analysis revealed degradation events in important virulence genes in ST313 L3, which had not occurred in other ST313 lineages. Despite arising only recently in the clinic, ST313 L3 is a phylogenetic intermediate between ST313 L1 and L2, with a characteristic accessory genome. Our in-depth genotypic and phenotypic characterization identifies the crucial loss-of-function genetic events that occurred during the stepwise evolution of invasive S. Typhimurium across Africa.

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Institut Pasteur, Santé publique France, the French Government's Investissement d'Avenir programme, the Fondation Le Roch-Les Mousquetaires.

Background: While studies have shown feasibility and reported preliminary evidence of utility, there is no evidence that multigene sequencing improves outcome in patients with metastatic cancer. The aim of the present study was to assess the clinical utility of multigene sequencing and DNA copy number analyses.. Methods: In SAFIR02-BREAST (NCT: 02299999) and SAFIR-PI3K (NCT: 03386162), open-label multicentric phase II randomized trials, patients were selected if they had a Her2-negative metastatic breast cancer eligible to 1st or 2nd line chemotherapy. Patients underwent a pre-treatment biopsy of metastatic disease when feasible, followed by genomic analysis by next generation sequencing and SNParray. After 6 to 8 cycles of induction chemotherapy, patients without progressive disease and presenting an actionable genomic alteration, were randomized between targeted therapies matched to genomic alterations or maintenance chemotherapy. The primary objective was to evaluate whether targeted therapies guided by genomics improves progression-free survival (PFS) as compared to maintenance chemotherapy, in a pooled analyses of SAFIR02-BREAST and SAFIR-PI3K populations. A hierarchical testing was applied. The efficacy of targeted therapies matched to genomic alterations was first tested in patients presenting an ESCAT I/II alteration (ESMO Scale of Actionability of Molecular Targets). If a p value <0.1 was observed in the first step, analyses were then performed in the Intent-to-treat population. Results: Out of the 1462 patients included, 238 (16%) were subsequently randomized between maintenance chemotherapy (n=81) and targeted therapy (n=157). In 115 patients presenting an ESCAT I/II genomic alteration, the median PFS was 9.1 months (90%CI: 7.1-9.8) and 2.8 (90%CI: 2.1-4.8) in matched targeted therapy and maintenance chemotherapy arms respectively (adjusted HR for stratification factors =0.41;90%CI: 0.27-0.61, p<0.001). In the overall population, there was no significant difference in the duration of PFS between the two arms (adjusted HR: 0.77 (95%CI: 0.56- 1.06, p=0.109). ESCAT classification was highly predictive for the benefit of targeted therapies matched to genomic alterations (interaction test, p= 0.004). Targeted therapies matched to genomic alterations were not effective in patients without ESCAT I/II alteration (HR: 1.15, 95%CI: 0.76-1.75). The SNP array analyses (n=926) identified 21 genes altered more frequently in metastases as compared to primary tumors (TCGA+ METABRIC). Of these, focal TERT amplifications were associated with a poor outcome. Focal CDK4 amplifications were observed after resistance to CDK4 inhibitors. Finally, high HRD was associated with longer PFS in patients with BRCA mutation treated with olaparib (HR: 0.32 [95%CI: 0.12;0.83], p=0.013).. Conclusion: SAFIR02/PI3K trials report that the clinical use of multigene sequencing must be driven by a framework of actionability, and identifies new genomic alterations associated with metastatic evolution and drug resistance or sensitivity. Citation Format: Fabrice André, Anthony Gonçalves, Thomas Filleron, Florence Dalenc, Amélie Lusque, Mario Campone, Marie-Paule Sablin, Hervé Bonnefoi, Ivan Bieche, Ludovic Lacroix, Alicia Tran-Dien, Marta Jimenez, Alexandra Jacquet, Qing Wang, Etienne Rouleau, David Gentien, Isabelle Soubeyran, Alain Morel, Monica Arnedos, Thomas Bachelot. Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-10.

1092 Background: PARP-inhibitors improve PFS in mBC patients (pts) harboring a gBRCA mutation (mut). However, unlike ovarian cancer, there is no evidence until now that this class of agents has efficacy in gBRCA wild-type (WT) pts. In RUBY, we evaluated rucaparib in gBRCA WT mBC pts, and whose tumor present with HRD as assessed by genome-wide Loss of Heterozygosity (LOH) score. Methods: 713 gBRCA WT women with HER2- mBC, initiating a first metastatic chemo, were screened for high (≥18%) genomic tumor LOH generated from a SNP array on metastatic sample. Eligible pts with a high LOH score or somatic (s) BRCA mut and ≥1 prior chemo regimen were proposed to enter RUBY and receive oral rucaparib 600 mg BID continuously in 28-day cycles until disease progression. The primary endpoint was clinical benefit rate (CBR), defined by complete (CR) and partial response (PR) or stable disease (SD) ≥16 weeks. We used a Simon’s two-stage design (p0=20%; p1=40%), responses in ≥4/17 pts were expected to move to second step, and ≥11/37 pts to be considered of clinical interest (α=10% and power of 90%). Whole genome sequencing (WGS) was performed retrospectively to further assess potential biomarkers of PARP inhibitor response. Results: Tumors from 221 (31%) pts were LOH high. 41 pts were enrolled, including 4 pts with sBRCA mut. Median prior metastatic chemo lines was 2 (1-5), 17 pts had TNBC at diagnosis. As of 14 Jan 2019, 16 pts were alive, 5 are still on treatment. The median number of cycles was 2 (1 -20), and 37/40 patients were evaluable for CBR. 5 pts (13.5%) demonstrated clinical benefit (1 CR [LOH high], 3 PR [2 LOH high, 1 sBRCA2] and 1 SD>31 weeks [sBRCA1]). 19 pts had grade 3-4 toxicities. 3 pts discontinued due to toxicity. 4/5 responders pts had their tumor profiled by WGS: preliminary analyses showed that 4 pts presented high large scale state transitions, and 3 presented a somatic biallelic loss of function in HR-related genes. The fifth responder harbored a mut on gPALB2 and sBRCA2 at inclusion. Conclusions: In this study, rucaparib demonstrates antitumor activity in a subset of gBRCA WT mBC pts whose tumor has high LOH. Final analyses of WGS will provide insights about HRD signatures and drivers alterations associated with response. Clinical trial information: NCT02505048.

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