Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triplenegative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB).Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib þ palbociclib) treatments.Results: EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone.Conclusions: We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy.

ObjectiveThe link between BRCA1 and homologous recombination deficiency (HRD) in cancer has gained importance with the emergence of new targeted cancer treatments, while the available data on the role of the gene in colorectal cancer (CRC) remain contradictory. The aim of this case series was to elucidate the role of known pathogenic BRCA1 variants in the development of early-onset CRC.DesignPatients were evaluated using targeted next generation sequencing, exome sequencing and chromosomal microarray analysis of the paired germline and tumor samples. These results were used to calculate the HRD score and the frequency of mutational signatures in the tumors.ResultsThree patients with metastatic CRC were heterozygous for a previously known BRCA1 nonsense variant. All tumors showed remarkably high HRD scores, and the HRD-related signature 3 had the second highest contribution to the somatic pattern of variant accumulation in the samples (23% in 1 and 2, and 13% in sample 3).ConclusionsA BRCA1 germline pathogenic variant can be involved in CRC development through HRD. Thus, BRCA1 testing should be considered in young patients with a personal history of microsatellite stable CRC as this could further allow a personalized treatment approach.

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focused on microRNAs (miRs), the most abundant class of small RNAs in these samples. Informed consent was given by all patients. Results and discussions On average, we detected 233 miRs in tumours and 175 in exosomes that were classified as present/ absent and interrogated across samples. Cross-sectional analysis: same timepoint across patients. Longitudinal analysis: tumour and exosomes from the same patient. Cross-sectional analysis identified 49 miRs shared by all tumours, 33 by all exosomes collected before surgery, 83 by all exosomes collected after surgery. To pinpoint miRs useful to monitor tumour dynamics in each patient, three criteria were defined: 1) miRs present both in tumours and exosomes before surgery, and; 2) miRs present in tumours and absent in exosomes soon-after surgery. We found 133 miRs in patients A, 50 in B, 34 in C and 11 in D. Combining the cross-sectional and longitudinal analysis, we found two miRs fulfilling the above criteria that were shared by three out of four patients. These two miRs were still detected in Patient D exosomes soon after surgery, likely reflecting non-curative surgery. Validation of these data is currently ongoing in a larger series of patients. Conclusion Overall, this study pinpointed two miRs that may prove useful to monitor tumour dynamics and response to treatment in GC. The longitudinal analysis holds the promise of revealing a set of miRs with clinical utility for anticipating disease relapse, on a personalised manner.