<p><i>In vivo</i> treatment causes permanent changes to a tumor’s drug response profile. <b>A,</b> Experimental framework of <i>in vivo</i> and <i>ex vivo</i> drug response profiling. <b>B,</b> High-throughput drug screening data of dissociated PDTX cells. AUC plots display the response of each tumor to drugs tested <i>ex vivo</i>. Color indicates the <i>in vivo</i> treatment to which each tumor was previously exposed. <b>C,</b> Dose–response curves of models 1040 (top) and 1141 (bottom) to olaparib and BMN-673. Plots compare the untreated PDTX tumors (black) to those previously treated <i>in vivo</i> with CT (red). <b>D,</b> Experimental framework to test alternative sequencing strategies of CT and olaparib <i>in vivo</i> using model 1040. Untreated PDTX tumors and those previously treated with CT or olaparib were each passaged into three cohorts of mice. These mice were left untreated or subsequently exposed to CT or olaparib. <b>E,</b> Estimated mean tumor growth for each experimental group. Panels display previous treatment groups (first-line treatment), and lines within each panel display the cohort of second-line treatment. <b>F,</b> Estimated log-daily growth rate of PDTX tumors, as predicted by the linear mixed models. Column panels display previous treatment groups (first-line treatment), and lines within each panel display the cohort of second-line treatment. <b>G,</b> Predicted tumor (log) volume at treatment end of each cohort treated sequentially with no treatment, CT, or olaparib based on the linear mixed models. Panels display previous treatment groups (first-line treatment), and boxes within each panel display the cohort of second-line treatment.</p>
Abstract Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT) and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.
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