Adverse events were mostly low grade. The most common grade 3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no approximately 3 years.

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(age range, 43-61 years) and all had brain metastases at baseline. All four patients achieved an objective partial response to ensartinib, including one patient with an acquired ALK F1174V crizotinib resistance mutation. Intracranial responses included one partial response, two stable disease, and resolution of a non-target lesion in another patient. The median progression free survival was 12.5 months (range, 8-15 months) and the median decrease in tumor size was 42% (range, 39-48%). Primary sites of disease progression included lung (n¼1), brain (n¼2), both lung and brain (n¼1). No somatic alterations were identified in the two patients who received post-ensartinib ctDNA sequencing. At progression, all patients received brigatinib as subsequent therapy with clinical benefit; one received lorlatinib after brigatinib failure and response is ongoing. Median post-ensartinib survival was 27 months (range, 20-38 months). Two patients remain alive 27 and 95 months after first anti-cancer therapy. The most common adverse events with ensartinib were mild rash, diarrhea, and fatigue that did not require dose reduction. Conclusion: Ensartinib is well tolerated and has clinical activity in advanced ALK-rearranged NSCLC patients with brain metastases, despite previously progressing on crizotinib, with durable post-ensartinib survival on subsequent next-generation ALK inhibitors such as brigatinib and lorlatinib.

The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, however, remain problematic. Recent advances in genomic technologies offer significant opportunities to identify critical changes that occur during cancer evolution and to distinguish in a complex and comprehensive manner the key similarities and differences between mouse models and human cancer. Comparisons between mouse and human tumors are being performed using comparative genomic hybridization, gene expression profiling, and proteomic analyses. The appropriate use of genetically engineered mouse models of mammary cancer in preclinical studies remains an important challenge which may also be aided by genomic technologies. Genomic approaches to cancer are generating huge datasets that represent a complex system of underlying networks of genetic interactions. Mouse models offer a tremendous opportunity to identify such networks and how they relate to human cancer. The challenge of the future remains to decipher these networks in order to identify the genetic nodes of oncogenesis that may be important targets for chemoprevention and therapy. Approximately 70% of human breast cancers are estrogen receptor alpha (ERα)-positive, but the origins of ERα-positive and ERα-negative tumors remain unclear. Most mouse models produce only ERα-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report that somatic mutations of p53 in mouse mammary epithelial cells lead to ERα-positive and ERα-negative tumors. p53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells. These tumors have a high rate of metastasis that is independent of tumor latency. An inverse relationship between the number of targeted cells and median tumor latency was also observed. The median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Since it is feasible to isolate ERα-positive epithelial cells from normal mammary glands and tumors, molecular mechanisms underlying ERα-positive and ERα-negative mammary carcinogenesis can be systematically addressed using this model. Breast tumor suppressor gene 1 (BRCA1) is a well-known transcription regulator, mutations of which cause tumor formation in a tissuespecific manner. In the past years, we have studied functions of Brca1 in mouse models carrying a number of different mutations. We showed that impaired Brca1 function causes chromosome damages, failure of the G2/M cell cycle checkpoint,...