Targeting chromosomal instability in patients with cancer.

Chromosomal instability (CIN) is a hallmark of cancer and a driver of metastatic dissemination, therapeutic resistance, and immune evasion. CIN is present in 60-80% of human cancers and poses a formidable therapeutic challenge as evidenced by the lack of clinically approved drugs that directly target CIN. This limitation in part reflects a lack of well-defined druggable targets as well as a dearth of tractable biomarkers enabling direct assessment and quantification of CIN in patients with cancer. Over the past decade, however, our understanding of the cellular mechanisms and consequences of CIN has greatly expanded, revealing novel therapeutic strategies for the treatment of chromosomally unstable tumours as well as new methods of assessing the dynamic nature of chromosome segregation errors that define CIN. In this Review, we describe advances that have shaped our understanding of CIN from a translational perspective, highlighting both challenges and opportunities in the development of therapeutic interventions for patients with chromosomally unstable cancers.

Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer.

PURPOSE: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. EXPERIMENTAL DESIGN: We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). RESULTS: All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. CONCLUSIONS: Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.

The Search for Genomic Biomarkers of Response to Immunotherapy in Ovarian Cancer.

Immune checkpoint blockade has been ineffective in ovarian cancer, and there is an ongoing effort to identify biomarkers of therapeutic benefit. Despite promising preclinical data, a substudy of the IMagyn050 trial found that patients with homologous recombination deficient tumors did not have improved progression-free survival with the addition of the PD-L1 inhibitor atezolizumab. See related article by Landen et al., p. 1698.

Chromosomal instability as a source of genomic plasticity.

Chromosomal instability (CIN) is a hallmark of the most aggressive malignancies. Features of these tumors include complex genomic rearrangements, the presence of mis-segregated chromosomes in micronuclei, and extrachromosomal DNA (ecDNA) formation. Here, we review the development of CIN, and examine CIN in the context of cancer evolution, tumor genomic evolution, and therapeutic resistance. We also discuss the role of whole-genome duplications, breakage-fusion-bridge cycles, ecDNA or double minutes in gene amplification promoting tumor evolution.

Baseline risk of hematologic malignancy at initiation of frontline PARP inhibitor maintenance for BRCA1/2-associated ovarian cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are FDA approved as frontline maintenance for BRCA-associated advanced stage high-grade ovarian cancer (HGOC), having demonstrated an unprecedented improvement in relapse-free survival. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are rare toxicities of PARPi. We describe three patients with germline BRCA-associated (gBRCA+) HGOC and alterations in AML driver genes. Although none evidenced overt hematologic malignancy, PARPi maintenance was cautiously considered given the potential risk of MDS/AML. A better understanding of the role of clonal hematopoiesis in the subsequent development of PARPi-associated MDS/AML will improve management of this patient population.