Genetics of Breast Cancer: Risk Models, Who to Test, and Management Options.

Genetic testing plays an important role in assessing breast cancer risk and often the risk of other types of cancers. Accurate risk assessment and stratification represents a critical element of identifying who is best served by increased surveillance and consideration of other prevention or treatment options while also limiting overtreatment and unnecessary testing. The indications for testing will likely continue to expand, and ideally, more women with a genetic predisposition to breast cancer will be identified before they are diagnosed with breast cancer and thus have the option to consider effective screening and prevention management strategies.

Implications of missing data on reported breast cancer mortality.

BACKGROUND: National cancer registries are valuable tools to analyze patterns of care and clinical outcomes; yet, missing data may impact the accuracy and generalizability of these data. We sought to evaluate the association between missing data and overall survival (OS). METHODS: Using the NCDB (National Cancer Database) and SEER (Surveillance, Epidemiology, End Results Program), we assessed data missingness among patients diagnosed with invasive breast cancer from 2010 to 2014. Key variables included demographic (age, race, ethnicity, insurance, education, income), tumor (grade, ER, PR, HER2, TNM stages), and treatment (surgery in both databases; chemotherapy and radiation in NCDB). OS was compared between those with and without missing data using Cox proportional hazards models. RESULTS: Overall, 775,996 patients in the NCDB and 263,016 in SEER were identified; missing at least 1 key variable occurred for 29% and 13%, respectively. Of those, the overwhelming majority (NCDB 80%; SEER 88%) were missing tumor variables. When compared to patients with complete data, missingness was associated with a greater risk of death: NCDB HR 1.23 (99% CI 1.21-1.25) and SEER HR 2.11 (99% CI 2.05-2.18). Patients with complete tumor data had higher unadjusted OS estimates than that of the entire sample: NCDB 82.7% vs 81.8% and SEER 83.5% vs 81.7% for 5-year OS. CONCLUSIONS: Missingness of select variables is not uncommon within large national cancer registries and is associated with a worse OS. Exclusion of patients with missing variables may introduce unintended bias into analyses and result in findings that underestimate breast cancer mortality.

The role of tumor phenotype in the surgical treatment of early-stage breast cancer.

BACKGROUND: We investigated whether tumor phenotype influences surgical decision-making, and how that may impact overall survival (OS) for early-stage breast cancer. METHODS: Women aged 18-69 with cT0-2/cN0/cM0 breast cancer in the National Cancer Database (2010-2017) were included. A generalized logistic model was used to identify factors associated with surgery type. A Kaplan-Meier curve was used to visualize unadjusted OS, and the log-rank test was used to test for differences in OS between surgery types. RESULTS: Of 597,149 patients, 58% underwent lumpectomy with radiation (BCT), 25% unilateral mastectomy (UM), and 17% bilateral mastectomy (BM). After adjustment, HER2+ and triple-negative (TN) tumors were less likely to undergo UM than BCT, versus hormone receptor-positive tumors (OR = 0.881, 95% CI = 0.860-0.903; OR = 0.485, 95% CI = 0.470-0.501). UM and BM had worse 5-year OS versus BCT (UM: 0.926, vs BM: 0.952, vs BCT: 0.960). CONCLUSIONS: BCT is increasingly used to treat HER2+ and TN tumors. More extensive surgery is not associated with better survival outcomes, regardless of tumor phenotype.

Association between circulating tumor DNA burden and disease burden in patients with ALK-positive lung cancer.

BACKGROUND: Plasma genotyping is an emerging approach for the identification of genetic alterations mediating resistance to anaplastic lymphoma kinase (ALK)-targeted therapy. The authors reviewed plasma genotyping and imaging findings to assess the correlation between circulating tumor DNA (ctDNA) burden and disease burden in patients with ALK-positive lung cancer. METHODS: The authors analyzed 97 plasma specimens from 75 patients with ALK-positive lung cancer to identify ALK and non-ALK alterations. Disease burden was estimated by tabulating lesions per organ and calculating lesion diameters, areas, and volumes. Disease burden was correlated with the allelic frequency (AF) of plasma alterations. RESULTS: The mean interval between plasma collection and imaging was 8 days. ctDNA was detected in approximately 85% of plasma specimens. An ALK fusion and ALK mutation were detected in 79% and 76%, respectively, of plasma specimens. Using the maximum plasma alteration AF and maximum ALK alteration AF as independent surrogates of ctDNA burden, a higher disease burden measurement on imaging was found to be associated with higher ctDNA burden. Total body and extrathoracic tumor volume but not intrathoracic tumor volume correlated with ctDNA burden. Of all the disease sites assessed, the ctDNA burden correlated most with involvement of the liver, bones, and adrenal glands. Despite being the defining alteration in ALK-positive lung cancer, isolated plasma ALK fusion AF did not perform as well as the maximum plasma alteration AF or maximum ALK alteration AF for correlating tumor burden. CONCLUSIONS: In patients with ALK-positive lung cancer, the maximum plasma alteration AF and maximum ALK alteration AF correlate with the extrathoracic burden of disease and are more predictive of tumor burden compared with the ALK fusion AF alone. LAY SUMMARY: Analysis of genetic material shed from cancer cells into the circulation offers insights into the molecular composition of tumors. The circulating tumor DNA (ctDNA) varies over time and across individuals and is impacted by the distribution of disease. Herein, the authors estimated tumor burden on imaging and correlated it with ctDNA by calculating the maximum allelic frequency. The current study findings demonstrated that the greatest correlation exists between extrathoracic, extracranial tumor burden (particularly involvement of the liver, adrenal glands, or bones) and ctDNA burden, suggesting a biological basis for the interpatient and temporal intrapatient differences in ctDNA yield that have been described in previous studies.

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer.

PURPOSE: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. EXPERIMENTAL DESIGN: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. RESULTS: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. CONCLUSIONS: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.

Imaging Features and Metastatic Patterns of Advanced ALK-Rearranged Non-Small Cell Lung Cancer.

OBJECTIVE.ALK rearrangements are an established targetable oncogenic driver in non-small cell lung cancer (NSCLC). The goal of this study was to determine the imaging features of the primary tumor and metastatic patterns in advanced ALK-rearranged (ALK+) NSCLC that may be different from those in EGFR-mutant (EGFR+) or EGFR/ALK wild-type (EGFR-/ALK-) NSCLC. MATERIALS AND METHODS. Patients with advanced ALK+, EGFR+, or EGFR-/ALK- NSCLC were retrospectively identified. Two radiologists concurrently assessed the imaging features of the primary tumor and the distribution of metastases in these patients. RESULTS. We identified a cohort of 333 patients with metastatic NSCLC (119 ALK+ cases, 116 EGFR+ cases, and 98 EGFR-/ALK- cases). Compared with EGFR+ and EGFR-/ALK- NSCLC, the primary tumor in ALK+ NSCLC was more likely to be located in the lower lobes (53% of ALK+, 34% of EGFR+, and 36% of EGFR-/ALK- tumors; p < 0.05), less likely to be subsolid (1% of ALK+, 11% of EGFR+, and 8% of EGFR-/ALK- tumors; p < 0.02), and less likely to have air bronchograms (7% of ALK+, 28% of EGFR+, and 29% of EGFR-/ALK- tumors; p < 0.01). Compared with EGFR+ and EGFR-/ALK- tumors, ALK+ tumors had higher frequencies of distant nodal metastasis (20% of ALK+ tumors vs 2% of EGFR+ and 9% of EGFR-/ALK- tumors; p < 0.05) and lymphangitic carcinomatosis (37% of ALK+ tumors vs 12% of EGFR+ and 12% of EGFR-/ALK- tumors; p < 0.01), but ALK+ tumors had a lower frequency of brain metastasis compared with EGFR+ tumors (24% vs 41%; p = 0.01). Although there was no statistically significant difference in the frequencies of bone metastasis among the three groups, sclerotic bone metastases were more common in the ALK+ tumors (22% vs 7% of EGFR+ tumors and 6% of EGFR-/ALK- tumors; p < 0.01). CONCLUSION. Advanced ALK+ NSCLC has primary tumor imaging features and patterns of metastasis that are different from those of EGFR+ or EGFR-/ALK- wild type NSCLC at the time of initial presentation.

Computed Tomography Imaging Features and Distribution of Metastases in ROS1-rearranged Non-Small-cell Lung Cancer.

BACKGROUND: ROS proto-oncogene 1 (ROS1) rearrangements are a known molecular target in non-small-cell lung cancer (NSCLC). Our goal was to determine whether ROS1-rearranged NSCLC has imaging features and patterns of metastasis, which differ from those of anaplastic lymphoma kinase (ALK)-rearranged or epidermal growth factor receptor (EGFR)-mutant NSCLC. PATIENTS AND METHODS: We retrospectively identified patients with metastatic ROS1-rearranged, ALK-rearranged, or EGFR-mutant NSCLC from January 2014 to June 2018 and included those with pretreatment imaging studies available. We assessed the imaging features of the primary tumor and the distribution of metastases in these patients. The Wilcoxon rank-sum test and Fisher exact test were used to compare the imaging features. RESULTS: We identified 257 patients (167 women and 90 men; median age, 56 years; range, 19-90 years) with metastatic NSCLC (ROS1, 53; ALK, 87; EGFR, 117). Compared with ALK-rearranged or EGFR-mutant NSCLC, ROS1-rearranged NSCLC was less likely to present with extrathoracic metastases (ROS1, 49%; ALK, 75%; EGFR, 72%; P < .01), including brain metastases (ROS1, 9%; ALK, 25%; EGFR, 40%; P < .04). Compared with EGFR-mutant NSCLC, ROS1-rearranged tumors were more likely to exhibit imaging features of lymphangitic carcinomatosis (ROS1, 42%; EGFR, 12%; P < .01) and less likely to have air bronchograms in the primary tumor (ROS1, 2%; EGFR, 28%; P < .01). ROS1-rearranged tumors were also more likely to present with distant nodal metastases (ROS1, 15%; EGFR, 2%; P < .01) and sclerotic-type bone metastases (ROS1, 17%; EGFR, 6%; P < .01). CONCLUSION: Although considerable overlap exists in the imaging features of ROS1-rearranged, ALK-rearranged, and EGFR-mutant NSCLC, we found that ROS1-rearranged NSCLC has certain distinct imaging features and patterns of spread.