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.
Plasma genotyping of circulating tumor DNA (ctDNA) has emerged as a clinical tool for the identification of underlying driver mutations and resistance mechanisms in patients with lung cancer. In patients with advanced, ALK‐positive lung cancer, plasma genotyping yields higher quantities of ctDNA in those patients found to have a high extrathoracic disease burden on imaging, particularly within the setting of hepatic, adrenal, and bone metastases.
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.
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
-rearranged (
+) NSCLC that may be different from those in
-mutant (
+) or
wild-type (
-/
-) NSCLC.
Patients with advanced
+,
+, or
NSCLC were retrospectively identified. Two radiologists concurrently assessed the imaging features of the primary tumor and the distribution of metastases in these patients.
We identified a cohort of 333 patients with metastatic NSCLC (119
cases, 116
cases, and 98
-/
- cases). Compared with
+ and
-/
- NSCLC, the primary tumor in
+ NSCLC was more likely to be located in the lower lobes (53% of
, 34% of
, and 36% of
-/
- tumors;
< 0.05), less likely to be subsolid (1% of
+, 11% of
, and 8% of
-/
- tumors;
< 0.02), and less likely to have air bronchograms (7% of
, 28% of
, and 29% of
-/
- tumors;
< 0.01). Compared with
+ and
-/
- tumors,
+ tumors had higher frequencies of distant nodal metastasis (20% of
tumors vs 2% of
and 9% of
-/
- tumors;
< 0.05) and lymphangitic carcinomatosis (37% of
tumors vs 12% of
and 12% of
-/
- tumors;
< 0.01), but
+ tumors had a lower frequency of brain metastasis compared with
+ tumors (24% vs 41%;
= 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
+ tumors (22% vs 7% of
tumors and 6% of
-/
- tumors;
< 0.01).
Advanced
+ NSCLC has primary tumor imaging features and patterns of metastasis that are different from those of
+ or
-/
- wild type NSCLC at the time of initial presentation.
We investigated whether tumor phenotype influences surgical decision-making, and how that may impact overall survival (OS) for early-stage breast cancer.
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.
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).
BCT is increasingly used to treat HER2+ and TN tumors. More extensive surgery is not associated with better survival outcomes, regardless of tumor phenotype.
•Tumor phenotype and histology influence patterns of breast cancer surgical care. (82).•BCT is increasingly used in the care of HER2+ and triple negative tumors. (75).•Tumors with lobular histology and high grade are more likely to undergo mastectomy. (85).•More extensive surgery is not associated with better survival. (63).
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.
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.
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).
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.
The present study is the largest study to analyze the imaging features of ROS1-rearranged non–small-cell lung cancer (NSCLC), including 257 patients with mutated NSCLC. We found that ROS1-rearranged NSCLC has distinct imaging features and metastatic patterns compared with those with ALK and EGFR mutations. These could help in selecting patients with advanced NSCLC, for whom appropriate genotyping should be prioritized.
Rearranged during transfection proto-oncogene (
) fusions represent a potentially targetable oncogenic driver in non-small cell lung cancer (NSCLC). Imaging features and metastatic patterns of ...advanced
fusion-positive (
+) NSCLC are not well established. Our goal was to compare the imaging features and patterns of metastases in
+,
+ and
+ NSCLC. Patients with
+,
+, or
+ NSCLC seen at our institution between January 2014 and December 2018 with available pre-treatment imaging were identified. The clinicopathologic features, imaging characteristics, and the distribution of metastases were reviewed and compared. We identified 215 patients with NSCLC harboring
,
, or
gene fusion (
= 32;
= 116;
= 67). Patients with
+ NSCLC were older at presentation compared to
+ and
+ patients (median age:
= 64 years;
= 51 years,
< 0.001; ROS = 54 years,
= 0.042) and had a higher frequency of neuroendocrine histology (
= 12%;
= 2%,
= 0.025;
= 0%,
= 0.010). Primary tumors in
+ patients were more likely to be peripheral (
= 69%;
= 47%,
= 0.029;
= 36%,
= 0.003), whereas lobar location, size, and density were comparable across the three groups.
+ NSCLC was associated with a higher frequency of brain metastases at diagnosis compared to
+ NSCLC (
= 32%,
= 10%;
= 0.039. Metastatic patterns were otherwise similar across the three molecular subgroups, with high incidences of lymphangitic carcinomatosis, pleural metastases, and sclerotic bone metastases.
+ NSCLC shares several distinct radiologic features and metastatic spread with
+ and
NSCLC. These features may suggest the presence of
fusions and help identify patients who may benefit from further molecular genotyping.
Circulating tumor DNA analysis is an emerging genotyping strategy that can identify tumor-specific genetic alterations in plasma including mutations and rearrangements. Detection of ROS1 fusions in ...plasma requires genotyping approaches that cover multiple breakpoints and target a variety of fusion partners. Compared to other molecular subsets of NSCLC, experience with detecting ROS1 genetic alterations in plasma is limited.
To describe the spectrum of ROS1 fusions in NSCLC and determine sensitivity for detecting ROS1 fusions in plasma, we queried the Guardant Health plasma dataset and an institutional tissue database and compared plasma findings to tissue results. In addition, we used the Guardant360 NGS assay to detect potential genetic mediators of resistance in plasma from patients with ROS1-positive NSCLC who were relapsing on crizotinib.
We detected seven distinct fusion partners in plasma, most of which (n = 6 of 7) were also represented in the tissue dataset. Fusions pairing CD74 with ROS1 predominated in both cohorts (plasma: n = 35 of 56, 63%; tissue: n = 26 of 52, 50%). There was 100% concordance between the specific tissue- and plasma-detected ROS1 fusion for seven patients genotyped with both methods. Sensitivity for detecting ROS1 fusions in plasma at relapse on ROS1-directed therapy was 50%. Six (33%) of 18 post-crizotinib plasma specimens harbored ROS1 kinase domain mutations, five of which were ROS1 G2032R. Two (11%) post-crizotinib plasma specimens had genetic alterations (n = 1 each BRAF V600E and PIK3CA E545K) potentially associated with ROS1-independent signaling.
Plasma genotyping captures the spectrum of ROS1 fusions observed in tissue. Plasma genotyping is a promising approach to detecting mutations that drive resistance to ROS1-directed therapies.
The current standard initial therapy for advanced ALK receptor tyrosine kinase (ALK)–positive NSCLC is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line ...therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third-generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in cases that are refractory to second-generation TKIs.
This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to one or more second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy.
Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11 of 37 patients; 95% confidence interval CI: 15.9% – 47.0%), with median duration of response of 6.4 months (95% CI: 1.6 months – not reached). The median progression-free survival for the entire cohort was 4.3 months (95% CI: 2.9 – 5.8 months). Progression-free survival was longer in patients who received platinum/pemetrexed in combination with an ALK TKI compared to those who received platinum/pemetrexed alone (6.8 months vs. 3.2 months, respectively; hazard ratio = 0.33; p = 0.025).
Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.
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