Many genetic lesions have been identified in lung cancers. The findings shed light on molecular pathogenesis and have led to the definition of abnormalities that can be targeted by therapeutic agents ...that occasionally elicit dramatic responses.
Lung cancer is one of the leading causes of death globally.
1
Tobacco smoking causes nearly 90% of lung cancers. The major histologic types of lung cancer include adenocarcinoma, squamous-cell carcinoma, small-cell carcinoma, large-cell neuroendocrine carcinoma, and pulmonary carcinoid tumors.
2
Although some molecular alterations are shared among various histologic subtypes, the majority of genomic alterations remain distinct. In this review, we discuss recent studies of large-scale genomic analyses of the three most common histologic types of lung cancer — adenocarcinoma, squamous-cell carcinoma, and small-cell carcinoma — and their implications for the management of this disease.
Genomic Alterations
The Genomic Landscape
Lung . . .
The discovery that certain activating mutations in the epidermal growth factor receptor (
EGFR
) tyrosine kinase domain may determine responses to EGFR tyrosine kinase inhibitors in patients with ...advanced non–small-cell lung cancer (NSCLC) allowed more precise selection of patients who were likely to have a response.
1
,
2
These mutations are seen in approximately 10 to 15% of metastatic NSCLC tumors, mostly in patients with adenocarcinoma who have never smoked. As compared with cytotoxic chemotherapy, EGFR tyrosine kinase inhibitors significantly improve the overall response rate and progression-free survival in previously untreated patients with
EGFR
-mutated NSCLC.
3
–
5
However, despite their . . .
Attack of the clones Govindan, Ramaswamy
Science (American Association for the Advancement of Science),
10/2014, Letnik:
346, Številka:
6206
Journal Article
Recenzirano
What makes lung cancer so resilient?
Also see Reports by
de Bruin
et al.
and
Zhang
et al.
Nearly 40 years ago, it was presciently observed (
1
) that each patient's cancer would require individual ...therapy and that this would be “thwarted” by the emergence of resistant cells. This prediction has proven to be depressingly true in various malignancies. It is now evident that malignant clones and subclones evolve not only through gradual acquisition of mutations but are also secondary to abrupt catastrophic events (such as massive chromosomal rerarrangement), leading to genomic heterogeneity in a tumor over time. The advent of next-generation sequencing has enabled these processes to be studied in unprecedented detail. Considerable intratumoral heterogeneity has been demonstrated in certain hematological malignancies and cancers of the breast, ovary, bladder, prostate, pancreas, and kidney (
2
–
8
). On pages 256 and 251 of this issue, Zhang
et al.
(
9
) and de Bruin
et al.
(
10
), respectively, describe the universal prevalence of intratumoral heterogeneity in lung cancer, with important implications for future research.
Summary Treatment for non-small-cell lung cancer is evolving from the use of cytotoxic chemotherapy to personalised treatment based on molecular alterations. This past decade has witnessed ...substantial progress in the treatment of patients with EGFR mutations and ALK rearrangements, and it is now possible to study complex genomic alterations in cancer using next-generation sequencing. Sequencing data from large-scale consortia, such as The Cancer Genome Atlas, as well as several independent groups, have helped identify novel drivers and potentially targetable alterations in lung adenocarcinomas. These data clearly suggest that lung adenocarcinoma is associated with distinct genomic alterations compared with other lung cancer subtypes, and highlight the widespread molecular heterogeneity that underlies the disease. In this Review, we discuss some of the key findings from genomic studies of lung adenocarcinoma.
Lung Cancer in Never Smokers: A Review SUBRAMANIAN, Janakiraman; GOVINDAN, Ramaswamy
Journal of clinical oncology,
02/2007, Letnik:
25, Številka:
5
Journal Article
Recenzirano
Lung cancer is the leading cause of cancer-related death in the United States. Although tobacco smoking accounts for the majority of lung cancer, approximately 10% of patients with lung cancer in the ...United States are lifelong never smokers. Lung cancer in the never smokers (LCINS) affects women disproportionately more often than men. Only limited data are available on the etiopathogenesis, molecular abnormalities, and prognosis of LCINS. Several etiologic factors have been proposed for the development of LCINS, including exposure to radon, cooking fumes, asbestos, heavy metals, and environmental tobacco smoke, human papillomavirus infection, and inherited genetic susceptibility. However, the relative significance of these individual factors among different ethnic populations in the development of LCINS has not been well-characterized. Adenocarcinoma is the predominant histologic subtype reported with LCINS. Striking differences in response rates and outcomes are seen when patients with advanced non-small-cell lung cancer (NSCLC) who are lifelong never smokers are treated with epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors such as gefitinib or erlotinib compared with the outcomes with these agents in patients with tobacco-associated lung cancer. Interestingly, the activating mutations in the EGFR-TK inhibitors have been reported significantly more frequently in LCINS than in patients with tobacco-related NSCLC. This review will summarize available data on the epidemiology, risk factors, molecular genetics, management options, and outcomes of LCINS.
Sotorasib is a selective irreversible inhibitor of the G12C-activated
KRAS
oncogene, present in approximately 13% of non–small-cell lung cancers. In a single-group, phase 2 trial involving 126 ...patients with previously treated
KRAS
p.G12C–mutated NSCLC, 37% had a response (median duration, 11 months). One fifth of patients had grade 3 toxic effects, mainly liver-enzyme abnormalities and diarrhea.
Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease ...progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.
The genomic and host factors that drive the progression of pre-invasive lesions in non-small cell lung cancer are poorly understood. Studying these factors can advance our knowledge of lung cancer ...biology, aid in the development of better screening strategies and improve patient outcomes.
Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (
) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, ...an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.
CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with
Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum
Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.
In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.
Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with
Exon20ins mutations after progression on platinum-based chemotherapy.
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