Lung Cancer in Nonsmoking Individuals: A Review

Importance: Lung cancer in nonsmoking individuals (defined as people who have smoked fewer than 100 cigarettes in their lifetime) accounts for 15% to 20% of all lung cancer cases worldwide. In the US, the annual incidence of lung cancer in nonsmoking individuals is 14.4 to 20.8 per 100 000 person-years in females and 4.8 to 12.7 per 100 000 person-years in males.

Observations: Most lung cancers in nonsmoking individuals are histologically adenocarcinomas (60%-80%) with the remainder being squamous or adenosquamous (10%-20%) and rarely small cell lung cancer (<10%). Risk factors include exposure to passive smoking, radon exposure, air pollution, asbestos, and history of lung cancer in a first-degree family member. Therapeutically targetable genomic variants, such as EGFR mutations or ALK gene rearrangements, are more common in tumors from nonsmoking individuals compared with those with a smoking history (defined as people who currently or formerly smoked) (43% vs 11% for EGFR and 12% vs 2% for ALK). In contrast, tumor mutation burden, the number of somatic mutations in a tumor cell, is lower in lung cancer among nonsmoking individuals (0-3 mutations/megabase [Mb] vs 0-30 mutations/Mb). Similar to individuals with a history of smoking, nonsmoking individuals with lung cancer may present with wheeze, chest pain, dyspnea, hemoptysis, or symptoms attributable to metastatic disease (eg, bone pain and headache) or be diagnosed with incidentally detected disease. The US Preventive Services Task Force does not currently recommend lung cancer screening with low-dose computed tomographic scans for nonsmoking individuals, although screening guidelines vary globally. Treatment typically involves a combination of surgery, radiotherapy, and systemic therapies depending on stage, performance status, and molecular features of the tumor. Comprehensive next-generation sequencing should be performed on stage Ib to IIIa lung cancer tumor tissue from nonsmoking individuals because actionable genomic alterations, such as EGFR mutations or ALK gene rearrangements, are treated with targeted therapy such as the tyrosine kinase inhibitors osimertinib or lorlatinib, respectively. Median survival among nonsmoking individuals with advanced non-small cell lung cancer (stage IIIb or higher) and actionable genomic alterations can exceed 3 to 5 years, while survival without these genomic alterations is similar to lung cancer in people with a history of smoking (1-2 years).

Conclusions: Lung cancer in nonsmoking individuals accounts for 15% to 20% of lung cancer cases worldwide. Among patients with lung cancer, nonsmoking individuals are more likely to have genomic alterations such as EGFR mutations or ALK gene rearrangements, and these patients have improved survival when treated with tyrosine kinase inhibitors compared with chemotherapy.

Author/s:

Cian Murphy, Tej Pandya, Charles Swanton

Active Monitoring With or Without Endocrine Therapy for Low-Risk Ductal Carcinoma In Situ: The COMET Randomized Clinical Trial

Erin Blanchette — Wed, 19 Mar 2025 21:22:41 +0000

Date Added:

March 19, 2025

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

March 18, 2025

Issue:

Volume:

333

Pages:

972-980

URL:

Active Monitoring With or Without Endocrine Therapy for Low-Risk Ductal Carcinoma In Situ: The COMET Randomized Clinical Trial

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1001/jama.2024.26698

Keywords

breast neoplasms

Carcinoma

breast cancer

Ductal Carcinoma In Situ

PMID (1):

39665585

MeSH

Antineoplastic Agents

Hormonal / therapeutic use

Hormonal

Breast Neoplasms* / therapy

breast neoplasms

Carcinoma

Intraductal

Noninfiltrating* / therapy

Noninfiltrating

Intention to Treat Analysis

Like low grade prostate cancer, low-risk DCIS appears to be a fairly benign disease. The problem is that it is called cancer, so once it is discovered, the cat's out of the bag. James W. Mold, MD, MPH

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Importance Active monitoring for low-risk ductal carcinoma in situ (DCIS) of the breast has been proposed as an alternative to guideline-concordant care, but the safety of this approach is unknown.

Objective To compare rates of invasive cancer in patients with low-risk DCIS receiving active monitoring vs guideline-concordant care.

Design, Setting, and Participants Prospective, randomized noninferiority trial enrolling 995 women aged 40 years or older with a new diagnosis of hormone receptor–positive grade 1 or grade 2 DCIS without invasive cancer at 100 US Alliance Cancer Cooperative Group clinical trial sites from 2017 to 2023.

Interventions Participants were randomized to receive active monitoring (follow-up every 6 months with breast imaging and physical examination; n = 484) or guideline-concordant care (surgery with or without radiation therapy; n = 473).

Main Outcomes and Measures The primary outcome was 2-year cumulative risk of ipsilateral invasive cancer diagnosis, according to planned intention-to-treat and per-protocol analyses, with a noninferiority bound of 5%.

Results The median age of the 957 participants analyzed was 63.6 (95% CI, 55.5-70.5) years in the guideline-concordant care group and 63.7 (95% CI, 60.0-71.6) years in the active monitoring group. Overall, 15.7% of participants were Black and 75.0% were White. In this prespecified primary analysis, median follow-up was 36.9 months; 346 patients had surgery for DCIS, 264 in the guideline-concordant care group and 82 in the active monitoring group. Forty-six women were diagnosed with invasive cancer, 19 in the active monitoring group and 27 in the guideline-concordant care group. The 2-year Kaplan-Meier cumulative rate of ipsilateral invasive cancer was 4.2% in the active monitoring group vs 5.9% in the guideline-concordant care group, a difference of −1.7% (upper limit of the 95% CI, 0.95%), indicating that active monitoring is not inferior to guideline-concordant care. Invasive tumor characteristics did not differ significantly between groups.

Conclusions and Relevance Women with low-risk DCIS randomized to active monitoring did not have a higher rate of invasive cancer in the same breast at 2 years compared with those randomized to guideline-concordant care.

Trial Registration ClinicalTrials.gov Identifier: NCT02926911

Author/s:

E. Shelley Hwang, Terry Hyslop, Thomas Lynch, et al.