Considerations for Incorporating Family History Into Low-dose Computed Tomography Screening Recommendations

In their article, “Low-dose CT screening in relatives with a family history of lung cancer,” Wang et al.1Wang C.-L. Hsu K.-H. Chang Y.-H. et al.Low-dose computed tomography screening in relatives with a family history of lung cancer.J Thorac Oncol. 2023; 18: 1492-1503Google Scholar perform a multicenter study with a baseline round and up to two annual rounds of low-dose computed tomography screening with long-term follow-up of 1102 participants with a family history of lung cancer. Whereas it is widely accepted that family history is an important risk factor, this is the first prospective study specifically designed to evaluate its impact and the authors are saluted for assembling these data. The performance of this study in Taiwan is particularly notable as based on their registry data, 53% of lung cancers occur in never-smokers (compared with global estimates of 25%), and in women, upward of 90% had never smoked. Even more concerning is that, among people who had never smoked, nearly 60% were stage IV at the time of initial diagnosis. Among this population, the overwhelming majority would not be eligible for screening on the basis of the National Lung Screening Trial criteria, thus, stimulating the need to identify better predictive risk factors for lung cancer. The population included in the study included people with either first or second-degree relatives with a lung cancer history, divided into those with single family members and those with multiple family members (MF). In addition, information regarding smoking status is included. A total of 50 cancers were diagnosed in 1102 participants during the course of the study; the median follow-up time was 12 years. Detection rates of cancer within the MF group were 9.4% and 4.4% for participants who had never smoked and those who smoked, respectively. The rates for the single-family members group were 3.7% and 2.7%, respectively. All of the cancers in participants who smoked were men, and 70% of the cancers in participants who had never smoked were among women. Whereas it might be expected that a higher proportion of cancers would be found in the MF group, the increased proportion found in participants who had never smoked could not be explained, although the authors hypothesized about the increased number of women in this group and possibly factors such as air pollution and environmental tobacco. The stage distribution of the lung cancers was 62% in stage I and 38% beyond stage I. Because of the overall small number of cancers, cumulative information is given at 3-year intervals, and their results revealed that, during the first interval, the frequency of early-stage lung cancer was higher and it was found in younger participants; later-stage cancers increased in frequency in subsequent rounds. This article begins to shed light on the frequency of subsolid cancers within this population, especially those that are nonsolid in participants who never smoked. They found that, of the 40 lung cancers in people who had never smoked, 60% were of the subsolid type, with 50% of these subsolid cancers being nonsolid. Among the participants who smoked, 50% of the 10 lung cancers were subsolid, all being nonsolid. The extent to which the screening program identifies these more indolent cancers will impact the overall balance of the benefit derived from the screening. Whereas the numbers were small, their results suggest that the distributions of cancer subtypes (primarily adenocarcinoma) and, within adenocarcinoma, the distribution of nodule consistency were similar between the smoking and nonsmoking populations. In addition, the distribution of the nodule detected by screening of nonsolid, part-solid, and solid was similar for participants who smoked and those who did not. Interestingly, most nodules in both groups, by a wide margin, were the nonsolids—58.2% for never-smokers and 57.6% for smokers. It would be useful to gain additional clarity as to how many among them, a cancer diagnosis was pursued, especially given that these lesions are so slow growing. Another point the authors make is that the rate of advanced-stage cancers increased beyond the 0- to 3-year interval, this is after the screening has stopped, and they suggest that this might be related to indolent cancers changing to more aggressive subtypes, although it may also be the usual tendency in screening for these more advanced cancers to be diagnosed in the follow-up period after screening stopped. The authors also point to the overall cancer rates being slightly lower than in the National Lung Screening Trial for the entire study group, but when looking specifically at the MF group it is higher. An intriguing finding in this study was that the increased risk was primarily a feature of having a mother or maternal relative having lung cancer. Overall, the study brings up many important considerations regarding the risk factor of having a family history of lung cancer and how this might explain the unusually high rates of cancer in their country among individuals who had never smoked. The authors then go on to suggest that the next step would be to perform randomized trials to confirm mortality benefits. However, randomized trials have already convincingly suggested the mortality benefits of lung cancer screening, and the particular meaning that finding cancers when they are earlier leads to a cure. Those randomized controlled trials (RCTs) and other studies have also reported the methods for managing subsolid cancers, one of the primary concerns with finding cancers among individuals who had never smoked, especially among Asian women. And, along those same lines concerns regarding management and surgical treatment continue to be refined to reduce harm. Thus, it would seem that the primary question here would not be proving a mortality benefit in people with a family history of lung cancer in the context of a new RCT, but rather, understanding whether cancers among this group indeed behave like cancers found in those traditional RCTs (those high-risk individuals who are eligible for screening on the basis of the current guideline), or more directly, is there any reason to believe that the cancers found in those with a family history of lung cancer, especially among people who had smoked, might be more indolent. To answer this question, it would seem that the answer can, in large part, be derived by measures of how they behave phenotypically, even more than genetic or molecular considerations. As a first consideration, do they have volume doubling times typical of those cancers found in other trials? The initial presumptive answer to this question is that they are indeed quite similar, as there has not been any consideration to place them in a different class of tumors in any staging system. Establishing this convincingly, and considering that there is already some evidence suggesting no statistically significant difference in the doubling times of cancers between individuals who have never smoked and those with a history of smoking,2Adler S. Yip R. Chan H. et al.Comparison of lung cancer aggressiveness in patients who never smoked compared to those who smoked.Lung Cancer. 2022; 171: 90-96Google Scholar would be an important step. It is this type of feature that drives the screening process, especially the way we can develop management algorithms. It is also an important consideration as there will continue to be newly defined risk factors for choosing who might benefit from screening, and it will not be possible to perform RCTs each time. The present study provides very important information about the frequency and subtypes of cancers found in the population of people with a family history of lung cancer and information of this type will be highly useful in helping develop new screening guidelines. David F. Yankelevitz: Conceptualization, Methodology, Formal analysis, Writing-original draft, Writing-review & editing. Rowena Yip: Conceptualization, Methodology, Formal analysis, Writing-review & editing. Claudia I. Henschke: Conceptualization, Methodology, Formal analysis, Writing-review & editing. Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung CancerJournal of Thoracic OncologyVol. 18Issue 11PreviewThe role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. Full-Text PDF Open Access