From Approximation to Precision: Fertility and Pregnancy Questions in Young Patients With Lung Cancer
Authors: Fedro A. Peccatori, Narjust Florez, Martina Imbimbo
Journal: Journal of Thoracic Oncology (2024)

The incidence of cancers in people younger than 50 years old continues to increase,1Dizon D.S. Kamal A.H. Cancer statistics 2024: all hands on deck.CA Cancer J Clin. 2024; 74: 8-9Crossref Scopus (0) Google Scholar and because of the delayed maternal age at birth, more women are faced with the unwanted event of cancer occurring during pregnancy, and questions surrounding becoming pregnant after having cancer.2Pierannunzio D. Maraschini A. Lopez T. et al.Cancer and pregnancy: estimates in Italy from record-linkage procedures between cancer registries and the hospital discharge database.Cancers. 2023; 15: 4305Crossref Scopus (0) Google Scholar Lung cancer during pregnancy, in particular, is a rare event. In the past, it was consistently associated with a dire prognosis,3Boussios S. Han S.N. Fruscio R. et al.Lung cancer in pregnancy: report of nine cases from an international collaborative study.Lung Cancer. 2013; 82: 499-505Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar but in the past few years, there have been several reports of pregnant patients diagnosed with oncogene-addicted lung cancer, which is more frequent in younger women.4Gitlitz B.J. Novello S. Vavalà T. et al.The genomics of young lung cancer: comprehensive tissue genomic analysis in patients under 40 with lung cancer.JTO Clin Res Rep. 2021; 2100194Google Scholar The treatment of cancer during pregnancy is very challenging and requires a multidisciplinary team to carefully balance advantages for the mother against risks for the fetus. However, as pregnant women have typically remained excluded from clinical research, safety information regarding drug tolerability during gestation is on the basis of epidemiologic studies, case reports, and animal studies, limiting generalizability and prompting many uncertainties about maternal and fetal outcomes. Though advanced preclinical models including organ-on-chips or microphysiologic analysis platforms have emerged to replicate human pregnancy in vitro, their application in cancer drug development remains understudied and poorly understood.5Park J.Y. Lim H. Qin J. Lee L.P. Creating mini-pregnancy models in vitro with clinical perspectives.EBiomedicine. 2023; 95104780Abstract Full Text Full Text PDF Scopus (2) Google Scholar Whereas in the past, most women were advised to terminate their pregnancy, we know now that some treatments are possible and potentially safe during gestation. There are, in fact, well-established data and guidelines for the use of chemotherapy that can be administered starting from the second trimester with no increased rate of fetal malformation, manageable adverse effects, and clinical activity similar to that observed outside of pregnancy.6Peccatori F. H Azim Jr., A. et al.Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi160-vi170Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar Moreover, the introduction of different generations of oncogene-specific tyrosine kinase inhibitors (TKIs) has led to prolongation of survival for some patients in ranges of 5 to 10 years.7Ramalingam S.S. Vansteenkiste J. Planchard D. et al.Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.N Engl J Med. 2020; 382: 41-50Crossref PubMed Scopus (1602) Google Scholar,8Mok T. Camidge D.R. Gadgeel S.M. et al.Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.Ann Oncol. 2020; 31: 1056-1064Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar Unfortunately, very few data are available about the fetal safety of TKIs in all trimesters of pregnancy,9Azim Jr., H.A. Peccatori F.A. Pavlidis N. Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: solid tumors.Cancer Treat Rev. 2010; 36: 101-109Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar and in some cases, pregnant patients may decline targeted therapy because of the unknown data about fetal toxicity. Though more research is needed to comprehensively inform reproductive counseling efforts, fertility preservation represents an important need for young patients.10Woodruff T.K. Ataman-Millhouse L. Acharya K.S. et al.A View from the past into our collective future: the oncofertility consortium vision statement.J Assist Reprod Genet. 2021; 38: 3-15Crossref PubMed Scopus (0) Google Scholar,11Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar Although there are no extensive clinical data on the effects of biological therapies on male or female gonad function, preclinical data suggest a possible impairment of fertility.12Rambhatla A. Strug M.R. De Paredes J.G. Cordoba Munoz M.I. Thakur M. Fertility considerations in targeted biologic therapy with tyrosine kinase inhibitors: a review.J Assist Reprod Genet. 2021; 38: 1897-1908Crossref PubMed Scopus (20) Google Scholar In the case of patients prescribed TKIs in the adjuvant setting who could potentially be cured of their lung cancer but still need 2 to 3 years of treatment when conception is contraindicated,13Tsuboi M. Herbst R.S. John T. et al.Overall survival with osimertinib in resected EGFR-mutated NSCLC.N Engl J Med. 2023; 389: 137-147Crossref PubMed Scopus (130) Google Scholar,14Solomon B.J. Ahn J.S. Dziadziuszko R. et al.LBA2 ALINA: efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC).Ann Oncol. 2023; 34: S1295-S1296Abstract Full Text Full Text PDF Google Scholar questions remain regarding the effects of TKIs on oocytes and sperm integrity and the washout time needed before conception. Whereas fertility preservation through sperm harvesting may be relatively easy, egg retrieval needs at least 2 weeks of gonadotropin administration. Whereas men treated with TKIs can plan a relatively short washout of drugs before conceiving,15Szakács Z. Hegyi P.J. Farkas N. et al.Pregnancy outcomes of women whom spouse fathered children after tyrosine kinase inhibitor therapy for chronic myeloid leukemia: a systematic review.PLoS One. 2020; 15e0243045Crossref Scopus (6) Google Scholar longer washouts are needed for women, particularly when the patient desires to carry her pregnancy (Fig. 1).11Lambertini M. Peccatori F.A. Demeestere I. et al.Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines.Ann Oncol. 2020; 31: 1664-1678Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar In the metastatic setting, patients are usually advised to adopt adequate contraceptive measures to avoid pregnancy during treatment. However, because TKI treatment is typically associated with progression free survival and overall survival around 2 and 4.5 years, respectively,7Ramalingam S.S. Vansteenkiste J. Planchard D. et al.Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.N Engl J Med. 2020; 382: 41-50Crossref PubMed Scopus (1602) Google Scholar it is not unusual for young patients with well-controlled disease to ask their oncologist whether pregnancy is still an option. In this context, the article "Lung cancer oncogene-directed therapy, fertility, and pregnancy" by Simons et al.16Simons E. Camidge D.R. Lung cancer oncogene-directed therapy, fertility and pregnancy.J Thorac Oncol. 2024; 19: 866-876Abstract Full Text Full Text PDF Google Scholar is a comprehensive and timely review of preclinical and clinical evidence of the effect on fertility, pregnancy, and egg retrieval of the TKIs more typically used for the treatment of oncogene-addicted lung cancer. The article found that, whereas there is a discrepancy between worrisome preclinical data and more reassuring clinical outcomes, the number of published clinical cases is scant and very heterogeneous in terms of drugs used and the timing of fetal exposures. Therefore, the counseling of patients cannot overlook numerous unanswered questions and rely solely on these limited case reports; to achieve an informed decision, comprehensive research is needed. In the meantime, clinicians should inform on available options, allow enough time for questions, and share uncertainties and unknowns, ultimately respecting the autonomy of patients. It is also important that clinicians discuss their patients within a structured multidisciplinary tumor board. This should include medical oncologists, surgeons, radiation therapists, maternal-fetal medicine specialists, neonatologists, and psychologists. Of note, the International Network on Cancer, Infertility and Pregnancy has developed an international platform to assist with expert counseling and management of pregnant patients with cancer.17Amant F. Heimovaara J.H. Lok C.A.R. Van Calsteren K. The Advisory board on Cancer, Infertility and Pregnancy: a virtual on demand multidisciplinary tumour board.Lancet Oncol. 2022; 12: 1484-1562Abstract Full Text Full Text PDF Scopus (3) Google Scholar It is also recommended that patients' data be collected within registries such as the International Network on Cancer, Infertility and Pregnancy database or the recently implemented Pregnancy and Lung Cancer Registry from Dana-Farber Cancer Institute. This will help to understand the unique characteristics of lung cancer among pregnant women, provide insight into diagnostic timelines, imaging patterns, and therapeutic tolerability throughout pregnancy, and allow for continuous learning from short and long-term maternal and fetal outcomes.18Maggen C. Wolters V.E.R.A. Cardonick E. et al.Pregnancy and cancer: the INCIP project.Curr Oncol Rep. 2020; 22: 17Crossref PubMed Scopus (72) Google Scholar,19Florez N. Kaufman R.A. Yanez-Sarmiento A. Abioye O. Kiel L.R. When the unimaginable happens: lung cancer diagnosis during pregnancy [e-pub ahead of print].Cancer. 2024; https://doi.org/10.1002/cncr.35227Crossref Scopus (0) Google Scholar In conclusion, we advocate more preclinical and clinical research on the effects of biological drugs on fertility and pregnancy. Quoting A. Koyré, "It is time to shift from the world of approximation to the universe of precision."20Koyré A. 'Du monde de l'"à-peu-près" à l'univers de la précision.in: Koyré A. Études d'histoire de la pensée philosophique Paris. Gallimard, France1961: 341-362Google Scholar Fedro A. Peccatori: Conceptualization; Roles/Writing - original draft; Writing - review & editing. Narjust Florez: Conceptualization; Roles/Writing - original draft; Writing - review & editing. Martina Imbimbo: Conceptualization; Roles/Writing - original draft; Writing - review & editing. Dr. Florez reports having consulting and advisory roles for Pfizer, Merck, Mirati, Janssen, Novocure, and Regeneron; and receiving research support/grants from Genentech, Daiichy-Sankyo, AstraZeneca, and Neogenomics. The remaining authors declare no conflict of interest. Lung Cancer Oncogene-Directed Therapy, Fertility, and PregnancyJournal of Thoracic OncologyVol. 19Issue 6PreviewAlterations in the highly actionable lung cancer oncogenes, EGFR, ALK, and ROS1, occur across the age spectrum. Pregnancy and plans for motherhood consequently overlap with diagnoses of advanced oncogene-driven NSCLC. Guidelines for cytotoxic agents and pregnancy are well established. Nevertheless, accessible data on targeted lung cancer therapy during pregnancy or egg retrieval has not been collated previously, nor have the issues of reproduction in the setting of specific oncogene-addicted advanced NSCLC been widely discussed. Full-Text PDF