In a brief report published in The New England Journal of Medicine, Arakawa et al described the identification of lung cancer in two children that likely resulted from transmission of maternal cervical cancer tumor cells during vaginal delivery.
As noted by the investigators, the transmission of maternal cancer to infants is an extremely rare event (with an estimated incidence of approximately 1 infant per every 500,000 mothers with cancer). The relatively small number of cases in the literature have been presumed to occur through hematogenous transmission via transplacental mother-to-fetus transmission. The reported cases have involved mothers with blood, skin, lung, and cervical cancers, and often included dissemination of tumor cells to multiple organs in the infant. However, transmission of tumor in the birth canal during vaginal delivery is also possible; in a mother with cervical cancer, the infant can be exposed to tumor cells in fluids in the birth canal and aspirate the cells into the lungs.
The two cases were incidentally identified during routine next-generation sequencing of paired samples of tumor and normal tissue as part of the TOP-GEAR trial, a prospective gene-profiling trial involving patients with advanced cancer.
The first boy was diagnosed with lung cancer in both lungs at age 23 months. Although cervical cytology at 7 months before the birth was negative, the mother was diagnosed with squamous cell carcinoma of the cervix 3 months after the birth.
Histologic similarities between the tumor samples from mother and child prompted comparison of findings on next-generation sequencing. It was found that both tumors had the same pathogenic KRAS (c.G38A: p.G13D) and TP53 (c.G853A:p.E285K) mutations, and that 47 exonic single-nucleotide polymorphism (SNP) alleles carried by the mother but not inherited in the child’s germline were present in the child’s tumor.
Fluorescence in situ hybridization (FISH) showed that the boy’s tumor lacked the Y chromosome. Whole-exome sequencing identified an additional 20 somatic mutations in both tumors. HLA class I alleles that were not inherited by the child were lost in samples from both tumors. Polymerase chain reaction analysis showed that both tumors were positive for human papillomavirus (HPV) type 18.
Spontaneous regression of some lesions in the child were observed during initial follow-up without treatment (parental decision), suggesting an alloimmune response against the transmitted tumor. After two courses of chemotherapy, the child still had multiple nodules in both lungs. He then received 14 cycles of nivolumab at 3 mg/kg every 2 weeks, with a major regression of remaining tumors being observed and the response being maintained for 7 months with no appearance of new lesions. Lobectomy was performed to remove a remaining nodule, and the patient had no evidence of disease recurrence at 12 months after lobectomy.
The second boy was diagnosed with mucinous adenocarcinoma of the left lung at age 6 years; the slow growth of the tumor again suggests an alloimmune response against the transmitted tumor. A cervical polypoid tumor had been found in the mother during pregnancy, but cervical cytology was negative, and the tumor was stable without any intervention. Biopsy of the cervical lesion after delivery showed adenocarcinoma.
Tumors in the mother and child had the same KRAS (c.G35A:p.G12D) and STK11 (c.464+1G→A) mutations, and 38 exonic SNP alleles carried by the mother but not inherited in the child’s germline were identified in the child’s tumor. FISH showed that the tumor lacked the Y chromosome. Whole-exome sequencing identified an additional 14 somatic mutations that were present in both tumors. Loss of HLA class I alleles was not detected in either of the tumor samples. Both tumors were positive for HPV type 16.
The tumor in the boy was considered inoperable. He exhibited a partial response to treatment with five cycles of paclitaxel and cisplatin, followed by three cycles of paclitaxel and carboplatin and two cycles of paclitaxel and irinotecan. Disease recurrence was found at 3 months after discontinuation of treatment. After five cycles of gemcitabine and docetaxel and one cycle of paclitaxel and carboplatin, he underwent total left pneumonectomy. He was free from disease during 15 months of follow-up after pneumonectomy.
The investigators concluded, “These cases indicate that mother-to-infant transmission of uterine cervical cancer is possible during vaginal delivery; therefore, cesarean section should be recommended for mothers with uterine cervical cancer…. Next-generation sequencing of paired samples of tumor and normal tissue may be a useful tool to diagnose cancer that is transmitted from mothers to infants and to understand the prevalence of this transmission.”
Disclosure: The study was supported by the Japan Agency for Medical Research and Development and others. For full disclosures of the study authors, visit nejm.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.