Abstract
Objective
To evaluate the efficacy of immune checkpoint inhibitors (ICIs) for fertility-sparing treatment in Lynch syndrome-associated endometrial cancer (LS-EC).
Methods
Four LS-EC cases received programmed cell death protein 1 (PD-1) inhibitors for fertility preservation at the Obstetrics and Gynecology Hospital of Fudan University from 2017 to 2023. The clinical data and long-term outcomes were retrospectively reviewed.
Results
Case 1, carrying germline MLH1 mutation, was diagnosed with Stage IIAmMMRd (International Federation of Gynecology and Obstetrics 2023) endometrial cancer (EC) at 38 years old. She received PD-1 inhibitor treatment and achieved a pathological complete response (CR) at 42 weeks. Case 2, carrying MLH1 mutation, underwent colorectal cancer surgery at 22 years and was diagnosed with EC and synchronous ovarian cancer at 39 years. After 24-week PD-1 treatment, CR of EC and ovarian cancer was achieved. Case 3, carrying MSH2 mutation, was diagnosed with endometrial atypical hyperplasia (EAH) at 35 years. After receiving 7-month progestin, she had the progressed disease with Stage IA2mMMRd EC and colon cancer was found soon after. She received PD-1 treatment for 18 weeks and achieved a CR of EC. She conceived naturally with full term delivery. Case 4, carrying MSH2 mutation, had a recurrence of Stage IBmMMRd EC 15 months after CR from EAH treated with progestin at 40 years. She received PD-1 treatment for 18 weeks and achieved CR. No recurrence was found in all cases after 3–41 months of follow-up after CR.
Conclusion
ICIs might be an effective choice for LS-EC patients desiring fertility preservation.
Keywords: Endometrial Cancer, Lynch Syndrome, Immune Checkpoint Inhibitors, Fertility-Preserving Treatment
BACKGROUND
Lynch syndrome (LS) is one of the most prevalent hereditary cancer-prone syndromes caused by germline pathogenic variants in mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2. LS patients are reported to have a 24%–51% risk of endometrial cancer (EC) [1] and they are also predisposed to synchronous and metachronous colorectal cancer, ovarian cancer (OC) and other cancers [1]. LS patients are diagnosed with EC on average nearly 15 years younger than those with sporadic EC [2,3,4] and many of them have not completed their childbearing. However, there is no consensus on whether Lynch syndrome-associated endometrial cancer (LS-EC) patients are suitable for fertility-sparing treatment [5].
LS-EC presents as loss of MMR protein by immunohistochemistry (IHC), a mismatch repair deficient (MMRd) molecular subtype, and microsatellite instability-high. At present, oral high dose progestin and/or levonorgestrel intrauterine system (LNG-IUS) is the first line fertility-sparing treatment for EC. However, existing studies have shown that resistance to treatment and recurrence are more common in MMRd EC compared to those with no specific molecular profile [6,7,8]. Immune checkpoint inhibitors (ICIs), including programmed cell death protein 1 (PD-1) inhibitors, have been proved to be effective in treating advanced or recurrent EC with MMRd [9,10], which might be more effective in LS-EC compared with EC with MLH1 hypermethylated [11]. The promising effect of ICIs had made it possible to use them in MMRd EC cases desiring fertility preserving treatment, especially LS-EC.
Therefore, we conducted a retrospective study to evaluate the efficacy of ICIs for fertility-sparing treatment in LS-EC patients.
A total of 1,384 consecutive patients diagnosed with EC or endometrial atypical hyperplasia (EAH) receiving fertility-sparing treatment at the Obstetrics and Gynecology Hospital of Fudan University between January 2017 and October 2023 were retrospectively investigated. Among the total patient group, 348 received gene testing and 21 were diagnosed with LS according to Amsterdam II criteria. Among the LS group, 17 received progestin treatment while 4 patients were treated with PD-1 inhibitors. All these 4 LS-EC cases treated with PD-1 inhibitors were retrospectively investigated.
All patients signed informed consent for conservative treatment and for the use of their data for research purposes. All cases were discussed and their treatment plans were approved by a multidisciplinary team. The study was approved by the Ethics Committee.
Patients were followed-up until June 2024. The median follow-up time from the date of initiating treatment to the last follow up was 24.9 months (range, 7.7–45.8 months). The median follow-up time from the date of achieving complete response (CR) to the last follow-up was 17.3 months (range, 3.4–40.8 months).
The general information of the 4 EC cases is shown in Table 1.
Table 1. Clinical data and treatment outcomes of four EC cases with LS.
| Characteristics | Case 1 | Case 2 | Case 3 | Case 4 |
|---|---|---|---|---|
| Age at diagnosis of EC (yr) | 38 | 39 | 35 | 40 |
| BMI (kg/m2) | 19.1 | 22.59 | 21.77 | 21.48 |
| HOMA-IR index*, IR† | 3.38, yes | 2.89, no | 14.27, yes | 2.56, no |
| Metabolic syndrome | No | No | No | No |
| Hypertension | No | No | No | No |
| Diabetes mellitus | No | No | Yes | No |
| Hyperlipidemia | Yes | No | No | Yes |
| Gravida/para | G2P1 | G0P0 | G0P0 | G0P0 |
| Family history of LS-related tumors (relationship, cancer, age at diagnosis) | 6 of her paternal family members were diagnosed as colorectal cancer at the median age of 47.5 (range, 25–52) | Mother, colon cancer, 48 | Father, gastric cancer, 52 | Mother, ovary cancer, 42, colon cancer, 61, breast cancer, 65 |
| Aunt, gastric cancer, 50 | Aunt, colon cancer, 60 | |||
| CA-125 (U/mL) | 12.69 | 59.54, elevated | 18.21 | 16.4 |
| HE-4 (pmol/L) | 74.0, elevated | 64.5, elevated | 39.01 | 45.4 |
| Germline mutation | MLH1, 199G>A, possible pathogenic | MLH1, 1975C>T, pathogenic | MSH2, 1864C>T, pathogenic | MSH2, 1418C>A, possible pathogenic |
| Pathology | EEC, G1 | EEC, G1 | EEC, G1 | EEC, G1 |
| Stage (FIGO 2023) | IIAmMMRd | IA1mMMRd | IA2mMMRd | IBmMMRd |
| Other malignancies, age at diagnosis (yr) | No | Rectal cancer, 22 | Transverse colon cancer, 37 | No |
| Ascending colon cancer, 37 | ||||
| Synchronous ovarian cancer, 39 | ||||
| Treatment regimen | Camrelizumab (a PD-1 inhibitor) ivgtt 200 mg every 2 weeks for 2 courses and then pembrolizumab (a PD-1 inhibitor) ivgtt 200 mg every 3 weeks for 6 courses | Pembrolizumab (a PD-1 inhibitor) ivgtt 200 mg every 3 weeks for 8 courses | Sintilimab (a PD-1 inhibitor) ivgtt 200 mg every 3 weeks for 6 courses | Tislelizumab (a PD-1 inhibitor) ivgtt 200 mg every 3 weeks for 6 courses |
| Treatment duration to CR (wk) | 42 | 24 | 18 | 18 |
| Maintenance treatment regimen | 2.0 mg cyproterone acetate and 0.035 mg ethinyl estradiol p.o. 21 days on medication and a 7-day interval without medication | Pembrolizumab (a PD-1 inhibitor) ivgtt 200 mg every 3 weeks for 22 courses | Sintilimab (a PD-1 inhibitor) ivgtt 200 mg every 3 weeks for 3 courses | Tislelizumab (a PD-1 inhibitor) ivgtt 400 mg every 6 weeks for 3 courses |
| Recurrence | No | No | No | No |
| Follow-up duration after CR (mo) | 15 | 20 | 41 | 3 |
| AE, Grade | Reactive cutaneous capillary endothelial proliferation, Grade 3‡ | Eczema, Grade 1 | No | No |
| Arthritis, Grade 1 |
AE, adverse event (according to CTCAR 5.0); BMI, body mass index; EEC, endometrioid endometrial carcinoma; FIGO, International Federation of Gynecology and Obstetrics; G1, grade 1; HOMA-IR, homeostasis model assessment-insulin resistance; IR, insulin resistant; PD-1, programmed cell death protein 1; ivgtt, intravenously guttae; p.o., by mouth.
*HOMA-IR = {Fasting Blood Glucose (mmol/L) × Fasting Insulin (µU/mL)}/22.5.
†Patients with HOMA-IR index ≥2.95 were defined as IR.
‡The AE occurred during camrelizumab treatment and then case 1 changed to pembrolizumab.
CASE DESCRIPTION
1. Case 1
Case 1, carrying a possible pathogenic germline mutation 199G>A in MLH1 gene, was diagnosed with EC at 38 years old. Transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) (Fig. S1A) showed a mass in the cervical canal with cervical stroma involvement. Hysteroscopy (Fig. S1A) was performed and the pathological examination (Fig. S1D-G) showed endometrioid endometrial carcinoma (EEC) grade 1 (G1) with cervical stroma involvement. IHC staining (Fig. S1H-N) showed an absence of MLH1 and PMS2 expression. She started PD-1 inhibitor treatment on September 3, 2021. After 8 courses of PD-1 inhibitor treatment and 3 months of megestrol acetate treatment, another hysteroscopy was conducted and pathological CR was achieved on June 21, 2022 (Fig. S1C).
After 2 courses of camrelizumab treatment, the patient developed G3 reactive cutaneous capillary endothelial proliferation. Therefore, she switched to pembrolizumab for the subsequent PD-1 inhibitor treatment. She did not attempt to conceive and received cyproterone acetate and ethinyl estradiol for maintenance treatment. No recurrence was found after 14.6 months of follow-up after CR.
2. Case 2
Case 2, carrying a pathogenic germline mutation 1975C>T in MLH1 gene, was diagnosed with EC and synchronous OC at 39 years. She had a history of rectal and colon cancer. She was diagnosed with rectal adenocarcinoma and underwent rectal cancer resection followed by chemotherapy at 22 years. At the age of 37, she was diagnosed with ascending colon cancer and underwent right radical hemicolectomy followed by chemotherapy. She reported unusual menstrual flow for one year. Positron emission tomography-computed tomography (PET-CT) (Fig. S2A) showed high 18F-fluorodeoxyglucose (FDG) uptake lesions in the uterus, cervix and right adnexal region. Hysteroscopy was performed and the pathological examination showed EEC G1 in the cervical canal and uterine cavity. IHC staining showed an absence of MLH1 and PMS2 expression. She initiated the PD-1 inhibitor treatment on September 24, 2021. After 6 courses of immunotherapy on January 22, 2022, PET-CT (Fig. S2B) suggested radiological relief of EC and OC. Then after 8 courses of immunotherapy on March 8, 2022, hysteroscopy showed a pathological CR was obtained.
The patient continued PD-1 inhibitor maintenance treatment for another 22 courses. She suffered from G1 eczema and arthritis during the maintenance treatment. She underwent PET-CT 20 months after CR and no recurrence was found (Fig. S2C).
3. Case 3
Case 3, carrying a pathogenic germline mutation 1864C>T in MSH2 gene, was diagnosed with EAH at 35 years. TVUS showed a mixed structure in the endometrium. The hysteroscopy and pathological examination showed EAH (Fig. S3A). IHC staining showed an absence of MSH2 and MSH6 expression. She initiated megestrol treatment on March 5, 2017. Seven months later, the patient underwent another hysteroscopy and pathological examination showed the disease progressed to focal EEC (Fig. S3C). MRI suggested possible myometrium invasion (Fig. S3D). She was referred to another hospital and received enantone 3.75 mg every month combined with letrozole 2.5 mg once a day. She achieved a pathological CR 6 months later.
In December 2019, MRI showed enlarged left pelvic lymph nodes and suspected metastases. Then the PET-CT showed a hypermetabolic lesion in the transverse colon, which was later confirmed as adenocarcinoma by colonoscopy biopsy. The patient received neoadjuvant immunotherapy with the PD-1 inhibitor from March 2020. On July 31, 2020, she underwent right hemicolectomy with radical lymphadenectomy. Pathological examination confirmed no cancer tissues in the enlarged left pelvic lymph nodes.
After the surgery, she planned to receive PD-1 treatment for 1 year. However, she conceived naturally and gave birth to a healthy baby. There were no immune-related adverse events (irAEs) in either the mother or the neonate during a 41-month follow-up.
4. Case 4
Case 4, carrying a possible pathogenic germline mutation 1418C>A in MSH2 gene, was diagnosed with EC with myometrial invasion at 40 years. She was diagnosed with EAH at 38 years (Fig. S4A). The patient then received LNG-IUS treatment and achieved a pathological CR in 8 months (Fig. S4C). However, after 2 cycles of ovulation induction, she experienced a recurrence of EEC 13 months after CR (Fig. S4D). The patient underwent hysteroscopy 1 month later and found no tumors in the endometrium (Fig. S4E). However, MRI showed possible myometrium invasion (Fig. S5A). Therefore, she initiated the PD-1 treatment on October 17, 2023.
After 4 courses of PD-1 treatment, MRI showed no obvious change in the suspected malignant mass in the uterus myometrium (Fig. S5B). Therefore, she underwent combined hysteroscopy and laparoscopy to remove the mass in the myometrium and to take endometrial biopsies in February 2024. Pathological examination showed leiomyoma and a pathological CR was achieved. The patient then received maintenance treatment with the PD-1 inhibitor for 3 cycles. There were no irAEs and no recurrence during a 3-month follow-up.
CONCLUSION
The treatment outcomes and long-term follow-up consequences of our 4 LS-EC cases that received ICIs treatment were satisfactory. Our findings suggested that ICIs might be a first choice for LS-EC patients desiring fertility preservation, even for those who did not meet the internationally recognized criteria [12]. ICIs might also be an effective choice for sporadic MMRd EC patients. Furthermore, our study also suggested that ICIs treatment in LS-EC patients might simultaneously treat or prevent other LS-associated tumors.
However, there are also some limitations. First, it is a retrospective study with a relatively small sample. Second, patients did not receive a uniform regimen. They were treated with different kinds of PD-1 inhibitors. And they had different treatment duration and maintenance treatment duration. As for the maintenance treatment duration, internation guidelines recommend ICIs maintenance treatment for 2–3 years in advanced or recurrent ECs [9,13]. Based on experiences from our cases, we recommended at least 6 months of maintenance treatment. Third, the duration of follow-up is relatively short, which may mean that responses are evolving. Finally, only 1 case accidentally conceived during the maintenance treatment which makes it difficult to evaluate the pregnancy outcomes in LS-EC patients treated with ICIs.
In conclusion, our study reported 4 cases of LS-EC patients who received ICIs treatment for fertility preserving and achieved CR. Our study illustrated that ICIs might be an effective choice for LS-EC patients desiring fertility preservation. In addition, further studies are needed to explore the treatment duration, the influence of fertility and offspring and irAEs.
ACKNOWLEDGEMENTS
We gratefully acknowledge our funding source that supported this project, and we thank Xuezhen Luo, Fenghua Ma, Hongwei Zhang and Shuang Zhou for their contribution to the data work.
Footnotes
Funding: This work was supported by the National Key R&D Program of China (2022YFC2704305) and the Shanghai Technical Innovation Program (20Z11900700). The funder did not have any role in the study design; data collection, data analysis, and interpretation of data; the writing of the report; nor the decision to submit the paper for publication.
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: C.X.
- Data curation: Y.X., X.Y., S.W.1, S.W.2, X.Z.
- Formal analysis: Y.X., X.Y.
- Investigation: Y.X., X.Y., S.W.1, S.W.2, X.Z., W.Y.
- Methodology: Y.X., X.Y., C.X.
- Project administration: C.X.
- Supervision: W.Y., C.X.
- Writing - original draft: Y.X., X.Y.
- Writing - review & editing: C.X.
S.W.1, Wenyu Shao; S.W.2, Weiwei Shan.
SUPPLEMENTARY MATERIALS
MRI, hysteroscopy and pathological images of Case 1 showed a CR of EC after 8 courses of PD-1 treatment.
PET-CT/MRI, hysteroscopy and pathological images of Case 2 showed a CR of EC and ovarian cancer after 8 courses of PD-1 treatment.
MRI, hysteroscopy and pathological images of Case 3 showed EAH progressed to focal EEC after 7 months of megestrol treatment.
Hysteroscopy and pathological images of Case 4 showed a CR of EAH after 8 months of LNG-IUS treatment but recurrence of EEC 13 months after CR.
MRI of Case 4 showed no obvious change in the suspected malignant mass within the myometrium (arrowheads) after 4 courses of PD-1 treatment.
References
- 1.Møller P, Seppälä T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66:464–472. doi: 10.1136/gutjnl-2015-309675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lu KH, Broaddus RR. Endometrial cancer. N Engl J Med. 2020;383:2053–2064. doi: 10.1056/NEJMra1514010. [DOI] [PubMed] [Google Scholar]
- 3.Ryan NAJ, Morris J, Green K, Lalloo F, Woodward ER, Hill J, et al. Association of mismatch repair mutation with age at cancer onset in Lynch syndrome: implications for stratified surveillance strategies. JAMA Oncol. 2017;3:1702–1706. doi: 10.1001/jamaoncol.2017.0619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wang Y, Xue F, Broaddus RR, Tao X, Xie SS, Zhu Y. Clinicopathological features in endometrial carcinoma associated with Lynch syndrome in China. Int J Gynecol Cancer. 2009;19:651–656. doi: 10.1111/IGC.0b013e3181a12fb9. [DOI] [PubMed] [Google Scholar]
- 5.La Russa M, Zapardiel I, Halaska MJ, Zalewski K, Laky R, Dursun P, et al. Conservative management of endometrial cancer: a survey amongst European clinicians. Arch Gynecol Obstet. 2018;298:373–380. doi: 10.1007/s00404-018-4820-7. [DOI] [PubMed] [Google Scholar]
- 6.Chung YS, Woo HY, Lee JY, Park E, Nam EJ, Kim S, et al. Mismatch repair status influences response to fertility-sparing treatment of endometrial cancer. Am J Obstet Gynecol. 2021;224:370.e1–370.e13. doi: 10.1016/j.ajog.2020.10.003. [DOI] [PubMed] [Google Scholar]
- 7.Raffone A, Catena U, Travaglino A, Masciullo V, Spadola S, Della Corte L, et al. Mismatch repair-deficiency specifically predicts recurrence of atypical endometrial hyperplasia and early endometrial carcinoma after conservative treatment: a multi-center study. Gynecol Oncol. 2021;161:795–801. doi: 10.1016/j.ygyno.2021.03.029. [DOI] [PubMed] [Google Scholar]
- 8.Zakhour M, Cohen JG, Gibson A, Walts AE, Karimian B, Baltayan A, et al. Abnormal mismatch repair and other clinicopathologic predictors of poor response to progestin treatment in young women with endometrial complex atypical hyperplasia and well-differentiated endometrial adenocarcinoma: a consecutive case series. BJOG. 2017;124:1576–1583. doi: 10.1111/1471-0528.14491. [DOI] [PubMed] [Google Scholar]
- 9.Mirza MR, Chase DM, Slomovitz BM, dePont Christensen R, Novák Z, Black D, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388:2145–2158. doi: 10.1056/NEJMoa2216334. [DOI] [PubMed] [Google Scholar]
- 10.O’Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol. 2022;40:752–761. doi: 10.1200/JCO.21.01874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ozawa R, Nishikawa T, Yoshida H, Shiraishi K, Shimoi T, Kato T, et al. Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers. J Gynecol Oncol. 2024;35:e103. doi: 10.3802/jgo.2024.35.e103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Abu-Rustum N, Yashar C, Arend R, Barber E, Bradley K, Brooks R, et al. Uterine neoplasms, version 1.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21:181–209. doi: 10.6004/jnccn.2023.0006. [DOI] [PubMed] [Google Scholar]
- 13.Eskander RN, Sill MW, Beffa L, Moore RG, Hope JM, Musa FB, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388:2159–2170. doi: 10.1056/NEJMoa2302312. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
MRI, hysteroscopy and pathological images of Case 1 showed a CR of EC after 8 courses of PD-1 treatment.
PET-CT/MRI, hysteroscopy and pathological images of Case 2 showed a CR of EC and ovarian cancer after 8 courses of PD-1 treatment.
MRI, hysteroscopy and pathological images of Case 3 showed EAH progressed to focal EEC after 7 months of megestrol treatment.
Hysteroscopy and pathological images of Case 4 showed a CR of EAH after 8 months of LNG-IUS treatment but recurrence of EEC 13 months after CR.
MRI of Case 4 showed no obvious change in the suspected malignant mass within the myometrium (arrowheads) after 4 courses of PD-1 treatment.