Checkpoint Inhibitors May Impact Fertility in Early TNBC Treatment

The addition of the immune checkpoint inhibitor Tecentriq (atezolizumab) to neoadjuvant chemotherapy and as a single agent adjuvant therapy numerically increased the rates of chemotherapy-induced ovarian failure (CIOF) compared with chemotherapy alone for patients with early triple-negative breast cancer (TNBC), according to findings from a prospectively completed substudy of the GeparDouze trial presented at the 2025 San Antonio Breast Cancer Symposium.

In the study, CIOF rates were highest immediately following the end of therapy and fell as time progressed. After 18 and 24 months of follow-up, respectively, CIOF was present for one of 37 (2.7%) and one of 40 (2.5%) for patients receiving chemotherapy alone and for five of 43 (11.6%) and seven of 40 (17.5%) for those who received Tecentriq; however, there was no statistical differences between arms at any time point in the study.

"These findings support the hypothesis that checkpoint inhibitors may adversely affect fertility and underscores the need for further studies to elucidate the underlying biological mechanisms and to improve counseling strategies for the patient population," lead investigator Dr. Mattea Reinisch, from the Interdisciplinary Breast Unit at the University Medical Center Mannheim, University of Heidelberg, in Mannheim, Germany, said during a presentation of the results.

Study Design and Patient Characteristics

In the GeparDouze trial, which was conducted entirely in Europe, patients received neoadjuvant treatment with chemotherapy plus either placebo or Tecentriq followed by surgery and adjuvant treatment with placebo or Tecentriq alone for one year. There were two groups of chemotherapy regimens used in the neoadjuvant arm: weekly paclitaxel plus carboplatin ever three weeks or the choice between doxorubicin plus cyclophosphamide (AC) every two or three weeks or epirubicin plus cyclophosphamide (EC) every two or three weeks.

The researchers selected those enrolled under the age of 45 to study ovarian function. There were 380 patients in the study who met this criterion of which 172 were in the placebo arm and 208 were in the Tecentriq group; however, nearly half of these patients were in the study before the ovarian function substudy was initiated, leaving 79 in the placebo group and 94 in the Tecentriq arm for enrollment. Impaired ovarian function was defined as a postmenopausal estradiol (E2) levels (<5 pg/ml) and follicle-stimulating hormone (FSH) of greater than 25.8 IU/I.

Patient characteristics were similar across both groups. The median age of patients was 37 years, with 37% younger than 35 years at diagnosis. Only 7.5% of patients received a GnRH analog at any points during treatment. Seven and a half percent of patients underwent a salpingo-oophorectomy during the study.

Regarding GnRH analogs, Reinisch noted that usage was low, adding that these agents are commonly underutilized. “In the future, if I am counseling my patient that is getting checkpoint inhibitors, I would recommend giving GnRH analogs, although it is a data-free zone at the moment,” she said.

The most common schedule of AC and EC was every two weeks (65.9%) and the relative dose intensity for cyclophosphamide was 88.3%. The median BMI was 24.2, with 55.5% of patients in the normal range and 43.3% in the overweight range. A portion of patients (18.5%) received postneoadjuvant capecitabine if a pathological complete response was not achieved during surgery.

CIOF and Ovarian Reserve Findings

Numerically more patients in the Tecentriq arm had CIOF at the end of therapy than compared with the chemotherapy group. At the end of therapy, 26 of 64 patients (40.6%) with assessable serum levels had CIOF compared with 15 of 56 (26.7%) with assessable serum levels in the placebo group.

"Patients who received checkpoint inhibitor in addition to chemotherapy had higher rates of CIOF at end of therapy and remained higher during follow-up," said Reinisch. "A numerical recovery of hormonal levels was observed in both arms during follow-up, indicating a regain of ovarian function. This change was more pronounced in the chemotherapy arm."

At six months following treatment, eight of 41 (19.5%) in the chemotherapy group had CIOF compared with 10 of 55 (18.2%) in the Tecentriq group. At 12 months, two of 39 (5.1%) had CIOF in the chemotherapy group compared with six of 49 (12.2%) for immunotherapy.

Amenorrhea occurred for 12.8% of patients (10 of 78) at baseline in the chemotherapy/placebo group and for 19.1% of those in the chemotherapy/Tecentriq arm (18 of 94), according to investigator assessment. At the end of therapy, this increased to 64.9% of those in the placebo group (48 of 74) and 62.6% for those in the Tecentriq arm (57 of 91). These rates declined with longer follow up.

After 12 months of follow-up, the rate of amenorrhea was 34.4% (22 of 64) in the placebo group and 33.3% (29 of 87) in the immunotherapy group. This remained consistent throughout the follow-up period. At 18 months and 24 months, respectively, the rate of amenorrhea was 34.4% (22 of 64) and 36.9% (24 of 65) in the placebo group and 32.9% (28 of 85) and 29.8% (25 of 84) in the Tecentriq arm.

At the end of therapy, the E2 and FSH levels were within the postmenopausal range but recovered for many patients during the follow up period across both treatment groups. At 24 months post-treatment, 10% of patients in both groups (eight of 80) had persistent postmenopausal E2 levels and 46.2% had postmenopausal FSH levels (37 of 80).

At baseline, Reinisch noted that anti-mullerian hormone (AMH) was lower than age-matched reference levels with many patients starting the study at around 1 ng/ml. Overall, at baseline, 10.5% of patients entered the study with an already severely reduced ovarian reserve (AMH <0.22 ng/ml). This rate was similar between arms. At the end of therapy, all patients had a severely reduced ovarian reserve, with AMH levels near 0. There was no recovery in the follow up period for this measure.

Reference

1. “Impact of Immune Checkpoint Inhibition (CPI) on Fertility in Young Women with Early Triple-Negative Breast Cancer (TNBC) receiving neoadjuvant Chemotherapy (NACT): A Prospective Substudy of the NSABP B-59/GBG-96-GeparDouze Trial” by Dr. Mattea Reinisch et al., presented at: San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. Abstract RF2-06.

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