HER2-Expressing Gynecological Cancers: Catching Up on Targeted Approaches

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In the field of gynecological malignancies, HER2 alterations such as HER2 amplification and mutation are found particularly in the three most common manifestations of cervical, endometrial, and ovarian cancer (1). As is well known, the classification of endometrial cancer has evolved in recent years from a purely pathological approach to a model in which the molecular profile has been integrated. The result is four molecular subgroups with relevance for prognosis and the choice of adjuvant therapy: those with POLE mutation, mismatch repair deficiency (dMMR), p53 abnormality, or an unspecified molecular profile (2). In addition to these four categories, there are various molecular aberrations, including HER2 alterations. Histologically, these are particularly often identified in the “copy-number high serous-like” subtype and even in some aggressive subtypes such as carcinosarcoma and clear cell carcinoma (3).

A retrospective analysis of the PORTEC-3 and TCGA cohorts evaluated possible associations between HER2 status and molecular classification. According to this analysis, HER2 positivity is mainly present in the subgroup with p53 abnormalities, while it is absent in the groups with POLE mutation and dMMR (4). As with other types of cancer, HER2-positive status generally appears to be associated with a less favorable prognosis compared to HER2-negative disease. However, despite the high prevalence of p53-aberrant high-risk endometrial cancer in this group, the presence of HER2 positivity does not result in a further worsening of the outcome, as p53 alteration determines the prognosis.

HER2-targeted substances in clinical trials

In 2018, the addition of trastuzumab to the first-line treatment of endometrial cancer with carboplatin/paclitaxel was successfully tested in a phase II trial (5). Compared to chemotherapy alone, progression-free survival (PFS) was extended by more than four months (12.6 vs. 8.0 months; HR: 0.44; p = 0.0052). The patient cohort was relatively small, but the results must be seen in the context of a disease in which there was a lack of effective treatment options after carboplatin/paclitaxel failure at that time. The current NCCN guidelines, therefore, recommend the administration of trastuzumab in addition to carboplatin/paclitaxel for patients with HER2-positive endometrial cancer (6).

A chemotherapy-free strategy was evaluated in the TAPUR basket study (7). Patients with HER2/3-positive endometrial cancer received trastuzumab in combination with pertuzumab. Only three people had HER2 mutations, while the others tested positive for HER2/3 amplification and/or overexpression, HER2 amplification, and HER2/3 mutations. The overall response rate was low at 7%, and the disease control rate was 37%. Given the aggressive nature of the serous subtype with HER2 amplification and overexpression, chemotherapy appears to be essential in this group.

Cervical and ovarian cancer

Little data is available on the use of anti-HER2 therapies in cervical carcinoma. The pan-HER2 inhibitor neratinib was investigated in the phase II basket study SUMMIT, which included a cohort with cervical carcinoma after failure of standard platinum-based chemotherapy (n = 22). Overall, 18.2% of patients responded to treatment and 45.5% achieved clinical benefit (8). These are relevant observations as they indicate that the HER2 signaling pathway plays a role in cervical cancer in some cases.

According to a retrospective study, HER2 expression varies considerably in ovarian cancer, with immunohistochemical (IHC) scores of 2+ being found in BRCA mutation and BRCA wild type (9). HER2 expression was observed in various histological subtypes. Up to 30% of patients with the high-grade serous subtype showed scores of 2+ and 3+, although the 3+ score was rare at 4.6%. Mucinous ovarian carcinoma is relatively resistant to chemotherapy; in this group, HER2 expression scores of 2+ and 3+ were present in 25% and 18.8% respectively. In view of the availability of increasingly better treatment options, HER2 should be kept in mind as a target in these tumors and consistent testing should be carried out.

Studies on T-DXd

Trastuzumab deruxtecan (T-DXd) was investigated in the phase II basket study DESTINY-PanTumor02, which included patients with various HER2-positive (IHC 2+ or 3+) solid tumors after at least one standard line of therapy (10). The administration of T-DXd led to considerable objective response rates (ORR) in the cohorts with cervical, endometrial, and ovarian cancer. In patients with IHC 3+ in these three groups, the ORRs were 75%, 84.6%, and 63.6% respectively. Most participants experienced tumor shrinkage. Similarly, PFS was longest in IHC 3+, although some activity was also observed in the IHC 2+ cohorts.

A small study investigated T-DXd in aggressive and rare carcinosarcoma of the uterus (11). The evaluation was carried out in patients with high HER2 expression (IHC ≥ 2+), but also in a HER2-low cohort (IHC 1+). According to the analysis, the ORR was 54.5% for IHC ≥ 2+ and 70% for IHC 1+. The majority of patients benefited from T-DXd therapy.

Take-home messages and open questions

Although the development of HER2-targeted treatments for gynecological cancers is still lagging behind other tumor types, there is no doubt that the identification of targets such as HER2 overexpression is a prerequisite for optimizing treatment outcomes. Given the availability of effective therapies, we need to capitalize on knowledge from the field of other cancers. Antibody-drug conjugates will change the treatment paradigm in gynecological oncology. Several phase III trials with T-DXd in HER2-positive tumors are planned to confirm the existing results.

However, there are still some unanswered questions, such as the optimal assessment and definition of HER2 positivity in gynecological tumors, the heterogeneity of HER2 expression, and the integration of anti-HER2 therapy into the treatment paradigm. Further considerations concern the composition of optimal combinations (e.g., with immunotherapy, PARP inhibitors) and the type of resistance mechanisms (e.g., PI3KCA, PTEN alteration). We have an exciting time ahead of us, as we will have to answer all these questions in our clinical trials.

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6. NCCN Guidelines Endometrial Carcinoma v2.2024
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