Advertisement

Evolving treatment landscape of advanced endometrial cancer – A current perspective from a German tertiary referral center for gynecological oncology

Open AccessPublished:January 07, 2023DOI:https://doi.org/10.1016/j.ejogrb.2023.01.008

      Keywords

      Expert opinion

      Endometrial cancer (EC) represents the most prevalent cancer of the female genital tract worldwide. Although EC has an overall good prognosis compared to other gynecological malignancies, a recent report from the American Cancer Society indicated that the cancer-specific survival of patients with EC has decreased since the 1970 s, while the incidence has remained stable [
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2022.
      ]. The increasing EC-specific mortality is particularly attributable to EC with non-endometrioid histology. Although non-endometrioid histology represents only about 20 % of all EC, non-endometrioid EC account for more than half of EC-related deaths [
      • Clarke M.A.
      • Devesa S.S.
      • Harvey S.V.
      • Wentzensen N.
      Hysterectomy-corrected uterine corpus cancer incidence trends and differences in relative survival reveal racial disparities and rising rates of nonendometrioid cancers.
      ,
      • McGunigal M.
      • Liu J.
      • Kalir T.
      • Chadha M.
      • Gupta V.
      Survival differences among uterine papillary serous, clear cell and grade 3 endometrioid adenocarcinoma endometrial cancers: a national cancer database analysis.
      ]. The determinants underlying the increase in non-endometrioid EC remain elusive. Overall, EC contrasts to the majority of other malignancies, whose cancer-specific survival has improved in recent years [
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2022.
      ]. Hence, it is crucial to reconsider and optimize existing therapy strategies and, to incorporate novel scientific findings into therapy algorithms. Here, we compile existing therapeutic concepts for advanced EC and propose a treatment algorithm based on current clinical and translational research findings.
      First-line systemic therapy of advanced, previously system-therapeutically untreated EC is a combination chemotherapy with carboplatin and paclitaxel (TC). This therapy sequence is repeated every 21 days up to six cycles unless disease progression or adverse treatment related events necessitate discontinuation. The basis for this therapy approach is provided by the Phase III NRG Oncology/GOG0209 trial. This study demonstrated noninferiority of TC to the alternative paclitaxel-doxorubicin-cisplatin (TAP) regimen (median overall survival (OS): 37 versus 41 months; hazard ratio (HR): 1.002; 90 % CI: 0.9–1.12; median progression-free survival (PFS): 13 versus 14 months; HR: 1.032; 90 % CI: 0.93–1.15) with a more favorable toxicity profile and a meaningful difference in health-related quality of life (HRQoL). Although carboplatin was administered in the referred study at a dosage of area under the curve (AUC) 6, a dosage of AUC 5 has been adopted in the clinic due to better tolerability. Paclitaxel is administered at a dosage of 175 mg/m2.
      Numerous studies have attempted to improve the efficacy of this first-line therapy by the additional administration of the angiogenesis inhibitor bevacizumab analogous to treatment of ovarian cancer. These include the GOG86P trial and MITO END-2 trial. In both studies referred to, the additional administration of bevacizumab had no significant impact on PFS and OS. Accordingly, bevacizumab is not part of the treatment algorithm in advanced EC [
      • Aghajanian C.
      • Filiaci V.
      • Dizon D.S.
      • Carlson J.W.
      • Powell M.A.
      • Secord A.A.
      • et al.
      A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer.
      ,
      • Lorusso D.
      • Ferrandina G.
      • Colombo N.
      • Pignata S.
      • Pietragalla A.
      • Sonetto C.
      • et al.
      Carboplatin-paclitaxel compared to Carboplatin-Paclitaxel-Bevacizumab in advanced or recurrent endometrial cancer: MITO END-2 - A randomized phase II trial.
      ]. Studies that aimed to identify druggable targets in EC have shown that approximately 30 % of all EC with serous histology exhibit overexpression of the human epidermal growth factor receptor 2 (Her2). The determination of Her2 expression and the classification into Her2 positive and Her2 negative is performed analogously to breast cancer [
      • Grushko T.A.
      • Filiaci V.L.
      • Mundt A.J.
      • Ridderstråle K.
      • Olopade O.I.
      • Fleming G.F.
      • et al.
      An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study.
      ]. Her2 positivity raises the possibility of Her2-targeted therapy. A recently published phase II study demonstrated that adding the Her2 antibody trastuzumab to the TC therapy sequence (8 mg/kg for the first dose and 6 mg/kg in subsequent cycles every 3 weeks) leads to a significant prolongation of PFS (12.9 versus 8.0 months; HR: 0.46, 90 % CI 0.28–0.76; p = 0.005) and OS (29.6 versus 24.4 months; HR: 0.58, 90 % CI 0.34–0.99; p = 0.046) [

      Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res Off J Am Assoc Cancer Res. 2020 Aug 1;26(15):3928–35.

      ]. Accordingly, testing of Her2 expression status in advanced serous endometrial cancer is of enormous importance.
      Research has shown that malignancies with mismatch repair deficiency (dMMR) and/or microsatellite instability (MSI) exhibit increased susceptibility to immune checkpoint inhibition (ICI) [
      • Le D.T.
      • Durham J.N.
      • Smith K.N.
      • Wang H.
      • Bartlett B.R.
      • Aulakh L.K.
      • et al.
      Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
      ]. Approximately 13 % to 30 % of recurrent/advanced EC are dMMR or MSI, rendering ICI an alternative therapy to conventional chemotherapy and/or a treatment option after failure of first-line chemotherapy [
      • Green A.K.
      • Feinberg J.
      • Makker V.
      A review of immune checkpoint blockade therapy in endometrial cancer.
      ]. Currently, two different ICI monotherapies are approved, namely pembrolizumab and dostarlimab. In the KEYNOTE-158 trial, pembrolizumab monotherapy (200 mg once every 3 weeks) resulted in an overall response rate (ORR) of 48 % (CR 14 %; PR 34 %; SD 18 %. The overall rate of high-grade toxicities (CTCAE grade > III) was low at 7 % [
      • Marabelle A.
      • Le D.T.
      • Ascierto P.A.
      • Di Giacomo A.M.
      • De Jesus-Acosta A.
      • Delord J.-P.
      • et al.
      Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.
      ,
      • O'Malley D.M.
      • Bariani G.M.
      • Cassier P.A.
      • Marabelle A.
      • Hansen A.R.
      • De Jesus Acosta A.
      • et al.
      Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study.
      ]. Comparable data were collected in the Garnet trial. Dostarlimab monotherapy (500mgevery3weeksfor4cycles, then 1000 mg every 6 weeks) resulted in a treatment response in 42.3 % (ORR; CR 12.7 %; PR 29.6 %). Higher grade toxicities occurred in 11.5 % of the study population [
      • Oaknin A.
      • Gilbert L.
      • Tinker A.V.
      • Brown J.
      • Mathews C.
      • Press J.
      • et al.
      Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
      ]. However, both studies included only patients with dMMR/MSI tumors. Accordingly, ICI monotherapy is an effective treatment option for this EC subtype. However, pMMR/MSS tumors show significantly lower response rates of <20 % [
      • How J.A.
      • Jazaeri A.A.
      • Fu S.
      • Rodon Ahnert J.
      • Gong J.
      • Stephen B.
      • et al.
      Clinical outcomes of patients with recurrent microsatellite-stable endometrial cancer in early-phase immunotherapy clinical trials.
      ]. The KEYNOTE-146 study demonstrated that the effect of ICI could be augmented by combined administration of the multikinase inhibitor Lenvatinib (20 mg, administered orally once daily) in pMMR/MSS EC [
      • Makker V.
      • Taylor M.H.
      • Aghajanian C.
      • Oaknin A.
      • Mier J.
      • Cohn A.L.
      • et al.
      Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer.
      ]. This positive effect was confirmed in the phase III study KEYNOTE-775 [
      • Makker V.
      • Colombo N.
      • Casado Herráez A.
      • Santin A.D.
      • Colomba E.
      • Miller D.S.
      • et al.
      Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer.
      ]. The KEYNOTE-755 study evaluated combination therapy of pembrolizumab and lenvatinib versus investigator's choice of mono-chemotherapy (doxorubicin or paclitaxel) in patients with advanced EC who had previously received at least one platinum-containing chemotherapy regimen. OS and PFS were defined as dual primary endpoints. N = 697 study participants had pMMR/MSS tumors, while 130 patients were dMMR/MSI. PFS in the ITT population was 7.2 versus 3.8 months in favor of the combination therapy (HR: 0.62; P < 0.001). This effect also remained with respect to OS, which was 18.3 months (vs 11.4 months; HR: 0.56; P < 0.001). Although the overall therapy efficacy was greater in the dMMR/MSI EC sub-population, the clinical benefit was also evident when the pMMR/MSS tumors were considered separately [
      • Makker V.
      • Colombo N.
      • Casado Herráez A.
      • Santin A.D.
      • Colomba E.
      • Miller D.S.
      • et al.
      Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer.
      ]. Overall, higher-grade therapy-associated adverse events (CTCAE ≥ 3) occurred in 88.9 % in the lenvatinib/pembrolizumab study arm. The most common adverse events were hypertension, hypothyroidism, diarrhea, nausea, decreased appetite, vomiting, decreased body weight, fatigue, and arthralgia. Hence, the combination therapy of lenvatinib plus pembrolizumab is associated with a considerable treatment-related toxicity. The extent to which dMMR/MSI EC patients should receive ICI monotherapy due to the favorable side effect profile requires individual assessment and adaptation to the patient's comorbidities. Conclusively, ICI +/- lenvatinib should be considered as second-line therapy after prior platinum-based chemotherapy in advanced EC.
      Endocrine therapy represents an alternative therapy approach to the aforementioned regimens, particularly in patients with comorbidities and/or contraindications. In this context, different therapeutic regimens have been established: (i) MPA (200–250 mg/d), (ii) MGA (160 mg/d), (iii) tamoxifen (20 mg/d or 40 mg/d), or (iv) a combination of tamoxifen and MPA/MGA [
      • Ethier J.L.
      • Desautels D.N.
      • Amir E.
      • MacKay H.
      Is hormonal therapy effective in advanced endometrial cancer? A systematic review and meta-analysis.
      ,
      • Jerzak K.J.
      • Duska L.
      • MacKay H.J.
      Endocrine therapy in endometrial cancer: An old dog with new tricks.
      ,

      Kokka F, Brockbank E, Oram D, Gallagher C, Bryant A. Hormonal therapy in advanced or recurrent endometrial cancer. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD007926.

      ]. Research has shown that response rates to endocrine therapy can be enhanced by selecting patients with tumoral progesterone and/or estrogen receptor expression [
      • Covens A.L.
      • Filiaci V.
      • Gersell D.
      • Lutman C.V.
      • Bonebrake A.
      • Lee Y.C.
      Phase II study of fulvestrant in recurrent/metastatic endometrial carcinoma: a Gynecologic Oncology Group study.
      ]. Recently, initial results from the NSGO-PALEO / ENGOT-EN3 trial (NCT02730429) were presented. This trial assessed the combination of the CDK4/6 inhibitor palbociclib (125mgorallyd1–21ina28–dcycle) with the aromatase inhibitor letrozole (2.5 mg orally daily) versus letrozole plus placebo in advanced EC. The addition of palbociclib significantly prolonged PFS (8.3 versus 3.0 months; HR: 0.56, 95 %CI (0.32–0.98); p = 0.041). Comparable results were obtained in another phase II study applying abemaciclib (NCT03675893.). Additionally, this study provided evidence that especially EC without p53 mutations may benefit from the combination therapy with palbociclib plus letrozole [

      Konstantinopoulos PA, Lee EK, Xiong N, Krasner C, Campos S, Kolin DL, et al. A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2022 Sep 29;JCO2200628.

      ]. Recently, tumor genetic studies have demonstrated that a substantial proportion of serous EC display deficient homologous recombination (HRD), rendering these patients eligible for PARP inhibitor therapy analogous to the treatment of ovarian cancer [

      de Jonge MM, Auguste A, van Wijk LM, Schouten PC, Meijers M, Ter Haar NT, et al. Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2019 Feb 1;25(3):1087–97.

      ]. However, to date, no randomized controlled trials evaluating efficacy of PARP-inhibitor treatment in EC have been conducted. PARP-inhibitor therapy in presence of HRD may be considered if the standard therapies outlined above have been completed. Further druggable tumor alterations may be identified by additional molecular diagnostics and a molecular tumor board. Initiation of this diagnostic approach should proceed early in the recurrent stage of disease.
      Additionally, it is advisable to assess for each patient whether inclusion in a clinical trial is reasonable.
      The systemic therapy of advanced or relapsed EC has evolved in recent years. Hence, the treatment of patients with EC should always incorporate a multidisciplinary approach in specialized centers. Treatment decisions should be guided by the patient’s condition, extent of the disease, prior therapies and the molecular tumor profile. The present work highlights possible treatment regimens that can be applied individually to each EC patient and is summarized in Fig. 1.
      Figure thumbnail gr1
      Fig. 1First and second line Treatment algorithm for advanced Endometrial Cancer.

      Funding/support

      Damian J. Ralser is supported by the BONFOR program of the Medical Faculty of the University of Bonn (grant ID 2021-1A-14).

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      References

        • Siegel R.L.
        • Miller K.D.
        • Fuchs H.E.
        • Jemal A.
        Cancer statistics, 2022.
        CA Cancer J Clin. 2022; 72: 7-33
        • Clarke M.A.
        • Devesa S.S.
        • Harvey S.V.
        • Wentzensen N.
        Hysterectomy-corrected uterine corpus cancer incidence trends and differences in relative survival reveal racial disparities and rising rates of nonendometrioid cancers.
        J Clin Oncol Off J Am Soc Clin Oncol. 2019; 37: 1895-1908
        • McGunigal M.
        • Liu J.
        • Kalir T.
        • Chadha M.
        • Gupta V.
        Survival differences among uterine papillary serous, clear cell and grade 3 endometrioid adenocarcinoma endometrial cancers: a national cancer database analysis.
        Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2017; 27: 85-92
        • Aghajanian C.
        • Filiaci V.
        • Dizon D.S.
        • Carlson J.W.
        • Powell M.A.
        • Secord A.A.
        • et al.
        A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer.
        Gynecol Oncol. 2018; 150: 274-281
        • Lorusso D.
        • Ferrandina G.
        • Colombo N.
        • Pignata S.
        • Pietragalla A.
        • Sonetto C.
        • et al.
        Carboplatin-paclitaxel compared to Carboplatin-Paclitaxel-Bevacizumab in advanced or recurrent endometrial cancer: MITO END-2 - A randomized phase II trial.
        Gynecol Oncol. 2019; 155: 406-412
        • Grushko T.A.
        • Filiaci V.L.
        • Mundt A.J.
        • Ridderstråle K.
        • Olopade O.I.
        • Fleming G.F.
        • et al.
        An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study.
        Gynecol Oncol. 2008; 108: 3-9
      1. Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res Off J Am Assoc Cancer Res. 2020 Aug 1;26(15):3928–35.

        • Le D.T.
        • Durham J.N.
        • Smith K.N.
        • Wang H.
        • Bartlett B.R.
        • Aulakh L.K.
        • et al.
        Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
        Science. 2017; 357: 409-413
        • Green A.K.
        • Feinberg J.
        • Makker V.
        A review of immune checkpoint blockade therapy in endometrial cancer.
        Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Annu Meet. 2020; 40: 1-7
        • Marabelle A.
        • Le D.T.
        • Ascierto P.A.
        • Di Giacomo A.M.
        • De Jesus-Acosta A.
        • Delord J.-P.
        • et al.
        Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.
        J Clin Oncol Off J Am Soc Clin Oncol. 2020; 38: 1-10
        • O'Malley D.M.
        • Bariani G.M.
        • Cassier P.A.
        • Marabelle A.
        • Hansen A.R.
        • 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 Off J Am Soc Clin Oncol. 2022; 40: 752-761
        • Oaknin A.
        • Gilbert L.
        • Tinker A.V.
        • Brown J.
        • Mathews C.
        • Press J.
        • et al.
        Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
        J Immunother Cancer. 2022; 10: e003777
        • How J.A.
        • Jazaeri A.A.
        • Fu S.
        • Rodon Ahnert J.
        • Gong J.
        • Stephen B.
        • et al.
        Clinical outcomes of patients with recurrent microsatellite-stable endometrial cancer in early-phase immunotherapy clinical trials.
        Cancers. 2022; 14: 3695
        • Makker V.
        • Taylor M.H.
        • Aghajanian C.
        • Oaknin A.
        • Mier J.
        • Cohn A.L.
        • et al.
        Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer.
        J Clin Oncol Off J Am Soc Clin Oncol. 2020; 38: 2981-2992
        • Makker V.
        • Colombo N.
        • Casado Herráez A.
        • Santin A.D.
        • Colomba E.
        • Miller D.S.
        • et al.
        Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer.
        N Engl J Med. 2022; 386: 437-448
        • Ethier J.L.
        • Desautels D.N.
        • Amir E.
        • MacKay H.
        Is hormonal therapy effective in advanced endometrial cancer? A systematic review and meta-analysis.
        Gynecol Oncol. 2017; 147: 158-166
        • Jerzak K.J.
        • Duska L.
        • MacKay H.J.
        Endocrine therapy in endometrial cancer: An old dog with new tricks.
        Gynecol Oncol. 2019; 153: 175-183
      2. Kokka F, Brockbank E, Oram D, Gallagher C, Bryant A. Hormonal therapy in advanced or recurrent endometrial cancer. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD007926.

        • Covens A.L.
        • Filiaci V.
        • Gersell D.
        • Lutman C.V.
        • Bonebrake A.
        • Lee Y.C.
        Phase II study of fulvestrant in recurrent/metastatic endometrial carcinoma: a Gynecologic Oncology Group study.
        Gynecol Oncol. 2011; 120: 185-188
      3. Konstantinopoulos PA, Lee EK, Xiong N, Krasner C, Campos S, Kolin DL, et al. A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2022 Sep 29;JCO2200628.

      4. de Jonge MM, Auguste A, van Wijk LM, Schouten PC, Meijers M, Ter Haar NT, et al. Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2019 Feb 1;25(3):1087–97.