MEK Inhibitors for the Treatment of Low-Grade Serous Ovarian Cancer: Expanding Therapeutic Options for a Rare Ovarian Cancer Subtype

Gershenson, David M.; Gourley, Charlie; Paul, James

doi:10.1200/jco.20.02190

Cited by 10 publications

(10 citation statements)

References 34 publications

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“…However, in GOG 0281, (pegylated liposomal doxorubicin or weekly paclitaxel, topotecan, letrozole), PFS was 7.2 months and ORR 6.2%. The reasons for this difference are not entirely clear and may relate to the number of prior lines of treatment allowed, with women in GOG 0281 being more heavily pre-treated (Gershenson et al 2020b).…”

Section: Low-response Rates To Platinum-based Chemotherapymentioning

confidence: 99%

New therapeutic opportunities for women with low-grade serous ovarian cancer

Moujaber

Balleine

Gao

et al. 2022

Endocrine-Related Cancer

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Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor, however the use of platinum-based chemotherapy in both the upfront and relapsed setting, is being questioned due to low response rates in LGSC. Most LGSC express steroid hormone receptors and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilization with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC have a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.

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Section: Low-response Rates To Platinum-based Chemotherapymentioning

confidence: 99%

New therapeutic opportunities for women with low-grade serous ovarian cancer

Moujaber

Balleine

Gao

et al. 2022

Endocrine-Related Cancer

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“…The high prevalence of MAPK pathway alterations in LGSOC has stimulated the evaluation of selective MEK inhibitors in patients with this malignancy (9,35).…”

Section: Mek Inhibitorsmentioning

confidence: 99%

“…Although not meeting its primary endpoint, the MILO study demonstrates that MEK inhibition results in disease control in a significant number of patients and is a strategy that should be seriously considered in this difficult-to-treat disease. More importantly, there are questions still to be answered regarding the extent to which various MAPK mutations confer MEK inhibitor sensitivity (35).…”

Section: Mek Inhibitorsmentioning

confidence: 99%

A therapeutic approach to low-grade serous ovarian carcinoma

Petrić-Miše

Šundov

2020

lib oncol

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Low-grade serous ovarian cancer (LGSOC) has less aggressive behavior and a better clinical outcome than high-grade serous ovarian cancer (HGSOC). Considering that this malignancy is relatively chemoresistant, surgery is the keystone of treatment, with a strong recommendation for maximal cytoreduction. Women with stage IA-IB disease should undergo observation alone after primary cytoreductive surgery. In contrast, observation, chemotherapy, or endocrine therapy are possible options for those with stage IC-IIA disease. Patients with stage IIB-IV disease receive either chemotherapy with carboplatin and paclitaxel for six cycles followed by endocrine therapy, most commonly with aromatase inhibitors, or endocrine therapy alone until disease progression or unacceptable toxicity. Surgery, chemotherapy, and endocrine therapy are also used in patients with recurrent disease. Targeted agents, especially mitogen-activated protein kinase (MEK) inhibitors and cyclin-dependent kinase (CDK) inhibitors, are currently under evaluation in this clinical setting. Additional research on the genomics of LGSOC to better define the activating gene mutations involved in the carcinogenesis is strongly warranted to improve the prognosis with this malignancy.

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“…Multiple studies showed that LGSOC often present activating mutations of genes involved in this molecular pathway, such as KRAS, BRAF, ERBB2 and NRAS ( Gadducci and Cosio, 2020 ). BRAF mutations occur in 2 to 20% of cases ( Gershenson et al, 2020 ), being more common in borderline serous tumours and early stage LGSOCs than in the advanced disease, which are found only in about 5% of the cases ( Gershenson, 2016 , Gadducci and Cosio, 2020 ). Compared to HGSOC, LGSOC have a much lower frequency of p53 mutations or expression, greater oestrogen and/or progesterone receptor expression, and rarely harbour BRCA mutations ( Gershenson, 2016 ).…”

Section: Introductionmentioning

confidence: 99%