US-12624399-B2 - P27 single-nucleotide polymorphism T2871099G as a predictor of the benefit of endocrine therapy alone or in combination with CDK inhibitors in breast cancer

US12624399B2US 12624399 B2US12624399 B2US 12624399B2US-12624399-B2

Abstract

The present invention relates to a method of determining the therapy for treating a subject afflicted from breast cancer comprising determining the P27 T2871099G SNP in a sample of said subject and administering only endocrine therapy if the polymorphism is other than T2871099G, and administering endocrine therapy in combination with at least one CDK4/6 inhibitor if the polymorphism is homozygous T2871099G.

Inventors

Miguel Ángel QUINTELA FANDIÑO

Assignees

FUNDACIÓN DEL SECTOR PÚBLICO ESTATAL CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III (F.S.P. CNIO)

Dates

Publication Date: 20260512
Application Date: 20220126
Priority Date: 20210127

Claims (10)

1 . A method of determining the therapy for treating a subject afflicted from breast cancer comprising: a. determining the P27 T2871099G SNP in a sample of said subject, and then b. administering only endocrine therapy if the polymorphism is other than T2871099G, and administering endocrine therapy in combination with at least one CDK4/6 inhibitor if the polymorphism is homozygous T2871099G.
2 . The method of the preceding claim , wherein the breast cancer is hormone-positive breast cancer.
3 . The method of claim 1 , wherein the breast cancer is advanced breast cancer or early breast cancer.
4 . The method of claim 1 , wherein the sample is selected from the group consisting of plasma, serum, blood, saliva, skin, hair, tears, urine, fecal material, sweat, buccal smears, and a breast tissue biopsy.
5 . The method of claim 1 , wherein the P27 T2871099G SNP is determined in step (a) using sequencing, PCR, RT-PCR, PCR and restriction enzyme, PCR and sequencing or next generation sequencing.
6 . The method of claim 1 , wherein the endocrine therapy consists of at least one aromatase inhibitor, and/or at least one estrogen inhibitor.
7 . The method of claim 1 , wherein CDK4/6 inhibitor is selected from palbociclib or ribociclib or abemaciclib or a combination thereof.
8 . The method of claim 3 , wherein the breast cancer is early breast cancer.
9 . The method of claim 4 , wherein the sample is saliva or blood.
10 . The method of claim 6 , wherein the aromatase inhibitor is letrozole and the estrogen inhibitor is tamoxifen.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This is a 35 U.S.C. 371 National Stage Patent Application of International Application No. PCT/EP2022/051700, filed Jan. 26, 2022, which claims priority to EP application 21382061.6, filed Jan. 27, 2021, each of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to a method for determining the therapy for treating a subject afflicted from breast cancer comprising the determination of the P27 T2871099G single-nucleotide polymorphism (SNP). More specifically, the present invention relates to a method to determine the necessity to combine endocrine therapy with CDK4/6 inhibitors, based on P27 T2871099G SNP, since wild-type or heterozygous patients benefit from endocrine therapy, while SNP homozygous patients have less benefit from the endocrine therapy and require the combined therapy with CDK4/6 inhibitors. BACKGROUND OF THE INVENTION Advanced hormone-positive breast cancer patients are currently treated with a combination of endocrine therapy and cyclin-dependent kinases (CDKs) inhibitors. Up until 2015, the standard of care for advanced hormone-positive breast cancer was endocrine therapy alone. The former agents have been the cornerstone drug for managing this disease for decades, and actually a percentage of patients experience very prolonged benefit from them. The different therapeutic endocrine therapies achieved approximately a 9-12 months disease control duration. After 2015 several trials showed that combining hormonal inhibitors with the CDK inhibitors palbociclib, ribociclib or abemaciclib led to a more than 2-fold increase in the disease control duration (more than 20 months in average). This increase was observed in virtually all subgroups, and soon became the new standard of care for advanced hormone-positive breast cancer. Given its widespread benefit, now, all patients are considered candidates for the double blockade in the first line for advanced hormone-positive breast cancer. However, in early hormone-positive breast cancer, this combination therapy implies two potential problems: 1) pharmaco-economy: the combination treatment costs more than 5,000 Euro per month, whereas endocrine therapy alone costs less than 100 Euro per month; 2) toxicity: the toxicity of endocrine therapy alone is very low and well managed without close and frequent visits to the hospital; CDK inhibitors add considerable toxicity (haematological, gastro-intestinal, asthenia, skin toxicity, etc.) and require frequent visits and tests, associated to a lower quality of life. No biomarker suggests or pinpoints a subgroup of patients with early hormone-positive breast cancer that could benefit from endocrine therapy alone and obtain a similar benefit to that observed from the combination, albeit at a lower toxicity and monetary cost. Cyclin Dependent Kinase 4 and 6 (CDK4/6) inhibitors have meant a great advance in metastatic, hormone-positive breast cancer. The addition of palbociclib, ribociclib or abemaciclib to aromatase inhibitors in the first line treatment has increased the progression-free survival time from 10 months (aromatase inhibitor alone) to more than 25 months (aromatase inhibitor plus either CDK4/6 inhibitor). The benefit of these drugs seems to be independent of several factors: being Luminal A, Luminal B or HER2-enriched, patient's age, presence or absence of visceral metastases and others. In early disease, the situation is quite different: approximately 80-85% of the patients suffering from an early, hormone-positive breast cancer are cured in the long-term, just with surgery and aromatase inhibitors. Recently, three clinical trials have tested the addition of palbociclib (PALLAS trial), ribociclib (NATALEE trial) or abemaciclib (monarch-E trial). All trials have accrued approximately 5,000 patients each, and the results are disappointing: the monarch-E trial has reported a 5% improvement in the outcomes (in the 3 years follow up, the ratio disease free survival is 83.4% for endocrine therapy alone and 88.8% for endocrine therapy combined with abemaciclib), whereas the PALLAS trial has not found apparent benefit of the strategy. The NATALEE trial has not been reported yet. Zembutsu et al. disclose that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer (Clin Cancer Res 2017; 23:2019-2026). At present, there is no way of determining if a patient with early hormone-positive breast cancer could benefit from endocrine therapy alone and obtain a similar benefit to that observed from the combination with CDK4/6 inhibitors. Thus, there is a need for an easy test to help discern which patients need the combination of the endocrine therapy with CDK4/6 inhibitors from those who would already benefit from the endocrine therapy alone. SUMMARY OF THE INVENTION In a first aspect, the present invention relates to a method of determining the therapy for treating a