EP-4737592-A1 - METHOD FOR PREDICTING A RESPONSE TO SYSTEMIC TREATMENT IN A HORMONE RECEPTOR-POSITIVE (HR+) AND HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-NEGATIVE (HER2-) BREAST CANCER PATIENT

Abstract

The present invention is in the field of molecular subtyping of tumor samples and therapy guidance. The present invention relates to methods, arrays, prognostic assays, systems and uses thereof for prediction of the response or resistance to and/or benefit from a systemic treatment, in particular adjuvant or neoadjuvant chemotherapy, of a subject suffering from a HR+ and HER2- breast cancer, based on the measurement(s) of expression level(s) of three or more markers in tumor samples of said subject. Equally, the present invention relates to methods, arrays, prognostic assays, systems and uses thereof for prediction of the outcome benefit from a systemic treatment, in particular adjuvant or neoadjuvant chemotherapy, of a subject suffering from a HR+ and HER2- breast cancer, based on the measurement(s) of expression level(s) of three or more markers in tumor samples of said subject.

Inventors

• LOIBL, SIBYLLE
• RACHAKONDA, Panduranga Sivaramakrishna
• WEBER, KARSTEN
• DENKERT, CARSTEN
• KARN, THOMAS

Assignees

• GBG Forschungs GmbH
• Johann-Wolfgang-Goethe-Universität Frankfurt am Main
• PHILIPPS-UNIVERSITÄT MARBURG

Dates

Publication Date

20260506

Application Date

20251031

Claims (15)

1. A method for predicting a response or resistance to and/or benefit from a systemic treatment in a subject suffering from a hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer, optionally in an early-stage, comprising the steps of: (a) determining in a sample obtained from said subject the expression levels of three or more markers selected from Table 1.1; (b) optionally normalizing the determined expression levels of said three or more markers; (c) mathematically combining the determined expression levels of the three or more markers selected from Table 1.1 to generate a prediction, preferably a predictive score; and (d) predicting the response or resistance to and/or benefit from said systemic treatment in said subject based on the prediction, preferably based on the predictive score; wherein the expression levels of the three or more markers are indicative for predicting the response or resistance to and/or benefit from the systemic treatment in said subject.
2. The method of claim 1, wherein the systemic treatment is neoadjuvant or adjuvant treatment, preferably wherein the systemic treatment is neoadjuvant treatment, preferably wherein the systemic treatment is chemotherapy, most preferably wherein the systemic treatment is neoadjuvant chemotherapy, optionally comprising a taxane-containing agent for at least six weeks.
3. The method of claim 1 or 2, wherein the method further comprises the determination of one or more clinical parameters selected from the group consisting of pathological grading of the tumor, clinical tumor size (cT), clinical nodal status (cN), proliferation (in particular Ki-67), immune system markers (in particular lymphocytes, preferably tumor infiltrating lymphocytes (TILs)), estrogen receptor status, progesterone receptor status, and variables derived from them (clinical and pathological stage, CPS-EG).
4. The method of any one of claims 1 to 3, wherein the mathematical combination of the determined expression levels of said three or more markers selected from Table 1.1 to generate a prediction, optionally a mathematical combination of the determined expression levels of said three or more markers and one or more additional markers, one or more clinical parameters and/or one or more non-clinical parameters, is performed using a statistical and/or mathematical model.
5. The method of any one of claims 1 to 4, wherein the response or resistance to the systemic treatment is measured by the long-term development of the disease, in particular development of invasive relapses, distant metastases, disease-related survival, and/or overall survival.
6. The method of any one of claims 1 to 5, wherein the expression levels of three or more markers selected from any one of Tables 3-8 are determined, preferably wherein the expression levels of three or more markers selected from Table 4 are determined, preferably Table 5, more preferably Table 6 or Table 8, most preferably Table 7.1.
7. The method of claim 6, wherein the expression levels of three or more markers selected from Table 6 or 7.1 are determined and the high expression levels of three or more markers selected from Table 6 or 7.1 in a tumor sample are indicative for a good response of the subject to the neoadjuvant chemotherapy and/or the patient is predicted to benefit from the neoadjuvant treatment, optionally wherein the three or more markers are DNA repair genes or wherein the expression levels of three or more markers selected from Table 8 are determined and high expression levels of a plurality of markers selected from Table 8 in a tumor sample are indicative for a bad response of the subject to the treatment and/or the patient is predicted to not benefit from the treatment.
8. The method of any one of claims 1 to 7, wherein said subject has a low chance to reach a pathological complete remission (pCR) after neoadjuvant treatment.
9. The method of any one of claims 1 to 8, wherein at least five markers are selected from Table 1.1, preferably at least ten markers from Table 1.1, more preferably at least twenty markers from Table 1.1, more preferably at least fifty markers from Table 1.1, most preferably all markers from Table 1.1 are selected.
10. The method of any one of claims 1 to 9, wherein the tumor sample is tumor tissue sample, preferably wherein the sample is a primary tumor tissue sample, more preferably a core biopsy sample, more preferably a core biopsy sample from a primary tumor before any systemic treatment, most preferably a core biopsy sample from a primary tumor before neoadjuvant treatment.
11. The method of any one of claims 1 to 10, wherein the expression levels are determined at gene level, preferably mRNA level, in a hybridization-based method, a PCR based method, a microarray-based method, a quantitative transcriptomic analysis, a sequencing and/or next generation sequencing (NGS) method.
12. Neoadjuvant chemotherapy for use in the treatment of a HR+ and HER2- breast cancer, wherein the neoadjuvant chemotherapy is to be administered to a subject who has been predicted to respond to and/or benefit from said treatment or for whom said treatment has been determined to have a positive outcome according to the method of any one of claims 1 to 11, optionally wherein the neoadjuvant chemotherapy comprises a taxane-containing agent and the taxane-containing agent is any one of paclitaxel, docetaxel, abraxane, cabazitaxel, and albumin-bound paclitaxel (nab-paclitaxel).
13. A method for therapy guidance, wherein a decision about systemic treatment, preferably neoadjuvant chemotherapy, is based on a prediction of response or resistance to and/or benefit from said systemic treatment, preferably neoadjuvant chemotherapy, wherein the prediction is made according to the method of any one of claims 1 to 11, a) wherein if the subject is predicted to respond to and/or benefit from said systemic treatment, preferably neoadjuvant chemotherapy, the patient is treated with said systemic treatment; or b) wherein if the subject is predicted not to respond to, to be resistant to and/or not to benefit from said systemic treatment, preferably neoadjuvant chemotherapy, the subject is treated with a different systemic treatment or with said systemic treatment and an additional systemic treatment.
14. A method for stratifying the risk of subjects suffering from HER+ and HER2- breast cancer, wherein the method comprises predicting the response or resistance to and/or benefit from systemic treatment, preferably neoadjuvant chemotherapy, according to the method of any one of claims 1 to 11.
15. Use of a prognostic assay for predicting the response or resistance to and/or benefit from a systemic treatment, preferably neoadjuvant chemotherapy, in a subject suffering from a HR+ and HER2- breast cancer, wherein the prognostic assay comprises a RNA-based assay, optionally wherein the prognostic assay is one or more of NGS-based RNA analysis, PCR-based RNA analysis, sequencing-based RNA analysis, quantitative transcriptome analysis, quantitative RNA expression analysis, RNA-hybridization-based technologies including spatial RNA analysis or microarrays including Affymetrix.

Description

FIELD OF THE INVENTION The present invention is in the field of molecular subtyping of tumor samples and therapy guidance. The present invention relates to methods, arrays, prognostic assays, systems and uses thereof for prediction of the response or resistance to and/or benefit from a systemic treatment, in particular adjuvant or neoadjuvant chemotherapy, of a subject suffering from a HR+ and HER2- breast cancer, based on the measurement(s) of expression level(s) of three or more markers in tumor samples of said subject. Equally, the present invention relates to methods, arrays, prognostic assays, systems and uses thereof for prediction of the outcome benefit from a systemic treatment, in particular adjuvant or neoadjuvant chemotherapy, of a subject suffering from a HR+ and HER2- breast cancer, based on the measurement(s) of expression level(s) of three or more markers in tumor samples of said subject. BACKGROUND OF THE INVENTION Molecular subtyping of tumor biopsies (Perou CM. et al. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52; Sørlie T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74) revealed that breast cancer constitutes a heterogeneous set of diseases with different biological features, requiring tailored therapeutic strategies. Breast cancer cells express receptors, e.g., on the surface, in the cytoplasm and the nucleus. Breast cancers can be classified according to their expression of three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2. ER and PR are hormone receptors (HR). ER+ cancer cells (i.e., cancer cells expressing estrogen receptors) depend on estrogen for their growth, allowing for treatment with drugs inhibiting estrogen effects (e.g., tamoxifen), and ER+ cancers generally have a better prognosis. Untreated, HER2+ breast cancers tend to be more aggressive than HER2- breast cancers, however treatment of HER2+ cancer cells with certain drugs, such as the monoclonal antibody trastuzumab (in combination with conventional chemotherapy), improves the prognosis significantly. Cells that lack expression of estrogen receptors, progesterone receptors and HER2 are called triple-negative (TN), although they frequently do express receptors for other hormones, such as androgen receptor and prolactin receptor. The definition of luminal A (LumA), luminal B (LumB), basal-like (BasalL), HER2-enriched (HER2E), and normal-like (NormL) tumors is based on gene expression profiling, including the PAM50 approach (WO2009158143A1) as well as absolute assignment of breast cancer intrinsic molecular subtype (AIMS)-based subtyping (Paquet ER, Hallett MT. Absolute assignment of breast cancer intrinsic molecular subtype. J Natl Cancer Inst. 2014 Dec 4;107(1):357). However, the subtypes identified using the PAM50- and the AIMS-based approach are not adapted to therapy-induced molecular plasticity. In addition, other molecular assays as well as proliferation markers such as Antigen Kiel 67(Ki-67) are used. Adaptive changes of Ki-67 can be used to decide whether patients should receive endocrine therapy or chemotherapy followed by endocrine therapy (Smith I. et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1443-1454; Nitz UA. et al. Endocrine Therapy Response and 21-Gene Expression Assay for Therapy Guidance in HR+/HER2- Early Breast Cancer. J Clin Oncol. 2022 Aug 10;40(23):2557-2567). Due to the limited availability of paired samples, little is known about the changes of molecular subtypes during and after therapy. Therefore, an improved understanding of molecular adaptation to neoadjuvant chemotherapy could generate new advanced options for classification of tumors and tailored therapeutic strategies. Luminal tumors consist of two different subtypes: LumA tumors have a low proliferation rate and are typically treated with endocrine therapy alone. In contrast, LumB tumors are characterized by increased proliferation and tumor aggressiveness and therapeutic strategies for these tumors often include chemotherapy, followed by endocrine therapy. BasalL tumors tend to have a high metastasis rate and are often triple-negative. Of the AIMS subtypes, BasaL breast cancers show the highest pathological complete response (pCR) rate to neoadjuvant chemotherapy. HER2E breast cancers are usually responsive to (neo)adjuvant trastuzumab in combination with chemotherapy and are sensitive to adjuvant anthracyclines and taxanes. NormL breast cancers are often enriched for ER (Hoadley et al. Breast cancer intrinsic subtypes. Nat Rev Clin Oncol. Poster. 2014 Dec). Genomic signatures have been developed to predict the response of breast can