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US-20260125764-A1 - POST-TREATMENT BREAST CANCER PROGNOSIS

US20260125764A1US 20260125764 A1US20260125764 A1US 20260125764A1US-20260125764-A1

Abstract

The disclosure includes the identification and use of gene expression profiles, or patterns, with clinical relevance to extended treatment and cancer-free survival in a patient. In particular, the disclosure includes the identities of genes that are expressed in correlation with benefit in a switch in endocrine therapy used to treat a patient. The levels of gene expression are disclosed as a molecular index for predicting clinical outcome, and so prognosis, for the patient. The disclosure further includes methods for predicting cancer recurrence, and/or predicting occurrence of metastatic cancer, after initial treatment with an anti-estrogen agent. The disclosure further includes methods for determining or selecting the treatment of a subject based upon the likelihood of life expectancy, cancer recurrence, and/or cancer metastasis.

Inventors

  • Dennis Sgroi
  • Mark G. Erlander
  • Yi Zhang
  • Catherine A. Schnabel

Assignees

  • BIOTHERANOSTICS, INC.
  • THE GENERAL HOSPITAL CORPORATION

Dates

Publication Date
20260507
Application Date
20251103

Claims (20)

  1. 1 - 20 . (canceled)
  2. 21 . A method of treating breast cancer in a subject who has undergone removal of hormone receptor positive (HR+) breast cancer and has been treated with a first endocrine therapy comprising a selective estrogen receptor modulator (SERM), a selective estrogen receptor down-regulator (SERD), or an aromatase inhibitor (AI), the method comprising: preparing or having prepared cDNA from nucleic acids in a breast cancer sample from the subject, measuring or having measured the subject's expression levels of HoxB13, IL17BR, Bub1B, CENPA, NEK2, RACGAP1, and RRM2 from the cDNA, calculating or having calculated a ratio of the subject's expression levels of HoxB13:IL17BR (“H:I ratio”), normalizing or having normalized the subject's expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2, calculating or having calculated a Molecular Grade Index (“MGI”) for the subject comprising summing the subject's normalized expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2, calculating or having calculated a breast cancer index (BCI) prognostic value for the subject by combining or having combined the subject's H:I ratio and MGI as continuous variables, comparing or having compared the subject's BCI prognostic value to a cut-off value that is or has been determined by the BCI values for a dataset of (i) HR+ breast cancer subjects that did not have cancer recurrence, (ii) HR+ breast cancer subjects that did have cancer recurrence, or (iii) HR+ breast cancer subjects that did not have cancer recurrence and HR+ breast cancer subjects that did have cancer recurrence; and treating the subject with a second endocrine therapy if the subject's BCI prognostic value is above the cut-off value.
  3. 22 . The method of claim 21 , wherein the subject's expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2 are normalized or have been normalized to the subject's expression levels of ACTB, HBMS, SDHA, and UBC.
  4. 23 . The method of claim 21 , wherein the cDNA is prepared or has been prepared using reverse-transcription polymerase chain reaction (PCR) or quantitative PCR.
  5. 24 . The method of claim 21 , wherein the second endocrine therapy comprises a SERM, SERD, or AI.
  6. 25 . The method of claim 21 , wherein the second endocrine therapy comprises a different SERM, SERD, or AI relative to the first endocrine therapy.
  7. 26 . The method of claim 21 , wherein the first endocrine therapy comprises tamoxifen.
  8. 27 . The method of claim 21 , wherein the first endocrine therapy comprises tamoxifen and the second endocrine therapy comprises letrozole.
  9. 28 . The method of claim 21 , wherein the HR+ breast cancer comprises estrogen receptor positive (ER+) breast cancer.
  10. 29 . The method of claim 21 , wherein the HR+ breast cancer comprises node-negative breast cancer.
  11. 30 . The method of claim 21 , wherein the HR+ breast cancer comprises ductal carcinoma in situ (DCIS).
  12. 31 . A method of treating breast cancer in a subject who has undergone removal of hormone receptor positive (HR+) breast cancer and has been treated with a first endocrine therapy comprising a selective estrogen receptor modulator (SERM), a selective estrogen receptor down-regulator (SERD), or an aromatase inhibitor (AI), the method comprising: preparing or having prepared cDNA from nucleic acids in in a breast cancer sample from the subject, measuring or having measured the subject's expression levels of the HoxB13, IL17BR, Bub1B, CENPA, NEK2, RACGAP1, and RRM2 genes from the cDNA, calculating or having calculated a ratio of the subject's expression levels of HoxB13:IL17BR (“H:I ratio”), normalizing or having normalized the subject's expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2, calculating or having calculated a Molecular Grade Index (“MGI”) for the subject comprising summing the subject's normalized expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2, calculating or having calculated a breast cancer index (BCI) prognostic value for the subject by combining or having combined the subject's H:I ratio and MGI as continuous variables, building or having built a continuous risk model based on a dataset of HR+ breast cancer subjects by calculating or having calculated the dataset's BCI values, wherein the dataset's BCI values have a specified cut-off value, comparing or having compared the subject's BCI prognostic value to the cut-off value, classifying or having classified the subject as having a high risk of breast cancer recurrence if the subject's BCI prognostic value is above the cut-off value, and treating the subject classified as having a high risk of breast cancer recurrence with a second endocrine therapy.
  13. 32 . The method of claim 31 , wherein the subject's expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2 are normalized or have been normalized to the subject's expression levels of ACTB, HBMS, SDHA, and UBC.
  14. 33 . The method of claim 31 , wherein the cDNA is prepared or has been prepared using reverse-transcription polymerase chain reaction (PCR) or quantitative PCR.
  15. 34 . The method of claim 31 , wherein the second endocrine therapy comprises a SERM, SERD, or AI.
  16. 35 . The method of claim 31 , wherein the second endocrine therapy comprises a different SERM, SERD, or AI relative to the first endocrine therapy.
  17. 36 . The method of claim 31 , wherein the first endocrine therapy comprises tamoxifen.
  18. 37 . The method of claim 31 , wherein the first endocrine therapy comprises tamoxifen and the second endocrine therapy comprises letrozole.
  19. 38 . The method of claim 31 , wherein the HR+ breast cancer comprises estrogen receptor positive (ER+) breast cancer.
  20. 39 . The method of claim 31 , wherein the HR+ breast cancer comprises node-negative breast cancer.

Description

RELATED APPLICATIONS This application is a continuation of PCT Application PCT/US2011/064290, filed Dec. 9, 2011 and published as WO 2012/079059 with designation of the U.S., and which claims benefit of priority to U.S. Provisional Patent Application 61/421,627, filed Dec. 9, 2010, both of which is hereby incorporated by reference in their entireties as if fully set forth herein. This application is related to International Application No. PCT/US2008/075528, filed on Sep. 6, 2008 (published as WO 2009/108215 A1) with designation of the U.S., and to U.S. patent application Ser. No. 12/718,973, filed Mar. 6, 2010. Both applications are hereby incorporated by reference as if fully set forth herein. FIELD OF THE DISCLOSURE The disclosure relates to the identification and use of gene expression profiles, or patterns, with clinical relevance to breast cancer. In particular, the disclosure is based in part on the identities of genes that are expressed in correlation with the likelihood of cancer recurrence after initial treatment with an aromatase inhibitor or other endocrine therapy. The levels of gene expression form a molecular index that is able to predict clinical outcome, and so prognosis, for a patient after initial treatment with an aromatase inhibitor or other endocrine therapy. The gene expression profiles, whether embodied in nucleic acid expression, protein expression, or other expression formats, may be used to predict the post-treatment clinical outcome of subjects afflicted with breast cancer, predict cancer recurrence, and/or predict occurrence of metastatic cancer. The profiles may also be used in the study of a subject's prognosis. When used for prognosis, the profiles are used to determine the treatment of cancer based upon the likelihood of life expectancy, cancer recurrence, and/or cancer metastasis. BACKGROUND OF THE DISCLOSURE The treatment of breast cancer has been a field of intense interest and study. After initial diagnosis of breast cancer by analysis of a sample of breast cancer cells from a subject, treatment methods often begin with surgical removal of the tumor cells. In cases of hormone-dependent breast cancer, such as estrogen receptor positive (ER+) breast cancer, the surgery is followed by antagonizing estrogen to reduce tumor growth or re-growth. In many cases, treatment with the anti-estrogen tamoxifen is used for five years to reduce the risk of disease recurrence and so breast cancer mediated mortality. Unfortunately, data from the field indicate that more than half of all breast cancer recurrences occur after five years of treatment with adjuvant tamoxifen. Goss et al. (J. Clin. Oncol., 26 (12): 1948-1955, 2008) report results from a trial examining the use of letrozole started within 3 months after five years of adjuvant tamoxifen in subjects with primary ER+ breast cancer. The results suggested that post-tamoxifen treatment with letrozole improves breast cancer-free survival and distant breast cancer-free survival. But Goss et al. provided no means by which to predict which subjects, treated for five years with tamoxifen, would benefit from subsequent letrozole treatment. Therefore, there was no means to direct letrozole treatment only to the subjects for whom a benefit is expected. So letrozole treatment was applied to subjects for whom no benefit would have been expected, resulting in an overtreatment of the population of breast cancer-free subjects treated with for five years with tamoxifen. The citation of documents herein is not to be construed as reflecting an admission that any is relevant prior art. Moreover, their citation is not an indication of a search for relevant disclosures. All statements regarding the dates or contents of the documents is based on available information and is not an admission as to their accuracy or correctness. BRIEF SUMMARY OF THE DISCLOSURE The disclosure is based in part on the discovery and determination of gene expression levels in breast cancer tumor cells that are correlated with a beneficial switch in anti-breast cancer chemotherapy. In some cases, the switch is from one form of endocrine therapy to another. The expression levels may be used to provide prognostic information, such as cancer recurrence, and predictive information, such as responsiveness to certain therapies. In a first aspect, the disclosure includes a method to identify, or classify, a population of subjects initially treated with an anti-estrogen or anti-aromatase therapy into at least two subpopulations. A first subpopulation would be expected to benefit from a switch in therapy, such as a switch to another anti-estrogen or anti-aromatase therapy. A second subpopulation would not be expected to benefit. In some cases, the initial therapy is with tamoxifen, such as adjuvant tamoxifen therapy for a period of about five years or less. Optionally, the switch is to letrozole, or other anti-aromatase, therapy. The disclosure includes means for a population of subject