RNA Disruption Assay (RDA)-Breast Cancer Response Evaluation for Individualized Therapy (BREVITY)

RNA Disruption Assay (RDA)-Breast Cancer Response Evaluation for Individualized Therapy (BREVITY / BREVITY-02 in Germany)

The current study aims to provide validation results of RNA Disruption Assay (RDA) as a tumour response assessment tool that uses tumour core biopsies taken starting from 35 +/- 4 days after the initiation of neoadjuvant chemotherapy.

Study Rationale: There is some evidence that identifying non-responders early in neoadjuvant treatment and offering alternative agents (response-guided therapy) increased pathological complete response (pCR) rates and/or survival resulting in improved care and incremental cost effectiveness. Differentiating non-responders to chemotherapy from responders with reliable guidance tools early during therapy is crucial to the success of response-guided therapy. The current study aims to provide validation results of RDA as a tumour response assessment tool that uses tumour core biopsies starting from 35 +/- 4 days after the initiation of neoadjuvant chemotherapy. Study Objectives and Endpoints: The primary objective of the study is to determine the 2 RDI cut-offs to have a diagnostic test optimized in terms of both negative and positive predictive values NPV and PPV (in a training set of patients i.e. phase 1 of the study) for predicting nopCR/pCR and to establish the performance characteristics for the first cut-off (test result "zone 1") in terms of NPV as primary endpoint (in a validation set i.e. phase 2). The secondary objective is to assess the test's NPV in the different cancer subtypes and the test's PPV in Her2+ patients; also to assess and compare pCR prevalence, residual cancer burden (RCB class at surgery) and DFS (secondary endpoints) in zones 1-3 for all patients and each cancer subtype. Patient Population: The study aims to enrol approximately 594 patients in centres in the US, Canada, Italy, Germany, Spain and France. The population consists of patients diagnosed with invasive breast cancer and scheduled to receive neoadjuvant chemotherapy as part of standard of care treatment. Throughout the study, patients will receive standard of care neoadjuvant chemotherapy treatments including taxanes, anthracyclines or other targeted drugs and drug combinations as prescribed based on the investigators' / clinicians' choice. Adjuvant therapies (e.g. radiotherapy, hormonal treatment … etc.) may be prescribed to patients according to standard of care and independently of the RDI score results. RDA is presently in an experimental stage and clinicians will not receive or use the RDA results in this study. Biopsy Collection: 1st core needle biopsy for RDA (2 specimens): Time Point: 35 +/- days after initiation of neoadjuvant chemotherapy; 2nd core needle biopsy for RDA (2 specimens): Time Point: if therapy is changed (as part of SoC), a second biopsy ~2-3 weeks after initiation of new drugs; Timing by type of drug schedule 3-weekly: at 16 days +/- 2 days, Bi-weekly: at day of 2nd dose preferably before drug admin., Weekly: at day of 4th dose preferably before drug admin. If Therapy is not changed (as part of SoC), a second biopsy is taken at 55 +/- 5 days after the first initiation of neoadjuvant therapy. Statistical Plan: The study consists of a training set / phase 1 (80 fully evaluable patients) to determine response zone cut-offs using pCR outcomes and RDA's predictive values, and a validation set / phase 2 (454 fully evaluable patients) to validate the performance characteristics of the RDA test. The study aims to enrol 594 patients in order to achieve an accrual of 534 fully evaluable patients which is the number required to adequately statistically power the trial. Combined statistical analysis and various subgroup analyses will be performed for the primary and secondary objectives. Duration and Follow-up: There will be an 18 months of active patient accrual (or until last patient is accrued) in addition to 60 months of patient follow-up.

There will be 2 biopsy collection time points with 2 core needle biopsy specimens taken at each biopsy collection time point for RDA analysis during neoadjuvant chemotherapy.

1st core needle biopsy for RDA (2 specimens): Time Point: 35 +/-4 days after initiation of chemotherapy. If no change is made to the therapy, a second biopsy (2 specimens) will be performed at 55 +/- 5 days after therapy initiation. If there is a change of drugs, the second biopsy (2 specimens) will be performed at ~2-3 weeks after initiation of new drugs; Timing by type of drug schedule 3-weekly: at 16 days +/- 2 days, Bi-weekly: at day of 2nd dose preferably before drug admin., Weekly: at day of 4th dose preferably before drug admin.

Inclusion Criteria Women aged at least 18 years; Patients must be able to provide informed consent and sign the informed consent form to participate in the RDA study before any study procedures starts; Newly diagnosed clinical stage I, II or III breast cancer with complete surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal; Tumour size at least 1 cm in one dimension by clinical or radiographic exam (WHO criteria); Must have histological confirmation of invasive breast cancer of any subtype or grade; Patient is scheduled for neoadjuvant chemotherapy +/- antibodies and +/- other drugs according to Standard of Care; Patient willing to have 2 research core needle biopsies (for RDA) taken at 2 collection timepoints during neoadjuvant chemotherapy treatment. Exclusion Criteria Patient who has had prior local (i.e. surgery or radiotherapy) or systemic (i.e. endocrine or cytotoxic) therapy for the current breast cancer; Participation in another interventional clinical trial with concurrent treatment with experimental drugs to treat the current breast cancer during the period of neoadjuvant therapy (from diagnosis until surgery); Stage IV breast cancer; Bilateral or multicentric breast tumour; Prior malignant disease except curatively treated in-situ maligancies; Concurrent pregnancy; Breast feeding woman; Concurrent medical, psychiatric or addictive disorders that may limit the ability to give informed consent or complete the trial; Reasons indicating risk of poor compliance with study procedures; Patient not able to consent;

Parissenti AM, Guo B, Pritzker LB, Pritzker KP, Wang X, Zhu M, Shepherd LE, Trudeau ME. Tumor RNA disruption predicts survival benefit from breast cancer chemotherapy. Breast Cancer Res Treat. 2015 Aug;153(1):135-44. doi: 10.1007/s10549-015-3498-9. Epub 2015 Jul 25.

Narendrula R, Mispel-Beyer K, Guo B, Parissenti AM, Pritzker LB, Pritzker K, Masilamani T, Wang X, Lanner C. RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines. BMC Cancer. 2016 Feb 24;16:146. doi: 10.1186/s12885-016-2197-1.

Toomey S, Eustace AJ, Pritzker LB, Pritzker KP, Fay J, O'Grady A, Cummins R, Grogan L, Kennedy J, O'Connor D, Young L, Kay EW, O'Donovan N, Gallagher WM, Kalachand R, Crown J, Hennessy BT. RE: RNA Disruption Assay as a Biomarker of Pathological Complete Response in Neoadjuvant Trastuzumab-Treated Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. J Natl Cancer Inst. 2016 Jul 4;108(8):djw111. doi: 10.1093/jnci/djw111. Print 2016 Aug. No abstract available.

Pritzker K, Pritzker L, Generali D, Bottini A, Cappelletti MR, Guo B, Parissenti A, Trudeau M. RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy. J Natl Cancer Inst Monogr. 2015 May;2015(51):76-80. doi: 10.1093/jncimonographs/lgv015.

von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, Gerber B, Hanusch C, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Kummel S, Paepke S, Schneeweiss A, Untch M, Zahm DM, Mehta K, Loibl S. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013 Oct 10;31(29):3623-30. doi: 10.1200/JCO.2012.45.0940. Epub 2013 Sep 3.

Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014 Jul 12;384(9938):164-72. doi: 10.1016/S0140-6736(13)62422-8. Epub 2014 Feb 14. Erratum In: Lancet. 2019 Mar 9;393(10175):986.