Kenneth Pritzker1, Laura Pritzker2, Daniele Generali2, Alberto Bottini2, Maria Rosa Cappelletti2, Baoqing Guo2, Amadeo Parissenti2, Maureen Trudeau2. 1. Rna Diagnostics Inc, Toronto, ON, Canada (KP, LP, AP); Department of Laboratory Medicine and Pathobiology and Department of Surgery, University of Toronto, Toronto, ON, Canada (KP, MT); Unita di Patologia Mammaria, Breasteast Unit, Azienda Ospedaliera Istituti Ospitaieri di Cremona, Cremona, Italy (DG, AB, MRC); Advanced Medical Research Institute of Canada, Sudbury, ON, Canada (BG, AP); Laurentian University, Sudbury ON, Canada (AP); Odette Cancer Centre, Sunnybrook Hospital, Toronto, ON, Canada (MT). kpritzker@rnadiagnostics.com. 2. Rna Diagnostics Inc, Toronto, ON, Canada (KP, LP, AP); Department of Laboratory Medicine and Pathobiology and Department of Surgery, University of Toronto, Toronto, ON, Canada (KP, MT); Unita di Patologia Mammaria, Breasteast Unit, Azienda Ospedaliera Istituti Ospitaieri di Cremona, Cremona, Italy (DG, AB, MRC); Advanced Medical Research Institute of Canada, Sudbury, ON, Canada (BG, AP); Laurentian University, Sudbury ON, Canada (AP); Odette Cancer Centre, Sunnybrook Hospital, Toronto, ON, Canada (MT).
Abstract
BACKGROUND: As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. METHODS: RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. RESULTS: In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an intermediate zone, and 38 patients in Zone 3, pCR responders and non-pCR patients who share RDI comparable to those achieving pCR. In the early response studies, after 14 days exposure to chemotherapy, some RNA disruption as measured by RDI elevation could be detected in 3/12 trastuzumab, 7/15 zoledronic acid, 5/29 letrozole + cyclophosphamide, and 5/23 letrozole + cyclophosphamide + sorafenib patients. CONCLUSIONS: RDA is a novel intermediate endpoint that has promise for clinical utility for breast cancers early in response-guided primary systemic therapy.
BACKGROUND: As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancerpatients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. METHODS: RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. RESULTS: In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an intermediate zone, and 38 patients in Zone 3, pCR responders and non-pCR patients who share RDI comparable to those achieving pCR. In the early response studies, after 14 days exposure to chemotherapy, some RNA disruption as measured by RDI elevation could be detected in 3/12 trastuzumab, 7/15 zoledronic acid, 5/29 letrozole + cyclophosphamide, and 5/23 letrozole + cyclophosphamide + sorafenibpatients. CONCLUSIONS: RDA is a novel intermediate endpoint that has promise for clinical utility for breast cancers early in response-guided primary systemic therapy.
Authors: Sinead Toomey; Alex J Eustace; Laura B Pritzker; Ken P H Pritzker; Joanna Fay; Anthony O'Grady; Robert Cummins; Liam Grogan; John Kennedy; Darran O'Connor; Leonie Young; Elaine W Kay; Norma O'Donovan; William M Gallagher; Roshni Kalachand; John Crown; Bryan T Hennessy Journal: J Natl Cancer Inst Date: 2016-07-04 Impact factor: 13.506