Publications by authors named "Josée-Anne Roy"

4 Publications

  • Page 1 of 1

Prognostic and predictive value of circulating tumor DNA during neoadjuvant chemotherapy for triple negative breast cancer.

Sci Rep 2020 09 7;10(1):14704. Epub 2020 Sep 7.

Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.

Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08-0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075-0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71236-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477566PMC
September 2020

A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability.

Mol Cancer Res 2019 12 19;17(12):2492-2507. Epub 2019 Sep 19.

Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.

The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer. IMPLICATIONS: These findings underlie the importance of a novel morphologic-metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-19-0264DOI Listing
December 2019

The identification of challenges in tissue collection for biomarker studies: the Q-CROC-03 neoadjuvant breast cancer translational trial experience.

Mod Pathol 2017 11 28;30(11):1567-1576. Epub 2017 Jul 28.

Department of Oncology, Lady Davis Institute, McGill University, Montreal, QC, Canada.

One of the major challenges in biomarker development is the collection of tumor tissue of adequate quality for analysis. A prospective clinical trial was initiated to collect tissues from triple negative breast cancers prior to and after neoadjuvant chemotherapy in order to study the mechanisms of chemoresistance. Sixty patients had pre-chemotherapy biopsies performed by either a surgeon or a radiologist, while those with residual tumor after chemotherapy had research-only biopsies and/or surgical samples collected in liquid nitrogen, RNA-later and formalin. We examined each core for tumor cellularity, stromal content, and necrosis after which, RNA and DNA extraction was performed. We found that biopsies collected with ultrasound guidance were more likely to contain tumor than those collected by the surgeon. Patient reluctance to undergo research-only biopsies after chemotherapy was not a problem. Pre-chemotherapy tumor biopsies frequently did not contain any tumor cells (15%) or did not have ≥50% tumor content (63%). Indeed, 50% of patients had at least 2 pre-chemotherapy core biopsies with <50% tumor content. After chemotherapy, 30% of biopsy or surgical samples in patients with incomplete response did not contain any tumor. Finally, RNA-later not only made histopathological assessment of tumor content difficult, but yielded less DNA than fresh snap frozen samples. We recommend that high-quality tissue procurement can be best accomplished if at least three image-guided core biopsies be obtained per sample, each of these cores be examined for tumor cellularity and that at least some of them be freshly snap frozen in liquid nitrogen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2017.82DOI Listing
November 2017

Quality of life in ovarian cancer patients: comparison of paclitaxel plus cisplatin, with cyclophosphamide plus cisplatin in a randomized study.

J Clin Oncol 2004 Nov 4;22(22):4595-603. Epub 2004 Oct 4.

University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.

Purpose: Formal quality-of-life (QOL) assessments may contribute important information on patient symptoms. Despite many trials of systemic chemotherapy in ovarian cancer, reports of its effect on QOL are few.

Patients And Methods: QOL was assessed in an Intergroup randomized trial comparing paclitaxel plus cisplatin to cyclophosphamide plus cisplatin in women with advanced ovarian cancer. One hundred fifty-two eligible patients accrued in Canada completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a trial-specific checklist at baseline (after surgical debulking) and at regular intervals during and after chemotherapy. Mean change scores over time in the two arms were calculated.

Results: Compliance with QOL questionnaire completion was excellent (81% to 93%). In general, deterioration was seen in the QOL domains immediately after chemotherapy (day 8 of cycle 1), followed by clinically meaningful improvements compared with baseline (change scores > or = 10) in both arms during the treatment period in a number of domains and items, including global QOL, emotional function, social function, fatigue, pain, sleep, constipation, appetite, abdominal swelling, and abdominal cramps. Improvements in global QOL persisted for the duration of follow-up. More neurosensory effects and myalgia were documented in the paclitaxel arm; however, this did not adversely affect global or other domains of QOL and improved once chemotherapy was completed.

Conclusion: Improvement from baseline in QOL measures was seen in both treatment arms. The greater neurologic and muscle toxicity of paclitaxel did not adversely influence QOL. QOL data can contribute useful information on the experience of symptoms and their time course, which may assist patients and physicians in their discussion about the anticipated effects of therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2004.08.080DOI Listing
November 2004