Publications by authors named "Saima Hassan"

14 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.
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http://dx.doi.org/10.1038/s41598-020-71236-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477566PMC
September 2020

Translating the role of PARP inhibitors in triple-negative breast cancer.

Oncoscience 2019 Jan 31;6(1-2):287-288. Epub 2019 Jan 31.

Division of Surgical Oncology, Department of Surgery, Centre Hospitalier de l'Université de Montréal (CHUM); Université de Montréal; Institut du cancer de Montréal and Centre de Recherche du CHUM (CRCHUM), Montreal, Quebec, Canada.

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http://dx.doi.org/10.18632/oncoscience.474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382255PMC
January 2019

Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer.

Mol Cancer Ther 2017 Dec 27;16(12):2892-2901. Epub 2017 Sep 27.

Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, Oregon.

Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose-response measures of cell viability, an EC value was calculated for each cellular phenotype and each PARP inhibitor. The EC values for both 53BP1 metrics strongly correlated with IC values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle-associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765867PMC
December 2017

Cross-linguistic patterns in the acquisition of quantifiers.

Proc Natl Acad Sci U S A 2016 08 1;113(33):9244-9. Epub 2016 Aug 1.

Laboratoire sur le Langage, le Cerveau, et la Cognition, CNRS-Université de Lyon, 69675 Bron Cedex, France;

Learners of most languages are faced with the task of acquiring words to talk about number and quantity. Much is known about the order of acquisition of number words as well as the cognitive and perceptual systems and cultural practices that shape it. Substantially less is known about the acquisition of quantifiers. Here, we consider the extent to which systems and practices that support number word acquisition can be applied to quantifier acquisition and conclude that the two domains are largely distinct in this respect. Consequently, we hypothesize that the acquisition of quantifiers is constrained by a set of factors related to each quantifier's specific meaning. We investigate competence with the expressions for "all," "none," "some," "some…not," and "most" in 31 languages, representing 11 language types, by testing 768 5-y-old children and 536 adults. We found a cross-linguistically similar order of acquisition of quantifiers, explicable in terms of four factors relating to their meaning and use. In addition, exploratory analyses reveal that language- and learner-specific factors, such as negative concord and gender, are significant predictors of variation.
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http://dx.doi.org/10.1073/pnas.1601341113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995931PMC
August 2016

The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers.

Cancer Res 2015 Oct 21;75(20):4351-63. Epub 2015 Aug 21.

Department of Surgery and Oncology, McGill University, Montréal, Québec, Canada. Department of Oncology and Surgery, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.

The treatment of breast cancer has benefitted tremendously from the generation of estrogen receptor-α (ERα)-targeted therapies, but disease relapse continues to pose a challenge due to intrinsic or acquired drug resistance. In an effort to delineate potential predictive biomarkers of therapy responsiveness, multiple groups have identified several uncharacterized cofactors and interacting partners of ERα, including Split Ends (SPEN), a transcriptional corepressor. Here, we demonstrate a role for SPEN in ERα-expressing breast cancers. SPEN nonsense mutations were detectable in the ERα-expressing breast cancer cell line T47D and corresponded to undetectable protein levels. Further analysis of 101 primary breast tumors revealed that 23% displayed loss of heterozygosity at the SPEN locus and that 3% to 4% harbored somatically acquired mutations. A combination of in vitro and in vivo functional assays with microarray-based pathway analyses showed that SPEN functions as a tumor suppressor to regulate cell proliferation, tumor growth, and survival. We also found that SPEN binds ERα in a ligand-independent manner and negatively regulates the transcription of ERα targets. Moreover, we demonstrate that SPEN overexpression sensitizes hormone receptor-positive breast cancer cells to the apoptotic effects of tamoxifen, but has no effect on responsiveness to fulvestrant. Consistent with these findings, two independent datasets revealed that high SPEN protein and RNA expression in ERα-positive breast tumors predicted favorable outcome in patients treated with tamoxifen alone. Together, our data suggest that SPEN is a novel tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ERα-positive breast cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3475DOI Listing
October 2015

Erratum to: Pathologic Complete Response to Intralesional Interleukin-2 Therapy Associated with Improved Survival in Melanoma Patients with In-Transit Disease.

Ann Surg Oncol 2015 Dec;22 Suppl 3:S1603

Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, ON, Canada.

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http://dx.doi.org/10.1245/s10434-014-4303-4DOI Listing
December 2015

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease.

Ann Surg Oncol 2015 1;22(6):1950-8. Epub 2014 Nov 1.

Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, ON, Canada.

Purpose: Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies. The aim of this study was to validate the role of intralesional interleukin (IL)-2, to understand its mechanism of action, and to better understand factors that may influence its response.

Methods: We retrospectively collected the clinicopathological data of 31 consecutive patients who presented to a tertiary care cancer center for treatment of in-transit melanoma with intralesional IL-2. Kaplan-Meier survival curves and multivariable Cox regression analysis were performed. Immunohistochemistry (IHC) was used to better understand the immune response to localized IL-2 therapy. Targeted next-generation sequencing was performed to genomically characterize the tumors.

Results: Ten patients (10/31, 32 %) achieved a pathologic complete response (pCR), 17/21 (55 %) had a partial response, and 4/21 (19 %) had progressive disease on treatment. pCR to IL-2 therapy was associated with overall survival (log-rank p = 0.004) and improved progression-free survival (PFS) [adjusted hazard ratio (HR) 0.11; 95 % CI 0.02-0.47; p = 0.003). A higher CD8+ T cell infiltrate was identified in in-transit lesions with a pCR compared with the other lesions (mean IHC score 3.78 vs. 2.61; p = 0.01). Patients with an elevated CD8+ infiltrate demonstrated an improved PFS (unadjusted HR 0.08; 95 % CI 0.01-0.52; p = 0.008).

Conclusions: Thirty-two percent of patients achieved pCR with intralesional IL-2 therapy and had a significantly improved PFS compared with the rest of the cohort, which may be explained by a systemic CD8+ T-cell response.
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http://dx.doi.org/10.1245/s10434-014-4199-zDOI Listing
February 2016

Endoplasmic reticulum stress induces PRNP prion protein gene expression in breast cancer.

Breast Cancer Res 2013 Mar 12;15(2):R22. Epub 2013 Mar 12.

Introduction: High prion protein (PrP) levels are associated with breast, colon and gastric cancer resistance to treatment and with a poor prognosis for the patients. However, little is known about the underlying molecular mechanism(s) regulating human PrP gene (PRNP) expression in cancers. Because endoplasmic reticulum (ER) stress is associated with solid tumors, we investigated a possible regulation of PRNP gene expression by ER stress.

Methods: Published microarray databases of breast cancer tissues and breast carcinoma cell lines were analyzed for PrP mRNA and ER stress marker immunoglobulin heavy chain binding protein (BiP) levels. Breast cancer tissue microarrays (TMA) were immunostained for BiP and PrP. Breast carcinoma MCF-7, MDA-MB-231, HS578T and HCC1500 cells were treated with three different ER stressors - Brefeldin A, Tunicamycin, Thapsigargin - and levels of PrP mRNA or protein assessed by RT-PCR and Western blot analyses. A human PRNP promoter-luciferase reporter was used to assess transcriptional activation by ER stressors. Site-directed mutagenesis identified the ER stress response elements (ERSE). Chromatin immunoprecipitation (ChIP) analyses were done to identify the ER stress-mediated transcriptional regulators. The role of cleaved activating transcription factor 6α (ΔATF6α) and spliced X-box protein-1 (sXBP1) in PRNP gene expression was assessed with over-expression or silencing techniques. The role of PrP protection against ER stress was assessed with PrP siRNA and by using Prnp null cell lines.

Results: We find that mRNA levels of BiP correlated with PrP transcript levels in breast cancer tissues and breast carcinoma cell lines. PrP mRNA levels were enriched in the basal subtype and were associated with poor prognosis in breast cancer patients. Higher PrP and BiP levels correlated with increasing tumor grade in TMA. ER stress was a positive regulator of PRNP gene transcription in MCF-7 cells and luciferase reporter assays identified one ER stress response element (ERSE) conserved among primates and rodents and three primate-specific ERSEs that regulated PRNP gene expression. Among the various transactivators of the ER stress-regulated unfolded protein response (UPR), ATF6α and XBP1 transactivated PRNP gene expression, but the ability of these varied in different cell types. Functionally, PrP delayed ER stress-induced cell death.

Conclusions: These results establish PRNP as a novel ER stress-regulated gene that could increase survival in breast cancers.
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http://dx.doi.org/10.1186/bcr3398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672785PMC
March 2013

CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model.

Int J Cancer 2011 Jul 12;129(1):225-32. Epub 2010 Nov 12.

Department of Oncology, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Canada.

CXCR4 is a chemokine receptor implicated in the homing of cancer cells to target metastatic organs, which overexpress its ligand, stromal cell-derived factor (SDF)-1. To determine the efficacy of targeting CXCR4 on primary tumor growth and metastasis, we used a peptide inhibitor of CXCR4, CTCE-9908, that was administered in a clinically relevant approach using a transgenic breast cancer mouse model. We first performed a dosing experiment of CTCE-9908 in the PyMT mouse model, testing 25, 50 and 100 mg/kg versus the scrambled peptide in groups of 8-16 mice. We then combined CTCE-9908 with docetaxel or DC101 (an anti-VEGFR2 monoclonal antibody). We found that increasing doses of CTCE-9908 alone slowed the rate of tumor growth, with a 45% inhibition of primary tumor growth at 3.5 weeks of treatment with 50 mg/kg of CTCE-9908 (p = 0.005). Expression levels of VEGF were also found to be reduced by 42% with CTCE-9908 (p = 0.01). In combination with docetaxel, CTCE-9908 administration decreased tumor volume by 38% (p = 0.02), an effect that was greater than that observed with docetaxel alone. In combination with DC101, CTCE-9908 also demonstrated an enhanced effect compared to DC101 alone, with a 37% decrease in primary tumor volume (p = 0.01) and a 75% reduction in distant metastasis (p = 0.009). In combination with docetaxel or an anti-angiogenic agent, the anti-tumor and anti-metastatic effects of CTCE-9908 were markedly enhanced, suggesting potentially new effective combinatorial therapeutic strategies in the treatment of breast cancer, which include targeting the SDF-1/CXCR4 ligand/receptor pair.
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http://dx.doi.org/10.1002/ijc.25665DOI Listing
July 2011

The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer.

Am J Pathol 2009 Jul 4;175(1):66-73. Epub 2009 Jun 4.

Department of Oncology, Lady Davis Institute, Sir Mortimer B Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.

The chemokine stromal cell-derived factor-1 (SDF-1) may function to attract CXCR4-expressing cancer cells to metastatic organs. We have previously demonstrated that low plasma SDF-1, a host-derived marker, increases distant metastatic risk in breast cancer. We therefore hypothesized that tumors overexpressing the SDF-1 receptor CXCR4 have an enhanced ability to metastasize in patients with low plasma SDF-1 levels. In this study, we determined the prognostic significance of activated CXCR4, or phosphorylated CXCR4 (p-CXCR4), and CXCR7, another receptor for SDF-1. Immunohistochemistry was performed on a tissue microarray built using 237 samples from the same cohort of patients for which we measured plasma SDF-1 levels. We found that the prognostic value of p-CXCR4 expression (hazard ratio or HR, 3.95; P = 0.004) was superior to total CXCR4 expression (HR, 3.20; P = 0.03). The rate of breast cancer-specific mortality was much higher in patients with both high p-CXCR4 expression and low plasma SDF-1 levels (HR, 5.96; P < 0.001) than either low plasma SDF-1 (HR, 3.59; P = 0.01) or high p-CXCR4 expression (HR, 3.83; P = 0.005) alone. The added prognostic value of low plasma SDF-1 was only effective in patients with high p-CXCR4 expression, and as such, provides clinical validation for modulation of the metastatic potential of tumor cells by an inherent host-derived metastatic risk factor.
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http://dx.doi.org/10.2353/ajpath.2009.080948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708795PMC
July 2009

Both t-Darpp and DARPP-32 can cause resistance to trastuzumab in breast cancer cells and are frequently expressed in primary breast cancers.

Breast Cancer Res Treat 2010 Feb 20;120(1):47-57. Epub 2009 Mar 20.

Department of Oncology and Surgery, Segal Cancer Center, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste Catherine, Montreal, QC, H3T 1E2, Canada.

The clinical use of trastuzumab (Herceptin), a humanized antibody against the HER2 growth factor receptor, has improved survival in patients with breast tumors with ERBB2 amplification and/or over-expression. However, most patients with advanced ERBB2 amplified breast cancers whose tumors initially respond to trastuzumab develop resistance to the drug, leading to tumor progression. To identify factors responsible for acquired resistance to trastuzumab, gene expression profiling was performed on subclones of an ERBB2 amplified breast cancer cell line, BT474, which had acquired resistance to trastuzumab. The most overexpressed gene in these subclones was PPP1R1B, encoding the DARPP-32 phosphatase inhibitor. Western analysis revealed that only the truncated isoform of the DARPP-32 protein, t-Darpp, was overexpressed in the trastuzumab resistant cells. Using gene silencing experiments, we confirmed that t-Darpp over-expression was required for trastuzumab resistance in these cells. Furthermore, transfecting t-Darpp in parental BT-474 cells conferred resistance to trastuzumab, suggesting that t-Darpp expression was sufficient for trastuzumab resistance. We also found that t-Darpp over-expression was associated with Akt activation and that the T75 residue in t-Darpp was required for both Akt activation and trastuzumab resistance. Finally, we found that full-length DARPP-32 and t-Darpp are expressed in a majority of primary breast tumors. Over-expression of full-length DARPP-32 can also confer resistance to trastuzumab and, moreover, is associated with a poor prognostic value in breast cancers. Thus, t-Darpp and DARPP-32 expression are novel prognostic and predictive biomarkers in breast cancer.
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http://dx.doi.org/10.1007/s10549-009-0364-7DOI Listing
February 2010

Plasma stromal cell-derived factor-1: host derived marker predictive of distant metastasis in breast cancer.

Clin Cancer Res 2008 Jan;14(2):446-54

Department of Oncology and Surgery, Lady Davis Institute, Sir Mortimer B Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

Purpose: Homing of breast cancer cells to metastatic sites may be regulated by the production of stromal cell-derived factor (SDF)-1 by specific target organs, which attracts CXCR4-expressing breast cancer cells. We investigated the value of SDF-1 as a predictive blood marker of distant metastasis in breast cancer, together with a common polymorphism of SDF-1, SDF-1-3'A.

Experimental Design: Plasma samples were collected prospectively for 270 consecutive primary breast cancer patients with a median follow-up of 3.3 years. Plasma SDF-1 levels were measured using an ELISA, and the polymorphism was identified via PCR-RFLP analysis.

Results: Plasma SDF-1 levels were divided into two groups, low and high, based on the median SDF-1 value of 2,661 pg/mL. Patients with low SDF-1 showed an increased risk of developing distant metastasis (relative risk, 1.94; P = 0.02) and poorer breast cancer-specific survival [adjusted hazard ratio (AHR), 3.92; P = 0.007]. Patients with both low plasma SDF-1 levels and the SDF-1-3'A polymorphism showed a poorer breast cancer-specific survival (AHR, 3.98; P = 0.001) and distant disease-free survival (AHR, 2.88; P = 0.003). In a separate cohort of 22 breast cancer patients, we found no significant difference in SDF-1 levels before and posttumor resection.

Conclusion: We found that low plasma SDF-1 is an independent host-derived predictive marker of distant metastasis in breast cancer. The prognostic value of the combination of a low plasma SDF-1 level and the SDF-1-3'A polymorphism identifies a cohort of patients with an intrinsic susceptibility for poorer survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-1189DOI Listing
January 2008

Tissue microarrays: emerging standard for biomarker validation.

Curr Opin Biotechnol 2008 Feb 3;19(1):19-25. Epub 2007 Dec 3.

Departments of Oncology and Surgery, Segal Cancer Center, 3755 Cote Ste Catherine Road, Montreal, Quebec, Canada H3T 1E2.

With the widespread use of DNA microarrays, hundreds of biomarkers are in need of validation in cohorts of well-annotated clinical samples. Tissue microarrays are emerging as the tool par excellence to rapidly perform DNA, RNA, and especially protein expression analyses on large numbers of clinical samples. Although still somewhat limited by the subjectivity of scoring methods and tissue sample representativeness, TMAs represent an increasingly validated means of understanding the clinical impact of diagnostic-related, prognostic-related, and therapy-related markers. Automated methods are being developed for TMA analysis and cell microarrays and frozen tissue TMAs have been better optimized. More and more biomarker studies are availing themselves of the high-throughput nature of TMAs, recognizing that they are becoming indispensable for rapid translation of laboratory data to the clinic.
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http://dx.doi.org/10.1016/j.copbio.2007.10.009DOI Listing
February 2008

Microarrays as validation strategies in clinical samples: tissue and protein microarrays.

OMICS 2006 ;10(3):311-26

Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis-Jewish General Hospital, and Department of Oncology, McGill University and Surgery, Montreal, Canada.

The widespread use of DNA microarrays has led to the discovery of many genes whose expression profile may have significant clinical relevance. The translation of this data to the bedside requires that gene expression be validated as protein expression, and that annotated clinical samples be available for correlative and quantitative studies to assess clinical context and usefulness of putative biomarkers. We review two microarray platforms developed to facilitate the clinical validation of candidate biomarkers: tissue microarrays and reverse-phase protein microarrays. Tissue microarrays are arrays of core biopsies obtained from paraffin-embedded tissues, which can be assayed for histologically-specific protein expression by immunohistochemistry. Reverse-phase protein microarrays consist of arrays of cell lysates or, more recently, plasma or serum samples, which can be assayed for protein quantity and for the presence of post-translational modifications such as phosphorylation. Although these platforms are limited by the availability of validated antibodies, both enable the preservation of precious clinical samples as well as experimental standardization in a high-throughput manner proper to microarray technologies. While tissue microarrays are rapidly becoming a mainstay of translational research, reverse-phase protein microarrays require further technical refinements and validation prior to their widespread adoption by research laboratories.
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http://dx.doi.org/10.1089/omi.2006.10.311DOI Listing
December 2006