Person: Bardia, Aditya
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Bardia
First Name
Aditya
Name
Bardia, Aditya
8 results
Search Results
Now showing 1 - 8 of 8
Publication HER2 expression identifies dynamic functional states within circulating breast cancer cells(2016) Jordan, Nicole Vincent; Bardia, Aditya; Wittner, Ben; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K.; Licausi, Joseph A.; Desai, Rushil; O’Keefe, Ryan M.; Ebright, Richard; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela Lika; Iafrate, Anthony; Kapur, Ravi; Sgroi, Dennis; Ting, David; Toner, Mehmet; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, DanielCirculating tumor cells (CTCs) in women with advanced estrogen receptor-positive/HER2-negative breast cancer acquire a HER2-positive subpopulation following multiple courses of therapy1,2. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here, we analyzed CTCs from 19 ER+/HER2− patients, 84% of whom had acquired CTCs expressing HER2. Cultured CTCs maintain discrete HER2+ and HER2− subpopulations: HER2+ CTCs are more proliferative but not addicted to HER2, consistent with activation of multiple signaling pathways. HER2− CTCs show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2− CTCs interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. While HER2+ and HER2− CTCs have comparable tumor initiating potential, differential proliferation favors the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2− phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic CTC-derived tumor models. Together, these results point to distinct yet interconverting phenotypes within patient-derived CTCs, contributing to progression of breast cancer and acquisition of drug resistance.Publication AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer(BioMed Central, 2017) Kabraji, Sheheryar; Solé, Xavier; Huang, Ying; Bango, Clyde; Bowden, Michaela; Bardia, Aditya; Sgroi, Dennis; Loda, Massimo; Ramaswamy, SridharBackground: Absence of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) correlates with poor long-term survival in patients with triple negative breast cancer (TNBC). These incomplete treatment responses are likely determined by mechanisms that enable cancer cells to resist being killed. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1low quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy-resistant subpopulation initially identified in experimental cancer models. Here, we asked whether QCCs exist in primary tumors from patients with TNBC and persist after treatment with NACT. Methods: We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with NACT at Massachusetts General Hospital (n = 25). Using quantitative automated immunofluorescence microscopy, QCCs were identified as AKTlow/H3K9me2low/HES1high cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented in 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample. Results: We showed that QCCs exist as non-random and heterogeneously distributed clusters within primary breast tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors and nodal and distant metastases in patients with triple negative breast cancer. Conclusions: These first-in-human data potentially qualify AKT1low quiescent cancer cells as a non-genetic cell state that persists after neoadjuvant chemotherapy in triple negative breast cancer patients and warrants further study. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0877-7) contains supplementary material, which is available to authorized users.Publication Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer(Nature Publishing Group UK, 2018) Stover, Daniel G.; Gil Del Alcazar, Carlos R.; Brock, Jane; Guo, Hao; Overmoyer, Beth; Balko, Justin; Xu, Qiong; Bardia, Aditya; Tolaney, Sara M.; Gelman, Rebecca; Lloyd, Maxwell; Wang, Yu; Xu, Yaomin; Michor, Franziska; Wang, Vivian; Winer, Eric P.; Polyak, Kornelia; Lin, Nancy U.Preclinical data support a role for the IL-6/JAK2/STAT3 signaling pathway in breast cancer. Ruxolitinib is an orally bioavailable receptor tyrosine inhibitor targeting JAK1 and JAK2. We evaluated the safety and efficacy of ruxolitinib in patients with metastatic breast cancer. This was a non-randomized phase II study enrolling patients with refractory, metastatic triple-negative breast cancer. The primary endpoint was objective response by RECIST 1.1. The study was designed to enroll patients whose archival tumor tissue was pSTAT3-positive (T-score >5) by central immunohistochemistry. pSTAT3 staining was available from 171 of 217 consented patients and pSTAT3 T-score was positive in 67/171 (39.2%) tumors, suggesting that JAK–STAT activation is frequent. Twenty-three patients including one patient with inflammatory breast cancer were enrolled. Ruxolitinib was well-tolerated with infrequent grade 3 or higher toxicities with fatigue as the most common toxicity. Among 21 patients who received at least one dose of protocol therapy, no objective responses were observed and the study was closed to further accrual. Pharmacodynamic analyses of baseline vs. cycle 2 biopsies suggest on-target activity, including a significant decrease in the proportion of pSTAT3+ cells in three patients with paired biopsies and downregulation of JAK–STAT target genes and signatures via transcriptional analyses of 11 total baseline and four metastatic biopsies. Immuno-FISH analyses demonstrate intratumoral heterogeneity of pSTAT3 and JAK2 amplification. Ruxolitinib, as a single agent, did not meet the primary efficacy endpoint in this refractory patient population despite evidence of on-target activity.Publication Precision medicine and personalized breast cancer: combination pertuzumab therapy(Dove Medical Press, 2014) Reynolds, Kerry; Sarangi, Sasmit; Bardia, Aditya; Dizon, Don STrastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer.Publication A microfluidic device for label-free, physical capture of circulating tumor cell-clusters(2015) Sarioglu, A. Fatih; Aceto, Nicola; Kojic, Nikola; Donaldson, Maria C.; Zeinali, Mahnaz; Hamza, Bashar; Engstrom, Amanda; Zhu, Huili; Sundaresan, Tilak K.; Miyamoto, David; Luo, Xi; Bardia, Aditya; Wittner, Ben; Ramaswamy, Sridhar; Shioda, Toshi; Ting, David; Stott, Shannon; Kapur, Ravi; Maheswaran, Shyamala; Haber, Daniel; Toner, MehmetCancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Using the Cluster-Chip, we identify CTC-clusters in 30–40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis.Publication Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital(AlphaMed Press, 2016) Bardia, Aditya; Iafrate, John A.; Sundaresan, Tilak; Younger, Jerry; Nardi, ValentinaThe last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the “right drug” for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article. Key Points ER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment. ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER and mediate resistance to aromatase inhibitors. ESR1 mutations may be detected by genomic sequencing of tissue biopsies of the metastatic tumor or by sequencing the circulating tumor cells or tumor DNA (ctDNA). Sequencing results may lead to a therapeutic “match” with an existing FDA-approved drug or match with an experimental agent that fits the clinical setting.Publication Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models(Springer Science and Business Media LLC, 2018-12-31) Keklikoglou, Donna; Cianciaruso, Chiara; Guc, Esra; Squadrito, Mario Leonardo; Spring, Laura M.; Tazzyman, Simon; Lambein, Lore; Poissonnier, Amanda; Ferraro, Gino B.; Baer, Caroline; Cassara, Antonino; Guichard, Alan; Iruela-Arispe, M. Luisa; Lewis, Claire E.; Coussens, Lisa M.; Bardia, Aditya; Jain, Rakesh K.; Pollard, Jeffrey W.; De Palma, MicheleCytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest pro-metastatic effects of chemotherapy. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin-A6 (ANXA6), Ca2+-dependent protein that promotes NF-kB-dependent endothelial cell activation, Ccl2 induction, and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells, or Ccr2 in host cells, blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially nriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy.Publication Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin‐Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations(AlphaMed Press, 2017) Spring, Laura; Zangardi, Mark L.; Moy, Beverly; Bardia, AdityaAbstract Aberrations of the cell cycle are pervasive in cancer, and selective cell cycle inhibition of cancer cells is a target of choice for a number of novel cancer therapeutics. Cyclin‐dependent kinases (CDKs) are key regulatory enzymes that control cell cycle transitions and the commitment to cell division. Palbociclib and ribociclib are both orally active, highly selective reversible inhibitors of CDK4 and CDK6 that are approved by the U.S. Food and Drug Administration (FDA) for hormone receptor‐positive metastatic breast cancer in combination with specific endocrine therapies. A third oral CDK4/6 inhibitor, abemaciclib, received Breakthrough Therapy designation status from the FDA and is also being developed in breast cancer. The most common adverse events associated with palbociclib and ribociclib are hematologic, particularly neutropenia. However, the neutropenia associated with CDK4/6 inhibitors is distinct from chemotherapy‐induced neutropenia in that it is rapidly reversible, reflecting a cytostatic effect on neutrophil precursors in the bone marrow. Most hematologic abnormalities seen with CDK4/6 inhibitors are not complicated and are adequately managed with standard supportive care and dose adjustments when indicated. Cytopenias are less prevalent with abemaciclib, although fatigue and gastrointestinal toxicity is more common with this agent. This review focuses on the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer, with a focus on palbociclib and ribociclib, and summarizes practical management strategies for an oncologist. Implications for Practice. The emergence of modern cyclin‐dependent kinase (CDK) inhibitors has changed the treatment paradigm for metastatic hormone receptor (HR)‐positive breast cancer. Palbociclib, ribociclib, and abemaciclib are highly selective reversible inhibitors of CDK4 and CDK6. Palbociclib is U.S. Food and Drug Administration (FDA)‐approved in the first‐ and second‐line settings in combination with endocrine therapy for HR‐positive metastatic breast cancer. Ribociclib is FDA‐approved in the first‐line setting. Abemaciclib has received FDA Breakthrough Therapy designation status. This review focuses on the clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors in breast cancer.