Summary:The majority of poor-risk lymphoma patients are not cured with conventional chemotherapy. There is evidence for the superiority of single high-dose chemotherapy in such patients, but many still die from recurrent disease. Strategies to improve survival in these poor-risk patients include dose-intensification with high-dose chemotherapy and PBPC support, tandem autologous HDC with PBPC support, and autologous followed by non-myeloablative allogeneic transplantation. These more aggressive strategies are feasible and tolerable. Whether tandem transplantation will prove more effective than current single high-dose therapy in appropriately selected patients remains to be determined. Bone Marrow Transplantation (2001) 28, 529-535. Keywords: tandem transplantation; lymphoma; autologous; allogeneicThe majority of patients with lymphoma achieve remission with standard therapy. A small percentage of patients are refractory to initial therapy, and approximately one-third of patients with stage III-IV disease will relapse after achieving a complete response. Treatment of minimally responsive or refractory lymphoma patients remains a challenge. Single transplantation and the poor prognosis patientProspective randomized trials show single HDC with autologous transplantation to be superior to standard-dose chemotherapy for relapsed and resistant Hodgkin's disease, 1 for consolidative therapy of poor-risk B cell NHL in first remission 2 and for relapsed chemo-sensitive intermediate or high-grade NHL. 3 An update of the PARMA study reports an 8-year EFS of 36% and OS of 47% for these latter patients. 4 Fewer than 5% of patients with poor-risk NHL or HD who have induction failure and receive conventional salvage chemotherapy are alive at 5 years. NHL patients with induction failure who undergo HDC and autotransplantation have an overall survival at 5 years of 37%. 5 Data from the ABMTR show HD patients with induction Correspondence: DR CS Hesdorffer, Division of Medical Oncology, MHB 6N 435, 177 Ft. Washington Avenue, New York, NY 10032, USA failure who subsequently undergo HDC have progressionfree and overall survivals at 3 years of 38% and 50%, respectively. 6 Data by Sweetenham et al 7 from the EBMT are similar, reporting an actuarial 5-year OS rate of 36% and PFS rate of 32%.Allogeneic transplantation alone does not appear to offer a survival advantage over autologous transplant for lymphoma. 8,9 Studies suggest a graft-versus-lymphoma effect, but this has not translated into increased survival due to the high treatment-related mortality associated with allogeneic transplantation. Further prospective trials, randomized on the basis of HLA-identical donor availability, may provide more reliable data on this issue. 10 While salvage rates of 45-60% are achieved with HDC in patients with relapsed NHL and HD with good prognostic factors, adverse prognostic factors, such as relapse within 1 year of initial treatment, stage III/IV relapse or chemoresistance, portend a poorer outcome, with likely cure in less than 40%. The IP...
The estrogen receptor (ER or ESR1) drives proliferation and growth of luminal type breast cancers. Endocrine therapies are highly effective in a majority of these cancers types; however, disease progression eventually occurs due to acquired resistance resulting in hormone-independent breast cancer. One mechanism of resistance is acquired mutations at codons 537 and 538 in the ligand binding domain of the receptor which are found in ∼12% of pretreated, ER+ patients. These mutations result in constitutive ER activation and hormone-independent progressive disease. Although ESR1 mutated breast cancers are insensitive to endocrine therapy, novel agents targeting these mutations may be effective; however few preclinical models of ESR1-mutant breast cancer are available for preclinical analysis. To this end we have established two patient derived xenograft (PDX) models harboring mutations at codon 537; ST941 with ESR1Y537S and ST1799 with ESR1Y537C. We have characterized these models using genomic analysis and compared with analysis from paired or serially collected clinical tissue and blood. Dependence on estradiol for model growth and sensitivity to endocrine therapies were also evaluated and compared with a hormone-dependent breast cancer models. The ESR1 mutations were not present in primary clinical tissue while several additional mutations were identified including in TP53 and PIK3CA genes. In vivo the ESR1 mutant models grew in the presence or absence of exogenous estradiol and demonstrated reduced sensitivity to endocrine therapies compared with hormone-dependent breast cancer models. ST941 treated with tamoxifen, letrozole or fulvestrant reported moderate tumor growth inhibition versus control while tumor stasis or regressions were reported in MCF-7 and hormone-dependent PDX breast models. Overall we have established and characterized two models of ESR1 mutant breast cancer which can be utilized for development of targeted therapies. Citation Format: Wick MJ, Helman E, Meade J, Clark MJ, Vaught T, Tolcher AW, Rasco D, Patnaik A, Lang A, Beeram M, Papadopoulos KP. Establishment and characterization of ESR1-mutant breast cancer PDX models. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-04.
Background: The estrogen receptor (ERα) plays an integral role in the progression of luminal type breast cancers and while targeted endocrine therapies provide effective initial treatment many patients develop acquired resistance to treatment even with continued ER receptor expression. Recently studies identified ER mutations as a possible mechanism for acquired resistance and several activating point mutations have been identified including Y537S (ESR1Y537S) resulting in hormone independent proliferation in preclinical studies. However, lack of validated ESR1-mutant cell lines has limited detailed mechanistic studies of these mutations in endocrine-resistant ER+ breast cancer. Previously we established and evaluated a patient derived xenograft (PDX) designated ST941 representing ESR1Y537S-mutated ER+ breast cancer (Wick et al, SABCS 2015). To better understand the role of ESR1-mutations in endocrine resistant breast cancer we established an immortalized cell line from ST941 designated ST941/C to use for in vitro mechanistic assays and correlative in vivo studies. Methods: The ST941/C cell line was generated from harvested low-passage ST941 PDX tissue using published methods. Once established the line was characterized by immunohistochemistry and NGS and its tumorigenicity assessed. Drug sensitivity studies were carried out evaluating relevant endocrine and chemotherapy agents and results compared with in vivo drug studies. Timepoints for cell proliferation assays were Days 4, 7 and 10 following cell plating using standard MTS assay. Endpoints for in vivo studies were a mean group tumor volume of ~1 cm3 or sixty days following treatment initiation. Results: Subcutaneous cell injection into athymic nude mice produced xenografts which grew in the absence of exogenous hormone. The ST941/C cell line and resulting xenograft retained immunohistologic and NGS characteristics of the parent model including receptor expression and ER mutation. Both the cell line and xenograft were insensitive to most endocrine therapies including tamoxifen, fulvestrant and aromatase inhibitors and reported correlative activity towards docetaxel and other chemotherapies. Conclusion: We have established and evaluated an ESR1-mutant cell line designated ST941/C which is tumorigenic in nude mice and potentially useful for mechanistic and correlative in vivo studies to better understand acquired resistance in endocrine-treated ER+ breast cancer. Citation Format: Wick MJ, Diaz A, Thomas M, Moriarty A, Quinn M, Guerra M, Zhu P, Smith P, Tolcher AW, Puyang X, Patnaik A, Korpal M, Rasco D, Papadopoulos KP. Establishment and characterization of ST941/C; an ESR1-mutant ER+ breast cancer cell line and xenograft from a patient with acquired resistance to endocrine therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-26.
Preclinical in vivo models of estrogen receptor positive (ER+) breast cancer rely on exogenous supplementation of hormones for growth. This requirement leads to animal toxicity and mortality over time, limiting development and drug testing in these types of models. Efficacy of test agents, particularly endocrine therapies, may also be altered in these models due to excessive hormone exposure, highlighting the need to improve methods for the establishment and testing of ER+ breast models. We have developed an alternative method of hormone supplementation in ER+ breast cancer models and optimized this method for testing of endocrine therapies. Using two cell-based breast models, we demonstrated improved breast tumor take and time to tumor volume endpoint while reducing animal toxicity and mortality associated with standard hormone supplementation. Subsequent studies identified the lowest effective dose (LED) of supplement for hormone dependent model growth with a preclinically relevant time to tumor volume endpoint. Activity of endocrine therapies including tamoxifen, letrozole, fulvestrant and exemestane were compared at the standard and LED hormone concentrations. In these studies tamoxifen treatment resulted in tumor regressions which was not appreciably improved using the LED dose of supplement. However letrozole activity was improved in the LED study suggesting hormone supplementation can impact activity of some agents. Using this process we also generated a panel of ER+ patient-derived xenograft (PDX) models, including two novel hormone therapy responsive models from chemo-naïve or hormone therapy pretreated patients, designated ST986 and ST2177, respectively. This improved method of hormone supplementation diminishes the adverse effects of standard hormone supplementation and provides utility for development of anticancer therapies in ER+ breast models. Citation Format: Wick MJ, Vaught T, Meade J, Gamez L, Farley M, Tolcher AW, Rasco D, Patnaik A, Drengler RL, Rosenthal A, Papadopoulos KP. Establishment and evaluation of ER+ breast cancer models using an optimized methodology for exogenous hormone delivery. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-05.
Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is an independent factor for development of brain metastases. Up to 37% of patients with HER2 positive disease relapse intracranially despite control of extra-cranial metastatic disease. Inability of anti-cancer agents to cross an intact blood-brain barrier (BBB) is a possible explanation for the increased incidence of brain metastases. Subcutaneous (SQ) patient-derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, orthotopic PDX models may confer a translational advantage as the patient tumor microenvironment is more closely mimicked. Especially when targeting brain tumors, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to develop a panel of intracranial PDX models of breast cancer brain metastases for pre-clinical efficacy studies of new anticancer drugs. Methods: SQ tumors from three different HER2 positive PDX breast cancer models designated ST340, ST1339 and ST1616B were enzymatically digested and used for intracranial stereotactic injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take. Intracranial tumor growth was monitored using MRI and positron emission tomography (PET) in conjunction with the amino acid radio tracer 18F-FET. Results: MRI confirmed tumor take in one model as early as 2 weeks after intracranial implantation. Increased 18F-FET uptake was detected in all models. MRI could be effectively used to monitor tumor growth and the corresponding 18F-FET PET images demonstrated increased 18F-FET uptake over time. Conclusion: Three different HER2 positive intracranial PDX breast metastases models were established from low passage SQ PDX models. We suggest, that using these intracranial PDX models of brain metastases, new drugs for advanced breast cancer can be evaluated in preclinical models that more closely mimic the microenvironment and the BBB in patients. In addition, translational imaging techniques can be evaluated during preclinical testing and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established SQ and orthotopic PDX models of breast cancer and brain metastases can be used as a relevant translational platform for testing of new drugs. Citation Format: Nielsen CH, Nedergaard MK, Wick MJ, Papadopoulos K, Tolcher AW, Kjaer A. Intracranial PDX models of breast cancer metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-01.
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