bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 858: Treatment resistance of colon cancer with low proteasome activity
Authors: Munakata Koji , Uemura Mamoru , Nishimura Junichi , Hata Taishi , Takemasa Ichiro , Mizushima Tsunekazu , Yamamoto Hirofumi , Doki Yuichiro , Mori Masaki
Published: May 2015

Background and aims:Emerging evidence indicates that cancer stem cells are resistant to chemotherapy and radiation therapy which result in recurrence after curative intent treatment for solid tumor. Recently, several reports have indicated that some cancer stem cells (CSCs) would be characterized by low proteasome activity. And cell of low proteasome activity could lead to new therapeutic targets.

Material and methods:

We engineered human colorectal adenocarcinoma cells (HCT116, KM12SM, SW480, LoVo, DLD1, HT29) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg supposed to be accumulated in CSC like cells as a result of low activity of the 26S proteasome. The feature of Gdeghigh cells were analyzed by sphere formation assay, surface marker analysis, reactive oxygen species (ROS) analysis and assessment of chemotherapy and radiation therapy sensitivity.

Results:

Population of Gdeghigh was up-regurated by chemotherapy (5-FU and oxaliplatin) and radiation therapy. Furthermore CSC markers were increased by chemotherapy and radiation therapy. ROS activity of Gdeghigh was lower than Gdeglow.

Conclusions:

Low proteasome activity cells suggested eatures of CSCs. Mechanisms of chemotherapy and radiation therapy resistance should be revealed to establish new therapeutic approach based on CSCs hypothesis.

Citation Format: Koji Munakata, Mamoru Uemura, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Treatment resistance of colon cancer with low proteasome activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 858. doi:10.1158/1538-7445.AM2014-858
Abstract 877: Detection of colorectal cancer-associated genetic alterations in urine of patients with CRC
Authors: Clemens Adam W. , Lin Selena , Jain Surbhi , Chen Sitong , Su Ying-Hsiu , Song Wei
Published: May 2015

Colorectal cancer (CRC) has been the second leading cause of cancer-related deaths due in part to a low compliance rate (<50%) of the current screening method, an invasive colonoscopy, resulting in failure of detecting cancer early in its curative stages. 20% of CRCs are only detected once the cancer has spread to a distant site, drastically reducing the 5-year survival rate from 90% to 12%. In order to improve the success of early detection methods of CRC, we have focused on developing non-invasive, multi-biomarker detection assays designed to identify CRC-associated genetic alterations. The genetic alterations of four genes, (mutations of the KRAS (muKras) and BRAF V600E (muBRAF) genes and aberrant hypermethylation of the Vimentin (mVIM) and Septin9 (mSEPT9) genes, have shown to be potential biomarkers of CRC through stool or serum-derived DNA. We set out to show that these four biomarkers could be used as a panel for a non-invasive urine test of CRC in a highly specific and sensitive manner. We have previously demonstrated that urine contains circulation-derived low molecular weight (LMW) DNA (<300 bp), which suggests that LMW urine DNA could be used to detect CRC-associated genetic alterations. A blinded concordance study was used to validate mVIM as a biomarker for CRC between 20 urine samples and the corresponding tissue sample. We have developed a locked nucleic acid (LNA) clamp and a Simple Probe to distinguish mVIM from normal VIM suitable for fragmented short DNA templates. By using this assay, we indicated that mVIM can be detected from LMW urine DNA, and it has the potential to serve as a CRC-specific biomarker (Song et al., 2012). This LNA-clamp short-qPCR assay has been adapted for quantitation of muBRAF, muKRAS, and mSEPT9, for testing these biomarkers with open-labeled CRC samples. In addition, a prevalidation study is in progress with blinded CRC samples to confirm the specificity and sensitivity of these genetic biomarkers.

References

Song, B. P., Jain, S., Lin, S. Y., Chen, Q., Block, T. M., Song, W., ... & Su, Y. H. (2012). Detection of hypermethylated vimentin in urine of patients with colorectal cancer. The Journal of Molecular Diagnostics, 14(2), 112-119.

Citation Format: Adam W. Clemens, Selena Lin, Surbhi Jain, Sitong Chen, Ying-Hsiu Su, Wei Song. Detection of colorectal cancer-associated genetic alterations in urine of patients with CRC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2014-877
Abstract 89: Development of preclinical lung adenocarcinoma model
Authors: Suh Young-Ah , Kim Minsuh , Lee Sun-Hye , Jung Chae Lim , Mun Hye-Min , Oh Ju-Hee , Choi Eun Kyung , Jang Se Jin
Published: May 2015

Lung cancer is a leading cause of cancer death in worldwide. 85% of lung cancers are classified as non-small cell lung cancers (NSCLC), and adenocarcinoma (ADC) type is the most prevalent cancer in NSCLC. Approximately 50% of non-small cell lung cancer (NSCLC) patients have mutations in some oncogenes. The K-ras activation due to the mutant is notorious in many kinds of cancer types, including pancreatic cancer and lung adenocarcinoma, as is generally accepted as driving mutation for lung malignancy of lung adenocarcinoma. Another predominantly alternated gene in lung cancer is the EGFR that would hit the similar signaling with K-ras activation, to which small molecules and antibodies target to halt the tumor progression. The tumor suppressor p53 is also often altered in almost all kinds of cancers and lung cancer. In this reason, K-ras activated mouse is utilized as lung cancer mouse model. K-ras activated mouse eventually develops lung adenocarcinoma, which can be accelerated with mutated p53. Due to the gain-of-function, mutant p53 protein contributes to tumor metastasis and shortening the latency of tumor progression. Thereby activated K-ras/mutant p53 mouse is preferentially used as lung adenocarcinoma preclinical model. Here, we have used mouse tumor cells derived from activated K-ras/mutant p53 mouse to establish syngeneic lung cancer mouse model, allowing in vivo imaging. We asked whether the gain-of-function metastatic phenotype observed in the mouse is responsible for the formation of lung tumors when inoculated intravenously. Tumor cells from the mice could efficiently develop tumors in four weeks at the same genetic background. Tumors from the mice were histologically identical with original lung adenocarcinoma, suggesting that these cells are the efficient tools to generate preclinical lung tumor mouse model. We have examined this model for evaluating the efficiency of chemotherapeutics and signaling pathways involved in tumor growth regulation.

Citation Format: Young-Ah Suh, Minsuh Kim, Sun-Hye Lee, Chae Lim Jung, Hye-Min Mun, Ju-Hee Oh, Eun Kyung Choi, Se Jin Jang. Development of preclinical lung adenocarcinoma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 89. doi:10.1158/1538-7445.AM2014-89
Abstract 899: Combination of PI3K and MEK inhibitor chemosensitivity in human tumor explants and cell lines using the Mosaic Blue assay and relationship to biomarkers by immunohistochemistry
Authors: Dauffenbach Lisa M. , Sia Gela C. , Cash Patricia A. , Girees Sherif K. , Lim Ryan S. , Zheng Jianping , Olsen Eric P. , Kerfoot Christopher A.
Published: May 2015

The PI3K and MEK pathways promote tumor cell survival through a variety of downstream signals and are commonly explored in cancer research. Many agents are in clinical development and new evidence suggests that a combination of these inhibitors may be required to achieve optimal anti-tumor activity. Twenty-one viable colorectal and non-small cell lung cancer tissue explants with matched formalin-fixed, paraffin embedded (FFPE) tissue and 8 cell lines (A431, AGS, HCT-116, HT-29, MCF-7, MDA-MB-468, MKN45, and T47D) were used for this study. Fresh tissues were disaggregated into single cells and exposed to GDC-0941, a PI3K inhibitor, and AZD6244, a MEK inhibitor, both as single agents and in combination in the Mosaic Blue assay. Combination results were compared to single agent results. Samples were classified as resistant or sensitive. Matched FFPE tissues and cells were stained with the following biomarkers to identify predictive relationships: pAKT, p4EBP1, pPRAS40, ppS6 kinase, pS6 ribosomal protein, pERK, PTEN, cMET, EGFR, HER3, Ki-67, and p53. To assess pharmacodynamics changes, the 8 cell lines were also exposed to 1 concentration of each inhibitor both as single agents and in combination. The cells were fixed and paraffin embedded for IHC staining of the following biomarkers to identify pharmacodynamic relationships: pAKT, p4EBP1, pPRAS40, ppS6 kinase, pS6 ribosomal protein, pEGFR, pHER3, pMET, pERK, and Ki-67. The combination of inhibitors demonstrated additive growth inhibition in the explants and cell lines. The average combination IC50 was more potent than single agents, with greater additivity demonstrated in colorectal cancer compared to lung cancer. Predictive and pharmacodynamic biomarkers were identified with both single agent and combination treatments, and differences were observed between the two inhibitors. In summary, this study demonstrated that the Mosaic Blue assay is a useful tool for classifying sensitive and resistant tumor explants and cell lines and also confirmed that dual targeting of PI3K and MEK pathways is a valuable approach to achieving higher therapeutic activity in vitro. Evaluation of biomarker profiles revealed predictive and pharmacodynamic relationships in this setting.

Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Patricia A. Cash, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Christopher A. Kerfoot. Combination of PI3K and MEK inhibitor chemosensitivity in human tumor explants and cell lines using the Mosaic Blue assay and relationship to biomarkers by immunohistochemistry. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 899. doi:10.1158/1538-7445.AM2014-899
Abstract 910: NOTCH3 expression is predictive of efficacy in pancreas tumor models treated with OMP-59R5, a monoclonal antibody targeting the NOTCH2 and NOTCH3 receptors
Authors: Cancilla Belinda , Yen Wan-Ching , Zhang Chun , Fischer Marcus M. , Ji May , Tang Tracy , Liu Yu-Wang , Tam Raymond S. , Wang Min , Gurney Austin , Hoey Timothy , Lewicki John , Kapoun Ann M.
Published: May 2015

The Notch signaling pathway regulates key functions during embryonic development, stem cell maintenance and differentiation in adult tissues, and is implicated in many human cancers. OMP-59R5 is a ligand-blocking antibody targeting both the NOTCH2 and NOTCH3 receptors. We have developed a series of primary human xenograft models from patients with pancreatic cancer and used these models to examine efficacy response to OMP-59R5. We found that anti-NOTCH2/3, either as a single agent or in combination with chemotherapeutic agents, was efficacious in pancreatic tumor models. Expression of NOTCH3 mRNA by next-generation sequencing in ten baseline pancreatic tumors correlates with response to OMP-59R5, where growth of tumors with moderate to high expression of NOTCH3 was significantly reduced compared to tumors with low expression. We developed a Research-Use-Only (RUO) qPCR assay for measuring NOTCH3 mRNA expression using Formalin-Fixed, Paraffin-Embedded (FFPE) samples. This assay shows consistent NOTCH3 expression data with the next-generation sequencing data in the ten pancreatic xenograft tumors. Expression levels of NOTCH3 were also examined in ∼120 human metastatic pancreatic specimens to determine the reportable range of the assay and to identify association with clinical factors. This analysis showed that NOTCH3 gene expression maintained the same distribution across different specimen types, such as biopsy, surgical biopsy and surgical resection, etc. Samples with clinically relevant sites of recurrence also showed a similar range in NOTCH3 gene expression. Moreover, we developed an immunohistochemistry (IHC) assay for NOTCH3 protein expression. The correlation between the IHC assay and the qPCR assay was examined in both the metastatic pancreatic human specimens and the primary human pancreatic xenograft models. A significant correlation was found between the gene and protein levels, suggesting that both NOTCH3 gene expression and protein expression may predict the response to OMP-59R5 in pancreatic cancer. We are evaluating NOTCH3 levels and patient response in ALPINE, a Ph1b/2 Anti-NOTCH2/3 trial in first-line advanced pancreatic cancer patients.

Citation Format: Belinda Cancilla, Wan-Ching Yen, Chun Zhang, Marcus M. Fischer, May Ji, Tracy Tang, Yu-Wang Liu, Raymond S. Tam, Min Wang, Austin Gurney, Timothy Hoey, John Lewicki, Ann M. Kapoun. NOTCH3 expression is predictive of efficacy in pancreas tumor models treated with OMP-59R5, a monoclonal antibody targeting the NOTCH2 and NOTCH3 receptors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2014-910
Abstract 911: Prostate-specific membrane antigen (PSMA) expression as a potential patient selection marker in patients with refractory solid tumors administered BIND-014, a PSMA-targeted nanoparticle containing docetaxel
Authors: Low Susan , Hoff Daniel Von , Mita Monica , Burris Howard , Eisenberg Peter , Hart Lowell , LoRusso Patricia , Weiss Glen , Sachdev Jasgit , Mita Alain , Ramanathan Ramesh , Hrkach Jeff , Summa Jason , Berk Gregory
Published: May 2015

Background: Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate adenocarcinomas and in non-prostatic tumor neovasculature. As a novel target for therapeutic approaches, the distribution pattern of PSMA in primary and metastatic tumors is of significant interest. In this study we addressed the cellular distribution and heterogeneity of PSMA expression in solid tumors from patients on a phase 1 study of BIND-014, a PSMA-targeted nanoparticle containing docetaxel.Methods: Paraffin-embedded sections of surgical specimens from 1 patient (pt) with prostate carcinoma and 4 pts with non-prostatic tumors (cervical, NSCLC, breast and hepatobiliary) were evaluated. Immunohistochemistry by platelet endothelial cell adhesion molecule (CD31) for the detection of endothelial cells and monoclonal mouse anti-human PSMA (Clone 3E6) for detection of PSMA were used to determine the cellular localization and staining intensity for each tumor type. Results: All pts evaluated experienced some clinical benefit from BIND-014 (including complete response, partial response or stable disease) which is targeted to PSMA. We demonstrated differences in staining intensity and localization of PSMA in neoplastic epithelium and neoplastic tissue-associated blood vessels. PSMA was detected in the epithelium of prostate tissue and in neoplastic tissue-associated vessels of cervical, anal, NSCLC, and hepatobiliary cancers. PSMA was not detected in benign tissue of any specimens evaluated. Conclusions: Our findings support the feasibility of developing this assay as a companion diagnostic to potentially select patients who may benefit from PSMA-directed targeted therapy. Ongoing Phase 2 studies with BIND-014 include further PSMA expression analysis.

Citation Format: Susan Low, Daniel Von Hoff, Monica Mita, Howard Burris, Peter Eisenberg, Lowell Hart, Patricia LoRusso, Glen Weiss, Jasgit Sachdev, Alain Mita, Ramesh Ramanathan, Jeff Hrkach, Jason Summa, Gregory Berk. Prostate-specific membrane antigen (PSMA) expression as a potential patient selection marker in patients with refractory solid tumors administered BIND-014, a PSMA-targeted nanoparticle containing docetaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 911. doi:10.1158/1538-7445.AM2014-911
Abstract 939: Serial monitoring of EGFR mutations in plasma and matched tissue from EGFR mutant non-small cell lung cancer patients on erlotinib
Authors: Paweletz Cloud P. , Oxnard Geoffrey R. , Kuang Yanan , O'Connell Allison , Yanagita Masahiko , Messineo Melissa M. , Kirschmeier Paul , English Jessie M. , Jackman David M. , Jänne Pasi A.
Published: May 2015

Tumor genotyping has become standard in the care of non-small cell lung cancer (NSCLC), colorectal cancer, and melanoma because of its power in guiding the personalization of treatment with molecularly targeted therapies. A major limitation of cancer genotyping is the availability of pre- and post-treatment tumor biopsy specimens for accurate assessment of cancer biology. In addition, serial tumor biopsies from NSCLC patients at time of disease response or progression are not always desirable from the patient perspective and feasibility can be limited due to accessible tumor tissue and cost. The analysis of circulating cell-free DNA (cfDNA) has demonstrated potential to be a non-invasive means of interrogating the biology underlying response and resistance.

Here we report the detection, quantification and monitoring of EGFR mutations by droplet digital PCR in cfDNA on a prospective clinical trial of EGFR-mutant NSCLC patients on erlotinib. Droplet digital PCR, a novel technology that emulsifies DNA input into ∼20,000 consistently sized droplets, each individually genotyped, represents a promising approach for non-invasive quantification of specific tumor mutations. EGFR L858R, Del(19) and T790M were serially measured in over 300 samples from 40 lung cancer patients treated on erlotinib. Complete plasma response was seen in 8 cases; in 6, rising levels of inhibitor sensitizing EGFR Del(19) and L858R and acquired EGFR T790M mutations were detected up to 4 months prior to objective radiographic progression. An analysis of patients that progressed showed that 53% had tumor-genotype-confirmed EGFR sensitizing mutations in their plasma at diagnosis. Four of these patients had a tumor rebiopsy adequate for EGFR genotyping at progression, and EGFR T790M was confirmed in each. This contrasts to the same analysis on circulating tumor cells (CTC), collected simultaneously: No CTCs were identified at diagnosis and only 22% of patients had any detectable CTCs at progression. Our results strongly suggest that cfDNA genotyping has clinical utility in the molecular assessment of patients at diagnosis, and providing molecular understanding of patient's tumor evolution, in real time, by serial monitoring for resistance mutations.

Citation Format: Cloud P. Paweletz, Geoffrey R. Oxnard, Yanan Kuang, Allison O'Connell, Masahiko Yanagita, Melissa M. Messineo, Paul Kirschmeier, Jessie M. English, David M. Jackman, Pasi A. Jänne. Serial monitoring of EGFR mutations in plasma and matched tissue from EGFR mutant non-small cell lung cancer patients on erlotinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 939. doi:10.1158/1538-7445.AM2014-939
Abstract 948: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia
Authors: Cherian Joseph , Nacro Kassoum , Poh Zhi Ying , Guo Samantha , Ho Melvyn , Yang Haiyan , Lim Sharon , Choong Meng Ling , Ding Jun L. , Joy Joma Kanikadu , Kwek Zekui Perlyn , Liu Boping , Ong Hongqian Esther , Pendharkar Vishal , Poulsen Anders , Lee May Ann , Sangthongpitag Kanda , Chuah Charles , Ong Tiong S. , Hill Jeffrey , Keller Thomas H. , Matter Alex
Published: May 2015

Although targeting the BCR-ABL kinase with tyrosine kinase inhibitors (TKI) is effective in chronic phase (CP) CML, targeting BCR-ABL alone is not sufficient to treat late-stage or blast crisis (BC) CML. In BC CML, granulocyte macrophage progenitors (GMPs) acquire the ability to function as leukemic stem cells (LSCs), and are thought to act as a reservoir for TKI resistance. While long-term remission in BC CML is possible with allogeneic stem cell transplantation, only a minority of patients are eligible for transplantation, and may experience high morbidity and mortality. Safe and effective BC CML therapy will likely have to target the BC LSC population to ensure long-term disease control.

Recent studies have shown the importance of the MAP kinase interacting serine/threonine kinase (MNK1/2)-eukaryotic translation initiation factor 4E (eIF4E) axis in sustaining BC LSC self renewal. Thus, a single agent which inhibits both BCR-ABL and MNK1/2 kinase simultaneously represents a rational approach to target BC LSCs. Such an agent should be able to distinguish between normal hematopoietic stem cells (HSC) and LSCs.

Here, we report the discovery, structure activity relationships, pharmacokinetic properties, and biochemical characteristics of dual MNK1/2 and BCR-ABL inhibitors, ETC-027 and ETC-219. These compounds are able to prevent eIF4E phosphorylation, BCR-ABL-driven growth and proliferation of BC CML cells, as well as inhibit the MNK-eIF4E-dependent self-renewal function of BC LSCs, while leaving normal HSCs untouched.

Citation Format: Joseph Cherian, Kassoum Nacro, Zhi Ying Poh, Samantha Guo, Melvyn Ho, Haiyan Yang, Sharon Lim, Meng Ling Choong, Jun Li Ding, Joma Kanikadu Joy, Zekui Perlyn Kwek, Boping Liu, Hongqian Esther Ong, Vishal Pendharkar, Anders Poulsen, May Ann Lee, Kanda Sangthongpitag, Charles Chuah, Tiong S. Ong, Jeffrey Hill, Thomas H. Keller, Alex Matter. Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2014-948
Abstract 955: Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors
Authors: Niederst Matthew J. , Sequist Lecia V. , Lockerman Elizabeth L. , Garcia Angel R. , Costa Carlotta , Mohamoud Farhiya , Borger Darrell R. , Shioda Toshi , Getz Gad , Iafrate Anthony J. , Mino-Kenudson Mari , Engelman Jeffrey A.
Published: May 2015

Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs) are sensitive to the EGFR inhibitors erlotinib and gefitinib. In the majority of patients with this type of cancer, EFGR inhibition leads to a dramatic reduction in tumor size coupled with an abatement of symptoms. These responses are temporary, and in most cases the cancers become resistant after an average of one year. Recently, we and others have found that a subset of these cancers transform from NSCLC to SCLC as they acquire resistance to EGFR TKI. Details underlying this novel resistance mechanism are largely undiscovered. To assess the genetic changes associated with NSCLC to SCLC transformation, we carried out next generation sequencing analysis on NSCLC and SCLC resistant tumors. The sequencing results revealed that Rb, along with p53 and PIK3CA were specifically altered in the SCLC transformed tumors. An IHC assay to detect Rb indicated that while 10 out of 10 SCLC transformed cases have loss of Rb, resistant cancers that maintained an NSCLC histology largely retained Rb. To address the mechanism underlying the resistance to EGFR inhibition in these tumors, we demonstrated that upon the transformation to SCLC there is a marked reduction in EGFR expression, suggesting that in transforming to SCLC these cells become a cell type that no longer requires EGFR for their survival. Finally, utilizing cell lines generated from biopsies taken from resistant cancers, we identify the Bcl-2/Bcl-XL inhibitor Abt-263 as a potential therapeutic approach to treat these resistant patients. Together, our results provide details underlying this novel mechanism of resistance to targeted therapy.

Citation Format: Matthew J. Niederst, Lecia V. Sequist, Elizabeth L. Lockerman, Angel R. Garcia, Carlotta Costa, Farhiya Mohamoud, Darrell R. Borger, Toshi Shioda, Gad Getz, Anthony J. Iafrate, Mari Mino-Kenudson, Jeffrey A. Engelman. Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2014-955
Abstract 957: The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer
Authors: Friboulet Luc , Li Nanxin , Katayama Ryohei , Lee Christian C. , Gainor Justin F. , Crystal Adam S. , Michellys Pierre-Yves , Awad Mark M. , Yanagitani Noriko , Kim Sungjoon , Pferdekamper AnneMarie , Li Jie , Kasibhatla Shailaja , Sun Frank , Sun Xiuying , Hua Su , McNamara Peter , Mahmood Sidra , Lockerman Elizabeth L. , Fujita Naoya , Nishio Makoto , Harris Jennifer L. , Shaw Alice T. , Engelman Jeffrey A.
Published: May 2015

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the ALK tyrosine kinase inhibitor (TKI) crizotinib. However, these cancers invariably relapse due to the development of resistance, and approximately 1/3 of such cancers develop resistance mutations within the ALK tyrosine kinase domain. Here we report the preclinical evaluation of the next-generation ALK TKI, LDK378 in the setting of crizotinib resistance. Using EML4-ALK mutant Ba/F3 cellular models, in vivo models of acquired resistance to crizotinib, and novel cell lines established from biopsies of crizotinib-resistant NSCLC patients, we have examined the efficacy of LDK378 in crizotinib-naïve and -resistant ALK-positive cancers. These studies reveal that LDK378 is more potent than crizotinib and effectively overcomes resistance in vitro and in vivo. In particular, LDK378 inhibits ALK harboring crizotinib resistance mutations, including L1196M, G1269A, I1171T and S1206Y. Cell lines derived from crizotinib-resistant biopsies were sensitive to LDK378, including one that did not harbor an ALK resistance mutation and was also sensitive to crizotinib, suggesting that some crizotinib-resistant cancers with wildtype ALK are still sensitive to complete ALK inhibition. We observed that LDK378 did not effectively overcome two crizotinib-resistant ALK mutations, G1202R and F1174C

ALK, and mutations in one of these residues was identified in 5 out of 11 biopsies from patients with acquired resistance to LDK378. Altogether our results demonstrate that LDK378 can overcome many mechanisms of crizotinib resistance, consistent with emerging clinical data showing marked efficacy of LDK378 in patients with crizotinib-resistant disease.

Citation Format: Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, Justin F. Gainor, Adam S. Crystal, Pierre-Yves Michellys, Mark M. Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L. Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L. Harris, Alice T. Shaw, Jeffrey A. Engelman. The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2014-957
Abstract CS1-1: Clinical implications of contralateral prohylactic mastectomy
Authors: Jatoi Ismail
Published: May 2015

Contralateral prophylactic mastectomy (CPM) refers to the removal of the opposite uninvolved breast in women with unilateral breast cancer, and rates are increasing worldwide. Several factors may explain this trend. Greater use of genetic testing in women with unilateral breast cancer may result in the identification of women at increased risk for contralateral breast cancer, and prompt CPM. However, most women who undergo CPM appear to be at low to moderate risk for developing contralateral breast cancer, so the wider use of genetic testing can only partly account for the trend towards greater utilization of CPM. Wider use of pre-operative breast MRI, although not shown to be beneficial, has also been associated with increased use of CPM. Moreover, some women with unilateral breast cancer may overestimate their risk of contralateral breast cancer, experience considerable anxiety over this issue, and request CPM. In this regard, it is somewhat ironic that CPM rates are increasing during a period when contralateral breast cancer rates are decreasing due to better adjuvant systemic therapies. Finally, several observational studies have demonstrated associations between CPM and reductions in breast cancer-specific and all-cause mortality, and these reports may influence treatment decisions. Yet, the results of such observational studies may reflect the selection of a healthier cohort of women for CPM (selection bias). Thus, there is no clinical justification for the wider use of CPM in the management of patients with unilateral breast cancer, and a better understanding of factors contributing to this trend is necessary.

Citation Format: Ismail Jatoi. Clinical implications of contralateral prohylactic mastectomy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr CS1-1.
Abstract ES1-2: Reconstruction for the high risk patient: challenges of chemotherapy, radiation therapy and patient selection
Authors: Golshan Mehra
Published: May 2015

Breast surgical oncology and breast reconstruction are intimately integrated into the multi-disciplinary management of women with breast carcinoma. The primary goal of care for the breast surgical oncologist and reconstruction surgeon remains the optimal treatment of the breast cancer, while the reconstruction surgeon strives to achieve a soft, symmetric, sensate and scar free breast mound. Factors that must be accounted for include the unpredictable nature of radiated structures and the inability to reliably determine the need for radiation. Next the timing or sequencing of chemotherapy and targeted therapy must be adequately addressed in relation to healing before or after surgery. Patient factors such as age, body habitus, donor site availability and institutional expertise are integral in the decision making process. Finally, the patient's lifestyle and preferences must be counterbalanced with co-morbidities, donor site availability and limitations in implant size and shape.

Citation Format: Mehra Golshan. Reconstruction for the high risk patient: challenges of chemotherapy, radiation therapy and patient selection [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES1-2.
Abstract ES3-2: Biomarkers for clinical management and research
Authors: Dowsett Mitchell
Published: May 2015

Neoadjuvant treatment of primary breast cancer provides an excellent scenario for integrating biomarker, clinical and pharmacological studies as well as being a valued treatment option for patients with primary breast cancer. ER+ breast cancer may be treated with either cytotoxic or endocrine therapy. Measurements of changes in proliferation and apoptosis have provided insights into the mechanisms of response to these agents. In both settings decreases in proliferation as measured using Ki67 as a biomarker occur in patients responding to treatment. In endocrine treatment the reduced proliferation occurs early and persists for many weeks appearing to be the main driver of response. Apoptosis is not increased but continues at a slightly reduced rate and leads to tumour shrinkage in a scenario in which cell replacement is now markedly attenuated. Changes in Ki67 induced by endocrine therapy have been validated as intermediate end-points reflecting long term benefit from treatment. In contrast the changes in Ki67 with cytotoxic therapy are best explained by a selective loss of more proliferative cells due to increased apoptotic death. Prognosis of patients is strongly influenced by the Ki67 in the residual disease at surgery. The integration of Ki67 with Residual Cancer Burden to form a Residual Proliferative Cancer Burden provides an attractive new end-point which may have generalisable applicability across different treatments. In all of these studies as well as others on multiple other biomarkers it is critical to understand the degree of reproducibility in tissue biopsies that most often sample less than 1% of the sometimes heterogenous tumour bed. Examples of the impact of this on expression profiles and exomic analyses will be shown.

Citation Format: Mitchell Dowsett. Biomarkers for clinical management and research [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES3-2.
Abstract ES5-2: Second primary cancers among breast cancer survivors: Incidence and risk factors
Authors: Li Christopher I.
Published: May 2015

Five-year survival after invasive breast cancer is now at 90% and an estimated 2.97 million U.S. women are breast cancer survivors. The high incidence of invasive breast cancer, with over 220,000 U.S. women newly diagnosed every year, coupled with continued advances in survival has resulted in an ever increasing number of women at risk of developing a second primary cancer. Indeed, 41% of all second primary cancers diagnosed among U.S. women occur among breast cancer survivors and approximately 10% of breast cancer survivors will develop a second primary cancer. The four most common sites of second primary cancer, breast, lung, colon and endometrium, account for 70% of these second primaries. The appreciable risk of second primary cancer in breast cancer survivors is well-documented, yet relatively little is known about the etiologic and molecular determinants of these second primaries and little to no information on second primary cancer risk has been incorporated into preventive efforts and clinical care because of this evidence gap. This presentation will provide information on the following: 1. Descriptive epidemiology of second primary cancers among breast cancer survivors, 2. Review of the literature on risk factors for second primary breast cancer, and 3. Briefly describe the limited knowledge regarding risk factors for non-breast second primary breast cancers. Further studies of factors contributing to second primary cancers among breast cancer survivors can 1. Define the relationships between therapies for a first breast cancer and risk of these second cancers; 2. Clarify contributions of patient/clinical factors including modifiable exposures; and 3. Molecular profiling of first primary breast tumors aimed at distinguishing those at high vs. low risk of second primaries could advance approaches to risk stratification, tailored surveillance, treatment choice, and preventive interventions.

Citation Format: Christopher I. Li. Second primary cancers among breast cancer survivors: Incidence and risk factors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES5-2.
Abstract ES6-3: Tumor infiltrating lymphocytes in breast cancer
Authors: Loi Sherene
Published: May 2015

Interest in evaluating the presence of tumor infiltrating lymphocytes (TILs) in breast cancer is growing due to robust data supporting significant prognostic associations as well as the success of the new T cell checkpoint inhibitors in other solid organ cancer types. The positive prognostic associations between TILs present at diagnosis in triple negative (TN) and HER2-overexpressing breast cancer and better outcomes after standard adjuvant therapy strongly suggests that these breast cancer subtypes will be amendable to immunotherapeutic approaches. Current research suggests that TILs represent pre-existing host anti-tumor immunity, with the data reporting that the more TILs that are present in the tumor at diagnosis, the stronger the pre-existing immune response and better clinical outomes. However, only a minority of patients present with high levels of TILs at diagnosis. Current data also reports that biopsies from metastatic disease still can contain significant amounts of TILs. This suggests that these patients can generate an immune response even in advanced disease, albeit weak, as the median values of TILs present seem to be less.

This presentation will discuss the data on the prognostic associations of TILs, our current understanding about the content of TILs in breast cancer and how they could be potentially triggered and/or suppressed. I will also discuss our recently published guidelines on how to evaluate TILs in breast cancer (Salgado R et al, 2014). Furthermore I will speculate on how we could potentially augment or re-kick start a more effective anti-tumor immune response in patients with breast cancer. I will also talk about the potential future clinical utility of TILs in breast cancer- it is currently not recommended that TILs are used in treatment decision-making concerning chemotherapy or no chemotherapy in TN breast cancer or trastuzuamb vs no trastuzumab in HER2-positive disease. Phase II efficacy data evaluating T cell checkpoint inhibitors is not yet available in advanced TN and HER2-positive breast cancer, however, phase I data using monotherapy T cell checkpoint inhibition in heavily pre-treated disease seems promising with objective responses meeting RECIST criteria seen. It is unclear what the best biomarker will be in breast cancer patients for immunotherapeutic approaches, but targeting patients with some degree of already pre-existing anti-tumor immunity seems logical.

Citation Format: Sherene Loi. Tumor infiltrating lymphocytes in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES6-3.
Abstract OI-1: Origin of Metastatic Traits in Breast Cancer
Authors: Kang Yibin
Published: May 2015

Metastasis represents the most devastating stage of cancer progression and is responsible for most of cancer-related death. How and when breast cancer cells acquire metastatic traits is a topic of intense investigation and debate in the field. It has become clear that the development of metastatic capability in cancer cells is a continuous process that is shaped by the tissue of origin of the primary tumor, early oncogenic events, as well as the stresses tumor cells endure when they encounter different microenvironments and therapeutic treatments. Many genes play multiple functions during primary tumorigenesis and metastatic progression, and may represent ideal targets for therapeutic intervention. In this lecture, I will discuss some latest findings in our understanding of the origin and evolution of metastasis traits in breast cancer, with emphasis on the connection of metastasis genes to early events of tumor initiation.

Citation Format: Yibin Kang. Origin of Metastatic Traits in Breast Cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OI-1.
Abstract OT2-2-02: Phase I/II clinical trial on the combination of carboplatin, eribulin and E7449
Authors: Kaklamani Virginia , o'Regan Ruth , Wisinski Kari , Hoskins Kent , Wade James , Gradishar William
Published: May 2015

The combination of carboplatin and eribulin has been found to be effective in triple negative breast cancer patients. A recently conducted neoadjuvant clinical trial showed a pathologic complete response (pCR) of 45% with four cycle of carboplatin and eribulin. Recent preclinical data from EISAI suggest that there is synergy between carboplatin, eribulin and E7449 (an oral PARP inhibitor) in BRCA deficient and PTEN mutated xenograft models.

Loss of Heterozygosity (LOH) is DNA alterations which develop through double strand DNA breaks. The homologous recombination (HRD) Score is calculated by the number of LOH regions greater 15Mb in length and less than an entire chromosome present in the genome. A high HRD score is present in BRCA deficient tumors and predicts for sensitivity to platinum-based chemotherapy. We propose a phase I/II clinical trial on the combination of carboplatin, eribulin and E7449. As part of the phase I clinical trial HRD will be performed and correlated to response to therapy. In the phase II clinical trial women with BRCA related breast or ovarian cancer, triple negative breast or ovarian cancer with high HRD score or PTEN deficient will be enrolled at a dose level found during the phase I clinical trial. Tissue will be requested to test for PARP inhibition. The primary endpoint of the phase II clinical trial is response rate. A total of 30 patients will be enrolled to the phase II clinical trial.

Citation Format: Virginia Kaklamani, Ruth o'Regan, Kari Wisinski, Kent Hoskins, James Wade, William Gradishar. Phase I/II clinical trial on the combination of carboplatin, eribulin and E7449 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-02.
Abstract P1-01-04: Evaluation of tumor response after neoadjuvant chemotherapy in breast cancer patients: Correlation between dynamic contrast-enhanced MRI and pathologic tumor cellularity
Authors: Kim Hak Hee , Kim Won Kyung , Cha Joo Hee , Shin Hee Jung , Chae Eun Young , Choi Woo Jung
Published: May 2015

Purpose: The objective of the study was to analyze whether the measurement of changes of the tumor on magnetic resonance imaging (MRI), could be applied to predict pathologic response after neoadjuvant chemotherapy.

Methods: Between January 2013 and October 2013, 155 patients (age range, 31-74 years; mean age, 47.6 years) with pathologically proven breast cancer who underwent neoadjuvant chemotherapy followed by surgery were retrospectively enrolled. Pre-and post-treatment measurements and changes in tumor size and dynamic curve pattern of MRI were analyzed. Histological regression was scored on the residual overall tumor cellularity based on Miller-Payne grading system.

Results: The change of maximal diameter (ρ = 0.681, p < 0.001), angio-volume of tumor (ρ = 0.683, p < 0.001) and washout ratio of dynamic curve (ρ = 0.607, p < 0.001) measured on MRI showed strong correlation with histological regression. Among them, the correlation factor was highest in the change of angio-volume. The change of plateau ratio of dynamic curve showed moderate correlation (ρ = 0.574, p < 0.001) with histological regression. However, the change of persistent ratio of dynamic curve showed weak correlation (ρ = 0.206, p = 0.011).

Conclusions: The change of maximal diameter, angio-volume of tumor and washout ratio of dynamic curve measured on MRI showed strong correlation with residual cellularity in lesions after neoadjuvant chemotherapy and could be applied to predict pathologic response.

Citation Format: Hak Hee Kim, Won Kyung Kim, Joo Hee Cha, Hee Jung Shin, Eun Young Chae, Woo Jung Choi. Evaluation of tumor response after neoadjuvant chemotherapy in breast cancer patients: Correlation between dynamic contrast-enhanced MRI and pathologic tumor cellularity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-01-04.
Abstract P1-02-07: Contrast-enhanced ultrasound for evaluation of therapeutic efficacy of radiofrequency ablation for primary breast cancer
Authors: Ito Toshikazu , Okayama Jyunji , Uji Kumiko , Izukura Masaaki
Published: May 2015

To evaluate therapeutic efficacy of percutaneous ultrasound (US) guided radiofrequency (RF) ablation therapy for primary breast cancer using contrast-enhanced US.

The study was approved by the institutional ethics committee, and written informed consent was obtained. Between January 2012 and April 2014, 25 patients with biopsy-confirmed T1 breast cancer underwent RF ablation therapy in one institution. We examined 25 patients with 25 T1 breast cancers by contrast-enhanced MRI/CT, and contrast-enhanced US before and after RF ablation therapy. US guided RF abltion was performed using a 17-gauge internally cooled electrode (Cool-TipTM, Valleylab, Boulder, CO, USA) under general anesthesia. After injection 0.015mL/kg body weight of Sonazoid®(perflubutane), contrast-enhanced US was performed at a low mechanical index (0.17-0.24). Therapeutic success was defined as a lack of contrast enhancement by contrast-enhanced MRI, US and non-viable cancer tissues by US guided vacuum assisted biopsy (VAB) or core needle biopsy (CNB).

Contrast-enhanced US and MRI four weeks or more after RF ablation therapy showed ablation zones and adequate tumor necrosis in all 25 cancer lesions treated. Contrast-enhanced US made it possible to see that tumor vessels of treated lesions had disappeared after treatment. Contrast enhanced MRI showed a lack of stain with ring-like enhancement of ablation zone and non-viable tissues were seen by VAB and/or CNB in 25 ablation zones.

Contrast-enhanced US using Sonazoid® was useful modalities for evaluating the efficacy of RF ablation therapy in breast cancer lesions.

Citation Format: Toshikazu Ito, Jyunji Okayama, Kumiko Uji, Masaaki Izukura. Contrast-enhanced ultrasound for evaluation of therapeutic efficacy of radiofrequency ablation for primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-02-07.