Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results

The largest study to correlate genetics with response to anticancer drugs released its first results on July 15. The researchers behind the study, based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, describe in this initial dataset the responses of 350 cancer samples (including ovarian cancer) to 18 anticancer therapeutics.

U.K.–U.S. Collaboration Builds a Database For “Personalized” Cancer Treatment

The Genomics of Drug Sensitivity in Cancer project released its first results on July 15th. Researchers released a first dataset from a study that will expose 1,000 cancer cell lines (including ovarian) to 400 anticancer treatments.

The largest study to correlate genetics with response to anticancer drugs released its first results on July 15. The researchers behind the study, based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, describe in this initial dataset the responses of 350 cancer samples (including ovarian cancer) to 18 anticancer therapeutics.

These first results, made freely available on the Genomics of Drug Sensitivity in Cancer website, will help cancer researchers around the world to obtain a better understanding of cancer genetics and could help to improve treatment regimens.

Dr. Andy Futreal, co-leader of the Cancer Genome Project at the Wellcome Trust Sanger Institute, said:

Today is our first glimpse of this complex interface, where genomes meet cancer medicine. We will, over the course of this work, add to this picture, identifying genetic changes that can inform clinical decisions, with the hope of improving treatment.  By producing a carefully curated set of data to serve the cancer research community, we hope to produce a database for improving patient response during cancer treatment.

How a patient responds to anticancer treatment is determined in large part by the combination of gene mutations in her or his cancer cells. The better this relationship is understood, the better treatment can be targeted to the particular tumor.

The aim of the five-year, international drug-sensitivity study is to find the best combinations of treatments for a wide range of cancer types: roughly 1000 cancer cell lines will be exposed to 400 anticancer treatments, alone or in combination, to determine the most effective drug or combination of drugs in the lab.

The therapies include known anticancer drugs as well as others in preclinical development.

To make the study as comprehensive as possible, the researchers have selected 1000 genetically characterized cell lines that include common cancers such as breast, colorectal and lung. Each cell line has been genetically fingerprinted and this data will also be publicly available on the website. Importantly, the researchers will take promising leads from the cancer samples in the lab to be verified in clinical specimens: the findings will be used to design clinical studies in which treatment will be selected based on a patient’s cancer mutation spectrum.

The new data released today draws on large-scale analyses of cancer genomes to identify genomic markers of sensitivity to anticancer drugs.

The first data release confirms several genes that predict therapeutic response in different cancer types. These include sensitivity of melanoma, a deadly form of skin cancer, with activating mutations in the gene BRAF to molecular therapeutics targeting this protein, a therapeutic strategy that is currently being exploited in the clinical setting. These first results provide a striking example of the power of this approach to identify genetic factors that determine drug response.

Dr. Ultan McDermott, Faculty Investigator at the Wellcome Trust Sanger Institute, said:

It is very encouraging that we are able to clearly identify drug–gene interactions that are known to have clinical impact at an early stage in the study. It suggests that we will discover many novel interactions even before we have the full complement of cancer cell lines and drugs screened. We have already studied more gene mutation-drug interactions than any previous work but, more importantly, we are putting in place a mechanism to ensure rapid dissemination of our results to enable worldwide collaborative research. By ensuring that all the drug sensitivity data and correlative analysis is freely available in an easy-to-use website, we hope to enable and support the important work of the wider community of cancer researchers.

Further results from this study should, over its five-year term, identify interactions between mutations and drug sensitivities most likely to translate into benefit for patients: at the moment we do not have sufficient understanding of the complexity of cancer drug response to optimize treatment based on a person’s genome.

Professor Daniel Haber, Director of the Cancer Center at Massachusetts General Hospital and Harvard Medical School, said:

We need better information linking tumor genotypes to drug sensitivities across the broad spectrum of cancer heterogeneity, and then we need to be in position to apply that research foundation to improve patient care.  The effectiveness of novel targeted cancer agents could be substantially improved by directing treatment towards those patients that genetic study suggests are most likely to benefit, thus “personalizing” cancer treatment.

The comprehensive results include correlating drug sensitivity with measurements of mutations in key cancer genes, structural changes in the cancer cells (copy number information) and differences in gene activity, making this the largest project of its type and a unique resource for cancer researchers around the world.

Professor Michael Stratton, co-leader of the Cancer Genome Project and Director of the Wellcome Trust Sanger Institute, said:

“This is one of the Sanger Institute’s first large-scale explorations into the therapeutics of human disease.  I am delighted to see the early results from our partnership with the team at Massachusetts General Hospital. Collaboration is essential in cancer research: this important project is part of wider efforts to bring international expertise to bear on cancer.”

Ovarian Cancer Sample Gene Mutation Prevalence

As part of the Cancer Genome Project, researchers identified gene mutations found in 20 ovarian cancer cell lines and the associated prevalence of such mutations within the sample population tested. For purposes of this project, a mutation — referred to by researchers as a “genetic event” in the project analyses description — is defined as (i) a coding sequence variant in a cancer gene, or (ii) a gene copy number equal to zero (i.e., a gene deletion) or greater than or equal to 8 (i.e., gene amplification).  The ovarian cancer sample analysis thus far, indicates the presence of mutations in twelve genes. The genes that are mutated and the accompanying mutation prevalence percentage are as follows:  APC (5%), CDKN2A (24%), CTNNB1 (5%), ERBB2/HER-2 (5%), KRAS (10% ), MAP2K4 (5%), MSH2 (5%), NRAS (10%), PIK3CA (10%), PTEN (14%), STK11 (5%), and TP53 (62%). Accordingly, as of date, the top five ovarian cancer gene mutations occurred in TP53, CDKN2A, CDKN2a(p14)(see below), PTEN, and KRAS.

Click here to view the Ovary Tissue Overview.  Click here to download a Microsoft Excel spreadsheet listing the mutations in 52 cancer genes across tissue types. Based upon the Ovary Tissue Overview chart, the Microsoft Excel Chart has not been updated to include the following additional ovarian cancer sample mutations and associated prevalence percentages: CDKN2a(p14)(24%), FAM123B (5%), FBXW7 (5%), MLH1 (10%), MSH6 (5%).

18 AntiCancer Therapies Tested; Next 9 Therapies To Be Tested Identified

As presented in the initial study results, 18 drugs/preclinical compounds were tested against various cancer cell lines, including ovarian. The list of drugs/preclinical compounds that were tested for sensitivity are as follows:  imatinib (brand name: Gleevec),  AZ628 (C-Raf inhibitor)MG132 (proteasome inhibitor), TAE684 (ALK inhibitor), MK-0457 (Aurora kinase inhibitor)sorafenib (C-Raf kinase & angiogenesis inhibitor) (brand name: Nexavar), Go 6976 (protein kinase C (PKC) inhibitor), paclitaxel (brand name: Taxol), rapamycin (mTOR inhibitor)(brand name: Rapamune), erlotinib (EGFR inhibitor)(brand name: Tarceva), HKI-272 (a/k/a neratinib) (HER-2 inhibitor), Geldanamycin (Heat Shock Protein 90 inhibitor), cyclopamine (Hedgehog pathway inhibitor), AZD-0530 (Src and Abl inhibitor), sunitinib (angiogenesis & c-kit inhibitor)(brand name:  Sutent), PHA665752 (c-Met inhibitor), PF-2341066 (c-Met inhibitor), and PD173074 (FGFR1 & angiogenesis inhibitor).

Click here to view the project drug/preclinical compound sensitivity data chart.

The additional drugs/compounds that will be screened by researchers in the near future are metformin (insulin)(brand name:  Glucophage), AICAR (AMP inhibitor), docetaxel (platinum drug)(brand name: Taxotere), cisplatin (platinum drug)(brand name: Platinol), gefitinib (EGFR inhibitor)(brand name:  Iressa), BIBW 2992 (EGFR/HER-2 inhibitor)(brand name:  Tovok), PLX4720 (B-Raf [V600E] inhibitor), axitinib (angiogenesis inhibitor)(a/k/a AG-013736), and CI-1040 (PD184352)(MEK inhibitor).

Ovarian cancer cells dividing. (Source: ecancermedia)

Ovarian Cancer Therapy Sensitivity

Targeted molecular therapies that disrupt specific intracellular signaling pathways are increasingly used for the treatment of cancer. The rational for this approach is based on our ever increasing understanding of the genes that are causally implicated in cancer and the clinical observation that the genetic features of a cancer can be predictive of a patient’s response to targeted therapies. As noted above, the goal of the Cancer Genome Project is to discover new cancer biomarkers that define subsets of drug-sensitive patients. Towards this aim, the researchers are (i) screening a wide range of anti-cancer therapeutics against a large number of genetically characterized human cancer cell lines (including ovarian), and (ii) correlating drug sensitivity with extensive genetic data. This information can be used to determine the optimal clinical application of cancer drugs as well as the design of clinical trials involving investigational compounds being developed for the clinic.

When the researchers tested the 18 anticancer therapies against the 20 ovarian cancer cell lines, they determined that the samples were sensitive to many of the drugs/compounds. The initial results of this testing indicate that there are at least six ovarian cancer gene mutations that were sensitive to eight of the anticancer therapies, with such results rising to the level of statistical significance.  We should note that although most (but not all) of the ovarian cancer gene mutations were sensitive to several anticancer therapies, we listed below only those which were sensitive enough to be assigned a green (i.e., sensitive) heatmap code by the researchers.

Click here to download a Microsoft Excel spreadsheet showing the effect of each of the 51 genes on the 18 drugs tested. Statistically significant effects are highlighted in bold and the corresponding p values for each gene/drug interaction are displayed in an adjacent table.  A heatmap overlay for the effect of the gene on drug sensitivity was created, with the color red indicating drug resistance and the color green indicating drug sensitivity.

The mutated genes present within the 20 ovarian cancer cell line sample that were sensitive to anticancer therapies are listed below.  Again, only statistically significant sensitivities are provided.

  • CDKN2A gene mutation was sensitive to TAE684, MK-0457, paclitaxel, and PHA665752.
  • CTNNB1 gene mutation was sensitive to MK-0457.
  • ERBB2/HER-2 gene mutation was sensitive to HKI-272.
  • KRAS gene mutation was sensitive to AZ628.
  • MSH2 gene mutation was sensitive to AZD0530.
  • NRAS gene mutation was sensitive to AZ628.

We will provide you with future updates regarding additional ovarian cancer gene mutation findings, and new anticancer therapies tested, pursuant to the ongoing Cancer Genome Project.



About The Genomics of Drug Sensitivity In Cancer Project

The Genomics of Drug Sensitivity In Cancer Project was launched in December 2008 with funding from a five-year Wellcome Trust strategic award. The U.K.–U.S. collaboration harnesses the experience in experimental molecular therapeutics at Massachusetts General Hospital Cancer Center and the expertise in large scale genomics, sequencing and informatics at the Wellcome Trust Sanger Institute. The scientists will use their skills in high-throughput research to test the sensitivity of 1000 cancer cell samples to hundreds of known and novel molecular anticancer treatments and correlate these responses to the genes known to be driving the cancers. The study makes use of a very large collection of genetically defined cancer cell lines to identify genetic events that predict response to cancer drugs. The results will give a catalogue of the most promising treatments or combinations of treatments for each of the cancer types based on the specific genetic alterations in these cancers. This information will then be used to empower more informative clinical trials thus aiding the use of targeted agents in the clinic and ultimately improvements in patient care.

Project leadership includes Professor Daniel Haber and Dr. Cyril Benes at Massachusetts General Hospital Cancer Center and Professor Mike Stratton and Drs. Andy Futreal and Ultan McDermott at the Wellcome Trust Sanger Institute.

About Massachusetts General Hospital

Massachusetts General Hospital (MGH), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

About The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the focus for U.K. gene sequencing efforts. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by the Wellcome Trust to enable the Institute to build on its world-class scientific achievements and exploit the wealth of genome data now available to answer important questions about health and disease. These programs are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, U.K.

About The Wellcome Trust

The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education, and the application of research to improve health. It is independent of both political and commercial interests.

Required Cancer Genome Project Disclaimer:

The data above was obtained from the Wellcome Trust Sanger Institute Cancer Genome Project web site, The data is made available before scientific publication with the understanding that the Wellcom Trust Sanger Institute intends to publish the initial large-scale analysis of the dataset. This publication will include a summary detailing the curated data and its key features.  Any redistribution of the original data should carry this notice: Please ensure that you use the latest available version of the data as it is being continually updated.  If you have any questions regarding the sequence or mutation data or their use in publications, please contact so as to obtain any updated or additional data.  The Wellcome Trust Sanger Institute provides this data in good faith, but makes no warranty, express or implied, nor assumes any legal liability or responsibility for any purpose for which the data are used.

European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer

“… ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”


“Amplification of the gene encoding estrogen receptor-alpha occurs in about 20% of breast cancers and is an important mechanism for estrogen receptor overexpression in this tumor type. In ovarian cancer, overexpression of estrogen receptor protein has been described in more than two thirds of cases.

To study a potential role of estrogen receptor-alpha gene amplification for estrogen receptor overexpression in ovarian cancer, a tumor tissue microarray containing 428 ovarian cancers was analyzed by fluorescence in situ hybridization [FISH] for estrogen receptor-alpha gene amplification and immunohistochemistry [IHC] for estrogen receptor expression. The estrogen receptor-alpha gene status was successfully determined in 243 of 428 arrayed cancers.

Estrogen receptor gene amplification was found in 5 of 243 (2%) of tumors. Amplification levels were usually low, with 4-8 estrogen receptor-alpha gene copies. However, one case had a high-level amplification, with more than 30 estrogen receptor-alpha gene copies. All five amplified tumors were estrogen receptor positive, with 3 of 5 tumors showing highest (Allred score, 7-8) estrogen receptor levels. The data demonstrate that estrogen receptor-alpha amplification occurs only rarely in ovarian cancer.”

Article Discussion Points:

  • “The results of this study show that ESR1 amplification is rare in ovarian cancers (2.1%). More than one-third of ovarian tumors showed immunohistochemically detectable estrogen receptor protein expression, most abundant in serous and endometroid subtypes. This is in line with previous studies done on the classical paraffin blocks. The good concordance between our data and previous studies demonstrates the representation of our tumor tissue microarray data obtained on a 0.6 mm tissue spot per tumor and enhances the results of other studies used in this method.”
  • “A small subset of ESR1 [gene] amplified estrogen receptor-positive cases was indeed found in ovarian cancers. In comparison, some other genes showed higher rates of amplifications in these cancers. For example, the amplification of ERBB2 ranges (0-66%),  EGFR (3.65-12%),  CCND1 (0-19%), C-MYC up to 54.5,  and KRAS (31%).”
  • “The significant frequency of estrogen receptor positivity in ovarian cancers had prompted treatment efforts using hormonal therapy early on. In addition their relatively little toxicity was another provoking factor to continue going on to achieve more advance in this therapeutic field. Monotherapy studies using tamoxifen, aromatase inhibitors, and GnRH analogues had yielded variable results with objective response rates ranging between 0 and 56%.  Combinatorial treatment regimens combining tamoxifen and goserelin or tamoxifen and Gefitinib had obtained results with objective response rates of up to 11.5%.”
  • “The role of estrogen receptor expression for response prediction to anti-hormonal drugs has been much better studied in breast cancer, where a strong association between estrogen receptor positivity and response to anti-hormonal drugs is well established. … More than 20% of breast cancers had amplified or at least elevated ESR1 [gene] copy number. Possible explanations for the predictive effect of ESR1 [gene] amplification could be a particularly high expression of amplified as compared to non-amplified cancers. Alternatively, it could be speculated, that ESR1 [gene] amplified are more dependent on the estrogen receptor pathway than other tumors that express estrogen receptors together with many other growth receptors. If this latter hypothesis was true, visualization of ESR1 [gene] amplification would pinpoint toward an ‘Achilles tendon‘ of a tumor that could be most successfully targeted.”
  • “The frequency of ESR1 [gene] amplified ovarian cancers (2.1%) is much lower than that in breast cancer. Interestingly, this fraction somehow parallels the percentage of ovarian cancers reported to show strong responses to hormonal therapies.”
  • “For example, in retrospective analysis was conducted of patients who received tamoxifen at a dose 20 mg twice daily for the treatment of advanced epithelial ovarian cancer,
    • Karagol et al found that out of 29 eligible patients included in the study, there were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease.
    • Papadimitriou et al have studied response rate in 27 patients treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n=21) and those with only increasing CA-125 serum levels (n=6) were eligible. Among the 21 patients with measurable or evaluable disease, 1 complete response (5%) and 2 partial responses were observed (10%) for an objective response rate of 15%.
    • Other studies, in which the combined regiment had been implicated, patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. In total, 26 patients entered this study, of which 17 had platinumresistant disease, using the definition of endocrine response that included patients with stable disease of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (3.8%), two partial responses (7.7%), and 10 patients with stable disease (38.5%).”
  • “In summary, ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Quoted SourceEstrogen receptor gene amplification occurs rarely in ovarian cancer, Issa RM et. al., Mod Pathol. 2009;22(2):191-196, reprinted in From Modern Pathology, Medscape Today, February 18, 2009. [Free Medscape subscription required to view full text article.]

Comment:  This study indicates that the occurrence of estrogen positivity (ER+)/ESR1 gene amplification with respect to ovarian cancer is significantly lower than such occurrence in the breast cancer area.  Nevertheless, it is prudent to request your doctor to have your ovarian cancer tumor tissue tested by a pathologist for estrogen positivity or ESR1 gene amplification (through IHC or FISH testing, respectively).  If your ovarian cancer tissue tests ER+, you may respond to anti-estrogen drugs.  Although this type of pathology testing is commonplace in the breast cancer area, it is not in the ovarian cancer area due to the much lower percentage of ER+ ovarian cancer tumors.  As the study above notes, further research of anti-estrogen therapy use within the area of ovarian cancer is needed, especially given the potential high effectiveness and low toxicity of such therapies.