New biomarkers can predict patients' response to certain drugs

Nov 19 2009

Recent advances in cancer therapeutics have led to the discovery of biomarkers that can predict patient response to certain drugs. Screening for mutations in the epidermal growth factor receptor (EGRF) prior to non-small cell lung cancer treatment, for example, has been shown to indentify patients who are likely to respond to treatment with erlontinib. This maximizes the drug's impact, and spares patients who are not likely to benefit from being subjected to potentially debilitating side effects.

"We now know that cancer is really millions of diseases, which begins to explain why there are such varying responses to different therapies," said Lewis Cantley, Ph.D., director of the Cancer Center at Beth Israel Deaconess Medical Center. "This is an exciting time, in that we see that the last 30 years of basic research into understanding what actually causes cancer is beginning to pay off. That knowledge is leading to therapies that are actually working."

As part of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Cantley will moderate a press conference on "Markers of Prognosis in Cancer Treatment" on Wednesday, Nov. 18, 2009, in Room 202 of the Hynes Convention Center in Boston, Mass., from 1:00 p.m. to 2:00 p.m. ET.

Reporters who cannot attend in person can call into the press conference using the following information:

U.S./Canada: (888) 282-7404
International: (706) 679-5207
Access Code: 36170468
Topic: AACR

Researchers will present new data on markers of prognosis associated with metastatic and HER2 positive breast cancers, renal cell carcinoma and other advanced solid tumors.

"This is really the future of cancer therapy," said Cantley. "We are taking the first few steps toward what I think will ultimately dominate cancer treatment in the future. We are seeing the beginnings of a change in the paradigm of cancer treatment, and this meeting will be at the forefront of that."

The following abstracts will be presented at the press conference:

#B134. PIK3CA mutations in patients with advanced cancers treated in phase I clinical trials
Embargo: 12:30 p.m ET, Tuesday, Nov. 17, 2009

Scientists have shown that patients with mutations in a PI3K gene responded to treatment that targeted an important PI3K signaling pathway.

PI3K is an enzyme that helps control cell growth and is thought to play a role in the development of tumors. Mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, have been found in many types of tumors. These mutations activate the PI3K-AKT-mTOR pathway, which is highly active in cancer cells.

"The implications of this study are two-fold. We demonstrated that PIK3CA testing is feasible and may contribute to the decision-making process when offering a patient a clinical trial. Although this study suffers from low numbers, the response rate observed in patients treated with inhibitors of PI3K/AKT/mTOR pathway based on their mutational status was well above what we usually see in Phase I clinical trials," said Filip Janku, M.D., Ph.D., a clinical research fellow of the University of Texas M. D. Anderson Cancer Center's Department of Investigational Cancer Therapeutics.

The researchers analyzed 117 tumor samples from patients with advanced cancers of various types. They found that 12 percent of patients had mutations in the PIK3CA gene. Mutations were most frequent in endometrial cancer, ovarian cancer, head and neck cancer, breast cancer and colon cancer, but no mutations were found in patients with melanoma or cervical cancer.

The team found that 40 percent of patients that received the PI3K-AKT-mTOR pathway inhibitor responded to treatment. Responses were observed in patients with endometrial cancer, ovarian cancer and breast cancer.

"These results are intriguing but at this point should be interpreted with caution," said Janku. "The promising response rate needs to be confirmed in larger groups of patients. We expect to learn more as this project continues to offer PIK3CA screening to patients considering a Phase I clinical trial."

#C118. Influence of CYP2D6 phenotype on tamoxifen-treatment outcome in women with metastatic breast cancer
Embargo: 12:30 p.m. ET, Wednesday, Nov. 18, 2009

Inherited variation of the gene Cytochrome P450 2D6 (CYP2D6), and use of CYP2D6-inhibiting medications, such as several commonly prescribed antidepressants, can have a negative impact on overall survival from metastatic breast cancer, according to research being presented at the International Conference on Molecular Targets and Cancer Therapeutics, co-sponsored by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer.

CYP2D6 is a gene that plays a crucial role in metabolizing several drugs, including tamoxifen. Previous studies have found that genetic variation in CYP2D6 and co-administration of medications that inhibit CYP2D6 reduce plasma levels of endoxifen, the active metabolite of tamoxifen, in patients being treated for breast cancer. However, little has been known about the effect on overall survival in patients receiving tamoxifen for metastatic disease.

In order to study the effect of CYP2D6 predicted phenotype (the combined effect of genetic variants and concomitant use of CYP2D6 inhibiting medication) on patient outcomes, Laureen A. Lammers, Pharm.D, and colleagues at Erasmus MC, in Rotterdam, Netherlands, reviewed patient charts for 99 women who received tamoxifen treatment for hormone receptor positive metastatic breast cancer, and analyzed the data to assess patient and tumor characteristics, time to progression (disease getting worse) and overall survival.

The researchers found that patients with predicted poor metabolizer (PM) phenotypes had worse overall survival compared to extensive metabolizer (EM) phenotypes, while patients with intermediate metabolizer (IM) phenotypes had similar outcomes to the EM group. PMs gave a shorter time to progression (1.7 years) compared to a combined IM/EM group (2.9 years), although this difference was not statistically significant. Overall survival of the IM/EM group (9.9 years) was significantly longer than for the PM patients (5.4 years). Patients who only took CYP2D6-inhibiting medications in conjunction with tamoxifen had worse time to progression and worse overall survival compared to patients who did not take CYP2D6-inhibitors.

"Our study found that, for women with hormone receptor positive metastatic breast cancer, CYP2D6 phenotype, as derived from both genotype information and co-medication use, is an important predictor of treatment outcomes associated with tamoxifen," said Lammers. "In addition, our study confirms that concomitant use of drugs that inhibit CYP2D6 limit the effectiveness of tamoxifen therapy, and should, therefore, be discouraged."

#A36. Plasma biomarkers predicting outcome in patients with advanced RCC: Results from the sorafenib phase III TARGET trial
Embargo: 12:30 p.m. ET, Monday, Nov. 16, 2009

Researchers have identified several plasma biomarkers that are predictive of overall survival in advanced renal cell carcinoma (RCC).

As an exploratory component of the landmark Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), researchers examined plasma biomarkers for possible prognostic value. TARGET was a phase 3 clinical trial which demonstrated the efficacy and safety of sorafenib for the treatment of RCC in patients for whom previous treatment had failed.

Sorafenib is a multikinase inhibitor which is active against RAF kinase and a number of receptor tyrosine kinases including VEGFR-2, VEGFR-3, PDGFR-beta, c-KIT, FLT-3, and RET. Patients in the TARGET trial were randomly assigned to receive sorafenib or placebo. Sorafenib was shown to double the length of time that patients lived without their RCC getting worse (progression-free survival).

Carol Peña, Ph.D., associate director for Clinical Cancer Biomarkers at Bayer HealthCare Pharmaceuticals, and colleagues analyzed a subset of the patients enrolled in TARGET to look for plasma biomarkers that could potentially predict clinical outcomes in patients with RCC. According to Peña, "the biomarker component of TARGET was intended to utilize this valuable study to search for biomarkers - in this case, proteins we can measure in plasma - that would help determine renal cell carcinoma prognosis, and predict patients who would benefit from treatment with sorafenib."

At the start of the trial, the researchers measured plasma levels of five biomarkers -VEGF, VEGFR-2, CAIX, TIMP-1, and Ras - and repeated those measures after three and 12 weeks of treatment. Statistical analysis was used to compare plasma levels of these biomarkers and progression-free survival or overall survival.

A previous report by these authors showed that baseline VEGF was prognostic, and possibly predictive of sorafenib benefit. In the current report, there was no correlation between levels of plasma VEGFR-2,CAIX, TIMP-1, or Ras and the efficacy of sorafenib. However, the researchers found that, in univariate analyses (where each biomarker's relationship with outcome is assessed individually), patients with higher levels of CAIX, TIMP-1 or Ras at the start of the trial had poorer overall survival when treated with placebo. Analysis of CAIX, TIMP-1, Ras and VEGF together with clinical variables in a group of 59 patients from the placebo group showed that TIMP-1 was independently prognostic for survival.

"For the moment, these findings are preliminary, but promising," said Peña. "Although the analysis included a relatively small number of patients, the strength of TIMP-1 as a prognostic marker for renal cell carcinoma is remarkable. It would be interesting to see further studies of TIMP-1 in RCC to confirm this finding, and evaluate its potential for clinical application."

#A64. Mechanistic insights into the misregulation of p27 in HER2-positive breast cancers
Embargo: 12:30 p.m. ET, Monday, Nov. 16, 2009

It is well known that levels of a protein called p27 are related to breast cancer outcomes, but less is known about the reasons behind this. Researchers at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle have determined that another protein, called Trim62, regulates p27 and may be one key to understanding the relationship between p27 and breast cancer prognosis.

In tumor cells, the cell cycle inhibitor p27 is often decreased in the tumor cell's nucleus (the control center of the cell), while retained or increased in the cytoplasm (the area outside the nucleus). When in the nucleus, p27 functions as a tumor suppressor by inhibiting cell proliferation (growth and duplication). However, when in the cytoplasm, p27 promotes cell migration and may thereby increase the tumor's potential to spread to other parts of the body. Thus, the location and distribution of p27 in the tumor cell may help indentify more aggressive tumors. To this end, Claire M. Faltermeier and colleagues in the Hutchinson Center's Basic Sciences Division developed antibodies that could reliably detect cytoplasmic p27. They observed that breast cancers positive for a certain growth factor receptor, called HER2, usually have increased cytoplasmic p27.

"While it has been established that cytoplasmic p27 could function as an oncogene, it has been difficult to determine which types of cancers have cytoplasmic p27 and its prognostic significance because of the lack of molecular tools to reliably detect cytoplasmic p27," said Faltermeier, lead author and research assistant in the lab of Jim Roberts, M.D., Ph.D., at the Hutchinson Center. "Now that antibodies have been developed to detect cytoplasmic p27, we can correlate cytoplasmic p27 to specific types of cancers and patient outcomes."

Faltermeier and co-author Erik Eide, Ph.D., post-doctoral research fellow in Robert's lab, also indentified a novel protein, Trim62, which not only regulates p27 stability but also its localization in HER2 positive breast cancers. When Trim62 levels were reduced (knocked-down) in HER2 positive cancer cells, p27 that was in the cytoplasm moved to the nucleus and the cells stopped proliferating. Furthermore, they showed that when Trim62 levels were reduced, HER2 positive cancer cells were more sensitive to the effects of lapatinib (a HER2/EGFR inhibitor) while increased levels of Trim62 had the opposite effect.

"Our research suggests that Trim62 is responsible for the misregulation of p27 in HER2 positive breast cancer tumors," said Faltermeier. "Because it regulates the stability and location of p27 in tumor cells, Trim62 could be a potential biomarker to predict patient response to anti-HER2 therapeutics such as lapatinib."

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