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Breast International Group (BIG)/ European Society for Medical Oncology (ESMO): IMPAKT Breast Cancer Conference
New imaging promises improved breast cancer utility
BRUSSELS – Researchers developing advanced imaging techniques for breast cancer patients are striving to move beyond merely documenting the size and shape of tumors to also generate information on a tumor’s physiologic characteristics and molecular composition. But these goals remain investigational, leaving the proven role of advanced imaging techniques somewhat limited.
Work is underway trying to combine the structural information obtained from MRI with metabolic imaging using a glucose tracer and positron emission tomography (PET). Investigators are also trying to expand the capabilities of PET and single-photon emission computed tomography (SPECT) with new labeled tracers that can help visualize estrogen receptors, androgen receptors, and HER2 receptors.
But even the most basic PET and SPECT analyses available today require more supporting data before they can enter routine practice. "We have to prove that it affects clinical decision making and is useful," said Dr. Elisabeth de Vries, during an imaging session at the IMPAKT 2013 Breast Cancer Conference.
Currently, the development of imaging modalities for assessing breast cancer drug targets like HER2 and estrogen receptors is "still in its infancy," said Dr. de Vries, professor and head of the department of medical oncology at the University of Groningen, the Netherlands.
The potential exists to use PET and SPECT to find and assess tumor metastases throughout a patient’s body, and to gain insight into receptor heterogeneity with a new tracer for each important breast cancer marker, but these methods still need refinement and documentation of utility, she said.
Dr. Katja Pinker-Domenig believes that the best imaging information to guide breast cancer management will come from combining information from multiple sources, such as MRI and PET or MRI and SPECT, and her group has begun to assess these couplings. Last December, they reported their experience using 3-Tesla MRI and labeled glucose in PET imaging to assess 60 patients with lesions initially detected by mammography or ultrasound and classified as categories 3-5 on the Breast Imaging Reporting and Data System (BI-RADS).
Combining the two methods resulted in a diagnostic sensitivity of 100%, a specificity of 91%, and a diagnostic accuracy of 97%, significantly better than the 97%/77%/90% rates obtained in the same patients using MRI alone, they reported at the annual meeting of the Radiological Society of North America (RSNA). Adding the metabolic PET assessment to MRI produced two false positives and unnecessary biopsies, compared with five false positives and unneeded biopsies that would have been done based on MRI only, said Dr. Pinker-Domenig, a radiologist at the Medical University of Vienna.
Another MRI enhancement she is working on adds information from MRI diffusion-weighted imaging, which can distinguish benign cells, which freely diffuse and have a high apparent diffusion coefficient, and malignant cells, which have much more restricted diffusion. In another report at the RSNA last December, Dr. Pinker-Domenig and her associates presented results from 233 patients with 279 suspicious breast lesions examined by diffusion-weighted imaging using a 3-Tesla magnetic field. Overall sensitivity was 92% and specificity was 90% compared with subsequent biopsy and histopathology.
"With diffusion-weighted imaging we can often see changes before they are visible with contrast-enhanced MRI. We can even see malignancies disappear during chemotherapy. What is thrilling about DWI is that we can see changes before we can pick them up with conventional imaging with contrast-enhanced MRI," she said.
Another way of dealing with the limitations of conventional, stand-alone MRI has been to move to higher magnetic field strengths, at 3 or 7 Tesla. Last year, Dr. Pinker-Domenig and her associates reported results using 3-Tesla MRI on 150 breast cancer patients with 99% sensitivity, 81% specificity, and a diagnostic accuracy of 93% (Eur. Radiol. 2012;22:322-30), results she called "pretty good but not sufficient." In February, the group reported at the annual meeting of the European Society of Radiology their initial experience in 25 patients using 7-Tesla MRI to image breast cancers. The boost in field strength produced only a modest uptick in sensitivity and diagnostic accuracy, but Dr. Pinker-Domenig maintained the extra cost was worth it because "the pictures are clearer," and they also likely provide more information on tumor heterogeneity, she said.
In contrast to these advances, using imaging to assess bone metastases in breast cancer patients has made little progress. "We’re not very good at looking at bone metastases with bone scans, x-rays, or PET," said Dr. Gary Cook, a radiologist at King’s College, London. These imaging modalities allow radiologists to see gross changes, but not in the detail needed for reproducible measurements. "There is a lack of sensitive, specific, reproducible, and quantifiable methods to monitor bone metastases," he said.
The conference was sponsored by the European Society for Medical Oncology.
Dr. Pinker-Domenig and Dr. Cook had no disclosures. Dr. de Vries said that she has received grant support from Genentech and Novartis.
On Twitter @mitchelzoler
BRUSSELS – Researchers developing advanced imaging techniques for breast cancer patients are striving to move beyond merely documenting the size and shape of tumors to also generate information on a tumor’s physiologic characteristics and molecular composition. But these goals remain investigational, leaving the proven role of advanced imaging techniques somewhat limited.
Work is underway trying to combine the structural information obtained from MRI with metabolic imaging using a glucose tracer and positron emission tomography (PET). Investigators are also trying to expand the capabilities of PET and single-photon emission computed tomography (SPECT) with new labeled tracers that can help visualize estrogen receptors, androgen receptors, and HER2 receptors.
But even the most basic PET and SPECT analyses available today require more supporting data before they can enter routine practice. "We have to prove that it affects clinical decision making and is useful," said Dr. Elisabeth de Vries, during an imaging session at the IMPAKT 2013 Breast Cancer Conference.
Currently, the development of imaging modalities for assessing breast cancer drug targets like HER2 and estrogen receptors is "still in its infancy," said Dr. de Vries, professor and head of the department of medical oncology at the University of Groningen, the Netherlands.
The potential exists to use PET and SPECT to find and assess tumor metastases throughout a patient’s body, and to gain insight into receptor heterogeneity with a new tracer for each important breast cancer marker, but these methods still need refinement and documentation of utility, she said.
Dr. Katja Pinker-Domenig believes that the best imaging information to guide breast cancer management will come from combining information from multiple sources, such as MRI and PET or MRI and SPECT, and her group has begun to assess these couplings. Last December, they reported their experience using 3-Tesla MRI and labeled glucose in PET imaging to assess 60 patients with lesions initially detected by mammography or ultrasound and classified as categories 3-5 on the Breast Imaging Reporting and Data System (BI-RADS).
Combining the two methods resulted in a diagnostic sensitivity of 100%, a specificity of 91%, and a diagnostic accuracy of 97%, significantly better than the 97%/77%/90% rates obtained in the same patients using MRI alone, they reported at the annual meeting of the Radiological Society of North America (RSNA). Adding the metabolic PET assessment to MRI produced two false positives and unnecessary biopsies, compared with five false positives and unneeded biopsies that would have been done based on MRI only, said Dr. Pinker-Domenig, a radiologist at the Medical University of Vienna.
Another MRI enhancement she is working on adds information from MRI diffusion-weighted imaging, which can distinguish benign cells, which freely diffuse and have a high apparent diffusion coefficient, and malignant cells, which have much more restricted diffusion. In another report at the RSNA last December, Dr. Pinker-Domenig and her associates presented results from 233 patients with 279 suspicious breast lesions examined by diffusion-weighted imaging using a 3-Tesla magnetic field. Overall sensitivity was 92% and specificity was 90% compared with subsequent biopsy and histopathology.
"With diffusion-weighted imaging we can often see changes before they are visible with contrast-enhanced MRI. We can even see malignancies disappear during chemotherapy. What is thrilling about DWI is that we can see changes before we can pick them up with conventional imaging with contrast-enhanced MRI," she said.
Another way of dealing with the limitations of conventional, stand-alone MRI has been to move to higher magnetic field strengths, at 3 or 7 Tesla. Last year, Dr. Pinker-Domenig and her associates reported results using 3-Tesla MRI on 150 breast cancer patients with 99% sensitivity, 81% specificity, and a diagnostic accuracy of 93% (Eur. Radiol. 2012;22:322-30), results she called "pretty good but not sufficient." In February, the group reported at the annual meeting of the European Society of Radiology their initial experience in 25 patients using 7-Tesla MRI to image breast cancers. The boost in field strength produced only a modest uptick in sensitivity and diagnostic accuracy, but Dr. Pinker-Domenig maintained the extra cost was worth it because "the pictures are clearer," and they also likely provide more information on tumor heterogeneity, she said.
In contrast to these advances, using imaging to assess bone metastases in breast cancer patients has made little progress. "We’re not very good at looking at bone metastases with bone scans, x-rays, or PET," said Dr. Gary Cook, a radiologist at King’s College, London. These imaging modalities allow radiologists to see gross changes, but not in the detail needed for reproducible measurements. "There is a lack of sensitive, specific, reproducible, and quantifiable methods to monitor bone metastases," he said.
The conference was sponsored by the European Society for Medical Oncology.
Dr. Pinker-Domenig and Dr. Cook had no disclosures. Dr. de Vries said that she has received grant support from Genentech and Novartis.
On Twitter @mitchelzoler
BRUSSELS – Researchers developing advanced imaging techniques for breast cancer patients are striving to move beyond merely documenting the size and shape of tumors to also generate information on a tumor’s physiologic characteristics and molecular composition. But these goals remain investigational, leaving the proven role of advanced imaging techniques somewhat limited.
Work is underway trying to combine the structural information obtained from MRI with metabolic imaging using a glucose tracer and positron emission tomography (PET). Investigators are also trying to expand the capabilities of PET and single-photon emission computed tomography (SPECT) with new labeled tracers that can help visualize estrogen receptors, androgen receptors, and HER2 receptors.
But even the most basic PET and SPECT analyses available today require more supporting data before they can enter routine practice. "We have to prove that it affects clinical decision making and is useful," said Dr. Elisabeth de Vries, during an imaging session at the IMPAKT 2013 Breast Cancer Conference.
Currently, the development of imaging modalities for assessing breast cancer drug targets like HER2 and estrogen receptors is "still in its infancy," said Dr. de Vries, professor and head of the department of medical oncology at the University of Groningen, the Netherlands.
The potential exists to use PET and SPECT to find and assess tumor metastases throughout a patient’s body, and to gain insight into receptor heterogeneity with a new tracer for each important breast cancer marker, but these methods still need refinement and documentation of utility, she said.
Dr. Katja Pinker-Domenig believes that the best imaging information to guide breast cancer management will come from combining information from multiple sources, such as MRI and PET or MRI and SPECT, and her group has begun to assess these couplings. Last December, they reported their experience using 3-Tesla MRI and labeled glucose in PET imaging to assess 60 patients with lesions initially detected by mammography or ultrasound and classified as categories 3-5 on the Breast Imaging Reporting and Data System (BI-RADS).
Combining the two methods resulted in a diagnostic sensitivity of 100%, a specificity of 91%, and a diagnostic accuracy of 97%, significantly better than the 97%/77%/90% rates obtained in the same patients using MRI alone, they reported at the annual meeting of the Radiological Society of North America (RSNA). Adding the metabolic PET assessment to MRI produced two false positives and unnecessary biopsies, compared with five false positives and unneeded biopsies that would have been done based on MRI only, said Dr. Pinker-Domenig, a radiologist at the Medical University of Vienna.
Another MRI enhancement she is working on adds information from MRI diffusion-weighted imaging, which can distinguish benign cells, which freely diffuse and have a high apparent diffusion coefficient, and malignant cells, which have much more restricted diffusion. In another report at the RSNA last December, Dr. Pinker-Domenig and her associates presented results from 233 patients with 279 suspicious breast lesions examined by diffusion-weighted imaging using a 3-Tesla magnetic field. Overall sensitivity was 92% and specificity was 90% compared with subsequent biopsy and histopathology.
"With diffusion-weighted imaging we can often see changes before they are visible with contrast-enhanced MRI. We can even see malignancies disappear during chemotherapy. What is thrilling about DWI is that we can see changes before we can pick them up with conventional imaging with contrast-enhanced MRI," she said.
Another way of dealing with the limitations of conventional, stand-alone MRI has been to move to higher magnetic field strengths, at 3 or 7 Tesla. Last year, Dr. Pinker-Domenig and her associates reported results using 3-Tesla MRI on 150 breast cancer patients with 99% sensitivity, 81% specificity, and a diagnostic accuracy of 93% (Eur. Radiol. 2012;22:322-30), results she called "pretty good but not sufficient." In February, the group reported at the annual meeting of the European Society of Radiology their initial experience in 25 patients using 7-Tesla MRI to image breast cancers. The boost in field strength produced only a modest uptick in sensitivity and diagnostic accuracy, but Dr. Pinker-Domenig maintained the extra cost was worth it because "the pictures are clearer," and they also likely provide more information on tumor heterogeneity, she said.
In contrast to these advances, using imaging to assess bone metastases in breast cancer patients has made little progress. "We’re not very good at looking at bone metastases with bone scans, x-rays, or PET," said Dr. Gary Cook, a radiologist at King’s College, London. These imaging modalities allow radiologists to see gross changes, but not in the detail needed for reproducible measurements. "There is a lack of sensitive, specific, reproducible, and quantifiable methods to monitor bone metastases," he said.
The conference was sponsored by the European Society for Medical Oncology.
Dr. Pinker-Domenig and Dr. Cook had no disclosures. Dr. de Vries said that she has received grant support from Genentech and Novartis.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM IMPAKT 2013 BREAST CANCER CONFERENCE
Intratumor heterogeneity drives need for multiple biopsies
BRUSSELS – When biopsying a primary breast cancer, once is probably not enough based on accumulating evidence of primary-tumor heterogeneity, but despite this evidence, taking multiple biopsies has not yet become routine practice.
"Intra-tumor heterogeneity is one of the causes of variation during genetic profiling" of tumors, Dr. Jorge S. Reis-Fiho said. "Taking multiple biopsies from a primary tumor and putting them all together may mitigate the effect of intra-tumor heterogeneity," but taking multiple biopsies has not yet become standard of care, he said at the conference, which was sponsored by the European Society for Medical Oncology.
"I think we should start to seriously consider taking more than one biopsy. Quite a few places already do it, and our radiologists will routinely take two or three biopsies," said Dr. Fiho, a surgical pathologist at Memorial Sloan-Kettering Cancer Center in New York. "With only a single, small biopsy of the primary tumor we may not have sufficient information to predict what the metastasis will respond to," he said in an interview.
Results from two studies reported at the meeting added to the evidence favoring multiple biopsies as a way to more precisely characterize primary tumors and target the best therapy.
In one study, Dr. Michal Jarzab and his associates took three core biopsies from the primary tumors of 26 patients and assessed them genetically for estrogen receptor, progesterone receptor, and HER2-receptor mutations. Their sample included some patients with early-stage disease and others with advanced-stage cancer. The results of the three individual biopsy tests showed significant heterogeneity in seven of the 26 tumors (27%), reported Dr. Jarzab, a researcher at the Maria Sklodowska-Curie Cancer Center and Institute of Oncology in Gliwice, Poland.
The intratumor heterogeneity in these seven patients "could negatively impact genomic assessment if done with one specimen," he said.
"If other studies report similar results" on intratumor heterogeneity, "then it could become common practice to evaluate prognostic or predictive breast cancer markers from more than one primary tumour area," Dr. Angelo Di Leo, chairman of oncology at Prato (Italy) Hospital, said in a written statement.
The second study looked at the impact of assessing one, two, or three biopsies on the variance in results from four different single- or multiple-genetic tests in biopsies collected from 51 breast cancer patients. The amount of variance depended on the gene or genes tested, but, overall, using three biopsy specimens rather than one substantially reduced the variance, reported Dr. Rosanna Lau, a researcher at the University of Texas M.D. Anderson Cancer Center in Houston.
"Pooling biopsies from a single tumor reduced outlier results and reduced variance more generally for certain genes," Dr. Lau said. "Pooling biopsies is usually preferable to a single biopsy." The results showed that "we can get a comprehensive picture of the genes being expressed in the tumor by sampling multiple areas of the tumor and pooling the samples together. This increases the precision of the assay and allows us to make more reliable predictions related to the disease," she said in a written statement.
Her study also looked at the scope of analytic variance – variance caused by technical issues – in the biopsies taken from a 20-patient subgroup and found that the extent of analytic variance also varied by gene and was generally of the same magnitude as intratumor heterogeneity. The analytic variance wasn’t helped by pooling multiple biopsies, but data-processing solutions such as normalizing and scaling reduced this part of the variance, Dr. Lau said.
Dr. Reis-Fiho, Dr. Lau, Dr. Jarzab, and Dr. Di Leo had no disclosures.
BRUSSELS – When biopsying a primary breast cancer, once is probably not enough based on accumulating evidence of primary-tumor heterogeneity, but despite this evidence, taking multiple biopsies has not yet become routine practice.
"Intra-tumor heterogeneity is one of the causes of variation during genetic profiling" of tumors, Dr. Jorge S. Reis-Fiho said. "Taking multiple biopsies from a primary tumor and putting them all together may mitigate the effect of intra-tumor heterogeneity," but taking multiple biopsies has not yet become standard of care, he said at the conference, which was sponsored by the European Society for Medical Oncology.
"I think we should start to seriously consider taking more than one biopsy. Quite a few places already do it, and our radiologists will routinely take two or three biopsies," said Dr. Fiho, a surgical pathologist at Memorial Sloan-Kettering Cancer Center in New York. "With only a single, small biopsy of the primary tumor we may not have sufficient information to predict what the metastasis will respond to," he said in an interview.
Results from two studies reported at the meeting added to the evidence favoring multiple biopsies as a way to more precisely characterize primary tumors and target the best therapy.
In one study, Dr. Michal Jarzab and his associates took three core biopsies from the primary tumors of 26 patients and assessed them genetically for estrogen receptor, progesterone receptor, and HER2-receptor mutations. Their sample included some patients with early-stage disease and others with advanced-stage cancer. The results of the three individual biopsy tests showed significant heterogeneity in seven of the 26 tumors (27%), reported Dr. Jarzab, a researcher at the Maria Sklodowska-Curie Cancer Center and Institute of Oncology in Gliwice, Poland.
The intratumor heterogeneity in these seven patients "could negatively impact genomic assessment if done with one specimen," he said.
"If other studies report similar results" on intratumor heterogeneity, "then it could become common practice to evaluate prognostic or predictive breast cancer markers from more than one primary tumour area," Dr. Angelo Di Leo, chairman of oncology at Prato (Italy) Hospital, said in a written statement.
The second study looked at the impact of assessing one, two, or three biopsies on the variance in results from four different single- or multiple-genetic tests in biopsies collected from 51 breast cancer patients. The amount of variance depended on the gene or genes tested, but, overall, using three biopsy specimens rather than one substantially reduced the variance, reported Dr. Rosanna Lau, a researcher at the University of Texas M.D. Anderson Cancer Center in Houston.
"Pooling biopsies from a single tumor reduced outlier results and reduced variance more generally for certain genes," Dr. Lau said. "Pooling biopsies is usually preferable to a single biopsy." The results showed that "we can get a comprehensive picture of the genes being expressed in the tumor by sampling multiple areas of the tumor and pooling the samples together. This increases the precision of the assay and allows us to make more reliable predictions related to the disease," she said in a written statement.
Her study also looked at the scope of analytic variance – variance caused by technical issues – in the biopsies taken from a 20-patient subgroup and found that the extent of analytic variance also varied by gene and was generally of the same magnitude as intratumor heterogeneity. The analytic variance wasn’t helped by pooling multiple biopsies, but data-processing solutions such as normalizing and scaling reduced this part of the variance, Dr. Lau said.
Dr. Reis-Fiho, Dr. Lau, Dr. Jarzab, and Dr. Di Leo had no disclosures.
BRUSSELS – When biopsying a primary breast cancer, once is probably not enough based on accumulating evidence of primary-tumor heterogeneity, but despite this evidence, taking multiple biopsies has not yet become routine practice.
"Intra-tumor heterogeneity is one of the causes of variation during genetic profiling" of tumors, Dr. Jorge S. Reis-Fiho said. "Taking multiple biopsies from a primary tumor and putting them all together may mitigate the effect of intra-tumor heterogeneity," but taking multiple biopsies has not yet become standard of care, he said at the conference, which was sponsored by the European Society for Medical Oncology.
"I think we should start to seriously consider taking more than one biopsy. Quite a few places already do it, and our radiologists will routinely take two or three biopsies," said Dr. Fiho, a surgical pathologist at Memorial Sloan-Kettering Cancer Center in New York. "With only a single, small biopsy of the primary tumor we may not have sufficient information to predict what the metastasis will respond to," he said in an interview.
Results from two studies reported at the meeting added to the evidence favoring multiple biopsies as a way to more precisely characterize primary tumors and target the best therapy.
In one study, Dr. Michal Jarzab and his associates took three core biopsies from the primary tumors of 26 patients and assessed them genetically for estrogen receptor, progesterone receptor, and HER2-receptor mutations. Their sample included some patients with early-stage disease and others with advanced-stage cancer. The results of the three individual biopsy tests showed significant heterogeneity in seven of the 26 tumors (27%), reported Dr. Jarzab, a researcher at the Maria Sklodowska-Curie Cancer Center and Institute of Oncology in Gliwice, Poland.
The intratumor heterogeneity in these seven patients "could negatively impact genomic assessment if done with one specimen," he said.
"If other studies report similar results" on intratumor heterogeneity, "then it could become common practice to evaluate prognostic or predictive breast cancer markers from more than one primary tumour area," Dr. Angelo Di Leo, chairman of oncology at Prato (Italy) Hospital, said in a written statement.
The second study looked at the impact of assessing one, two, or three biopsies on the variance in results from four different single- or multiple-genetic tests in biopsies collected from 51 breast cancer patients. The amount of variance depended on the gene or genes tested, but, overall, using three biopsy specimens rather than one substantially reduced the variance, reported Dr. Rosanna Lau, a researcher at the University of Texas M.D. Anderson Cancer Center in Houston.
"Pooling biopsies from a single tumor reduced outlier results and reduced variance more generally for certain genes," Dr. Lau said. "Pooling biopsies is usually preferable to a single biopsy." The results showed that "we can get a comprehensive picture of the genes being expressed in the tumor by sampling multiple areas of the tumor and pooling the samples together. This increases the precision of the assay and allows us to make more reliable predictions related to the disease," she said in a written statement.
Her study also looked at the scope of analytic variance – variance caused by technical issues – in the biopsies taken from a 20-patient subgroup and found that the extent of analytic variance also varied by gene and was generally of the same magnitude as intratumor heterogeneity. The analytic variance wasn’t helped by pooling multiple biopsies, but data-processing solutions such as normalizing and scaling reduced this part of the variance, Dr. Lau said.
Dr. Reis-Fiho, Dr. Lau, Dr. Jarzab, and Dr. Di Leo had no disclosures.
AT IMPAKT 2013 BREAST CANCER CONFERENCE
Major finding: Significant intratumor heterogeneity occurred in the genetic-profile results from three individual biopsies for 27% of primary breast cancers tested.
Data source: Single-center study of 26 patients with either early- or advanced-stage breast cancer.
Disclosures: Dr. Reis-Fiho, Dr. Lau, Dr. Jarzab, and Dr. Di Leo had no disclosures.
Cancer-cell reprogramming poses new treatment challenge
BRUSSELS – Metastatic breast cancer cells are even more adaptable and able to evade targeted treatment than researchers suspected as recently as a few months ago, which means they present a heightened treatment challenge that in many cases may be overcome only with multiple targeted therapies delivered at the same time.
The findings were discussed at IMPAKT 2013 Breast Cancer Conference, sponsored by the European Society for Medical Oncology.
The new wrinkle in drug resistance has been dubbed reprogramming, a way that metastatic breast cancer cells (but presumably a property shared by other advanced solid tumors as well) quickly respond to a drug that shuts down an essential cell protein, a kinase, by turning on other, alternative kinases within days of drug exposure. Many of the new, targeted therapies that have successfully treated advanced-stage breast cancer and other solid tumors are kinase inhibitors, such as trastuzumab (Herceptin) and lapatinib (Tykerb).
Using a newly-developed technique for assessing many different kinases within a cell at once, Gary Johnson, Ph.D., reported that treatment of isolated, advanced breast cancer cells in vitro with a kinase inhibitor drug produced within a week a dramatic shift in the cell’s overall kinase profile, something he calls the cell’s "kinome." Part of this reprogramming response probably occurs because of new genes that the cancer cell turns on or upregulates, and part is probably driven by epigenetic changes in the cell, said Dr. Johnson, professor and chairman of pharmacology at the University of North Carolina in Chapel Hill.
Clinicians familiar with this finding quickly recognized that the phenomenon is an important, new barrier to successful treatment in patients that will require creative solutions using rational, multidrug, or multi-sequence regimens.
Dr. Lisa A. Carey, an oncologist who collaborates with Dr. Johnson, said she believes that reprogramming may explain her recent, frustrating results treating metastatic breast cancer patients with an investigational inhibitor of the epidermal growth factor receptor (EGFR), a tyrosine kinase.
"We gave the inhibitor to patients with triple-negative breast cancer, where the EGFR is clearly upregulated, a big, juicy target, and yet only 25% of the patients responded. Most of the time, the cancers had alternative mechanisms to keep the EGFR pathway active," Dr. Carey hypothesized based on Dr. Johnson’s recent findings. "The good news was that 25% of the time the treatment worked," said Dr. Carey, professor of hematology oncology at the University of North Carolina and medical director of the university’s Breast Center.
The new finding on breast-cancer cell reprogramming "helps us understand why the EGFR inhibitor didn’t work in most patients, it helps us understand what cancer cells do, and it helps us design our next approach. Most cancer drug development right now targets kinases," she said in an interview.
"One way to approach this is to use multiple agents at once, but if you add drugs you also add toxicity and expense. And in some patients the cell doesn’t reprogram. We need to understand how reprogramming works," with the potential to develop agents that block reprogramming instead of trying to deal with the changes that reprogramming causes. "This is an explanation of why patients don’t respond to even targeted treatments, and it gives us a way forward to potentially prevent it. Reprogramming is reproducible and potentially targetable. I think we can get around it."
"Limiting emergence of heterogeneity is important because heterogeneity is what defeats us," Dr. Larry Norton, director of the Breast Center at Memorial Sloan-Kettering Cancer Center. New York, said at the conference.
"I need to understand reprogramming of the kinome, what a treatment does to the cancer, and how it influences the next treatment I should use," said Dr. David Cameron, professor of oncology at Edinburgh University. "Patients with breast cancer will be treated with a sequence of agents. We treat patients longer, more effectively, and with more drugs, so we need to worry about what the first drug does to the cancer before we come in with a second.
Giving a clinician’s perspective on the significance of reprogramming in a talk at the meeting, Dr. Cameron said, "we will have to optimize therapy by understanding what one treatment does so we can give the next treatment at the optimal time. If we unravel the way the biology changes in the presence of treatment perhaps we can hone our treatments more effectively."
Dr. Johnson said that he has started a company, KinoDyn, to apply kinase-assessment to treatment, although as of now the company has no funding or employees. Dr. Carey, Dr. Norton, and Dr. Cameron had no disclosures.
Twitter: @mitchelzoler
BRUSSELS – Metastatic breast cancer cells are even more adaptable and able to evade targeted treatment than researchers suspected as recently as a few months ago, which means they present a heightened treatment challenge that in many cases may be overcome only with multiple targeted therapies delivered at the same time.
The findings were discussed at IMPAKT 2013 Breast Cancer Conference, sponsored by the European Society for Medical Oncology.
The new wrinkle in drug resistance has been dubbed reprogramming, a way that metastatic breast cancer cells (but presumably a property shared by other advanced solid tumors as well) quickly respond to a drug that shuts down an essential cell protein, a kinase, by turning on other, alternative kinases within days of drug exposure. Many of the new, targeted therapies that have successfully treated advanced-stage breast cancer and other solid tumors are kinase inhibitors, such as trastuzumab (Herceptin) and lapatinib (Tykerb).
Using a newly-developed technique for assessing many different kinases within a cell at once, Gary Johnson, Ph.D., reported that treatment of isolated, advanced breast cancer cells in vitro with a kinase inhibitor drug produced within a week a dramatic shift in the cell’s overall kinase profile, something he calls the cell’s "kinome." Part of this reprogramming response probably occurs because of new genes that the cancer cell turns on or upregulates, and part is probably driven by epigenetic changes in the cell, said Dr. Johnson, professor and chairman of pharmacology at the University of North Carolina in Chapel Hill.
Clinicians familiar with this finding quickly recognized that the phenomenon is an important, new barrier to successful treatment in patients that will require creative solutions using rational, multidrug, or multi-sequence regimens.
Dr. Lisa A. Carey, an oncologist who collaborates with Dr. Johnson, said she believes that reprogramming may explain her recent, frustrating results treating metastatic breast cancer patients with an investigational inhibitor of the epidermal growth factor receptor (EGFR), a tyrosine kinase.
"We gave the inhibitor to patients with triple-negative breast cancer, where the EGFR is clearly upregulated, a big, juicy target, and yet only 25% of the patients responded. Most of the time, the cancers had alternative mechanisms to keep the EGFR pathway active," Dr. Carey hypothesized based on Dr. Johnson’s recent findings. "The good news was that 25% of the time the treatment worked," said Dr. Carey, professor of hematology oncology at the University of North Carolina and medical director of the university’s Breast Center.
The new finding on breast-cancer cell reprogramming "helps us understand why the EGFR inhibitor didn’t work in most patients, it helps us understand what cancer cells do, and it helps us design our next approach. Most cancer drug development right now targets kinases," she said in an interview.
"One way to approach this is to use multiple agents at once, but if you add drugs you also add toxicity and expense. And in some patients the cell doesn’t reprogram. We need to understand how reprogramming works," with the potential to develop agents that block reprogramming instead of trying to deal with the changes that reprogramming causes. "This is an explanation of why patients don’t respond to even targeted treatments, and it gives us a way forward to potentially prevent it. Reprogramming is reproducible and potentially targetable. I think we can get around it."
"Limiting emergence of heterogeneity is important because heterogeneity is what defeats us," Dr. Larry Norton, director of the Breast Center at Memorial Sloan-Kettering Cancer Center. New York, said at the conference.
"I need to understand reprogramming of the kinome, what a treatment does to the cancer, and how it influences the next treatment I should use," said Dr. David Cameron, professor of oncology at Edinburgh University. "Patients with breast cancer will be treated with a sequence of agents. We treat patients longer, more effectively, and with more drugs, so we need to worry about what the first drug does to the cancer before we come in with a second.
Giving a clinician’s perspective on the significance of reprogramming in a talk at the meeting, Dr. Cameron said, "we will have to optimize therapy by understanding what one treatment does so we can give the next treatment at the optimal time. If we unravel the way the biology changes in the presence of treatment perhaps we can hone our treatments more effectively."
Dr. Johnson said that he has started a company, KinoDyn, to apply kinase-assessment to treatment, although as of now the company has no funding or employees. Dr. Carey, Dr. Norton, and Dr. Cameron had no disclosures.
Twitter: @mitchelzoler
BRUSSELS – Metastatic breast cancer cells are even more adaptable and able to evade targeted treatment than researchers suspected as recently as a few months ago, which means they present a heightened treatment challenge that in many cases may be overcome only with multiple targeted therapies delivered at the same time.
The findings were discussed at IMPAKT 2013 Breast Cancer Conference, sponsored by the European Society for Medical Oncology.
The new wrinkle in drug resistance has been dubbed reprogramming, a way that metastatic breast cancer cells (but presumably a property shared by other advanced solid tumors as well) quickly respond to a drug that shuts down an essential cell protein, a kinase, by turning on other, alternative kinases within days of drug exposure. Many of the new, targeted therapies that have successfully treated advanced-stage breast cancer and other solid tumors are kinase inhibitors, such as trastuzumab (Herceptin) and lapatinib (Tykerb).
Using a newly-developed technique for assessing many different kinases within a cell at once, Gary Johnson, Ph.D., reported that treatment of isolated, advanced breast cancer cells in vitro with a kinase inhibitor drug produced within a week a dramatic shift in the cell’s overall kinase profile, something he calls the cell’s "kinome." Part of this reprogramming response probably occurs because of new genes that the cancer cell turns on or upregulates, and part is probably driven by epigenetic changes in the cell, said Dr. Johnson, professor and chairman of pharmacology at the University of North Carolina in Chapel Hill.
Clinicians familiar with this finding quickly recognized that the phenomenon is an important, new barrier to successful treatment in patients that will require creative solutions using rational, multidrug, or multi-sequence regimens.
Dr. Lisa A. Carey, an oncologist who collaborates with Dr. Johnson, said she believes that reprogramming may explain her recent, frustrating results treating metastatic breast cancer patients with an investigational inhibitor of the epidermal growth factor receptor (EGFR), a tyrosine kinase.
"We gave the inhibitor to patients with triple-negative breast cancer, where the EGFR is clearly upregulated, a big, juicy target, and yet only 25% of the patients responded. Most of the time, the cancers had alternative mechanisms to keep the EGFR pathway active," Dr. Carey hypothesized based on Dr. Johnson’s recent findings. "The good news was that 25% of the time the treatment worked," said Dr. Carey, professor of hematology oncology at the University of North Carolina and medical director of the university’s Breast Center.
The new finding on breast-cancer cell reprogramming "helps us understand why the EGFR inhibitor didn’t work in most patients, it helps us understand what cancer cells do, and it helps us design our next approach. Most cancer drug development right now targets kinases," she said in an interview.
"One way to approach this is to use multiple agents at once, but if you add drugs you also add toxicity and expense. And in some patients the cell doesn’t reprogram. We need to understand how reprogramming works," with the potential to develop agents that block reprogramming instead of trying to deal with the changes that reprogramming causes. "This is an explanation of why patients don’t respond to even targeted treatments, and it gives us a way forward to potentially prevent it. Reprogramming is reproducible and potentially targetable. I think we can get around it."
"Limiting emergence of heterogeneity is important because heterogeneity is what defeats us," Dr. Larry Norton, director of the Breast Center at Memorial Sloan-Kettering Cancer Center. New York, said at the conference.
"I need to understand reprogramming of the kinome, what a treatment does to the cancer, and how it influences the next treatment I should use," said Dr. David Cameron, professor of oncology at Edinburgh University. "Patients with breast cancer will be treated with a sequence of agents. We treat patients longer, more effectively, and with more drugs, so we need to worry about what the first drug does to the cancer before we come in with a second.
Giving a clinician’s perspective on the significance of reprogramming in a talk at the meeting, Dr. Cameron said, "we will have to optimize therapy by understanding what one treatment does so we can give the next treatment at the optimal time. If we unravel the way the biology changes in the presence of treatment perhaps we can hone our treatments more effectively."
Dr. Johnson said that he has started a company, KinoDyn, to apply kinase-assessment to treatment, although as of now the company has no funding or employees. Dr. Carey, Dr. Norton, and Dr. Cameron had no disclosures.
Twitter: @mitchelzoler
EXPERT ANALYSIS FROM IMPAKT 2013 BREAST CANCER CONFERENCE
Genetic tests gauge breast-cancer recurrence risk
BRUSSELS – A pair of genetic tests each showed the ability to aid long-term prognosis estimates in patients with estrogen receptor–positive breast cancer, based on results from two retrospective analyses reported at IMPAKT 2013 Breast Cancer Conference.
The new results mean that a total of three different genetic tests have now shown added prognostic utility in retrospective analyses, bringing the field closer to actually using these tests in routine practice. The tests would prove particularly useful for patients with estrogen receptor–positive, node-negative breast cancer by helping to find those who are at low risk for long-term metastatic disease and who could safely stop treatment after 5 years of hormonal therapy, said Dr. Michael Gnant, professor of surgery at the University of Vienna.
But other experts stressed that it’s premature to start routinely using these tests.
"We’re getting to a point where we can offer to our patients genomic assays that are clinically validated and with demonstrated utility," Dr. W. Fraser Symmans said during the meeting. But, he added, while oncologists are "on the brink" of using the tests routinely, "we need to confirm reproducibility among labs, and that the test works in that setting," said Dr. Symmans, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.
None of the three genetic test panels were designed to predict late recurrences, noted Dr. Peter C. Dubsky, a surgeon at the University of Vienna and a collaborator with Dr. Gnant. "These data will need further validation before actually being incorporated into clinical decision-making concerning adjuvant endocrine therapy beyond 5 years," Dr. Dubsky said in a written statement.
The analysis reported by Dr. Gnant and Dr. Dubsky included formalin-fixed and paraffin-embedded tumor specimens from 1,478 patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 trial, which had the primary goal of assessing two different 5-year treatment strategies in more than 3,700 postmenopausal women with estrogen receptor–positive breast cancer (J. Clin. Oncol. 2012;30:722-8).
Dr. Gnant, Dr. Dubsky, and their associates assessed the 1,478 specimens with the Prediction Analysis of Microarray test using a 58-gene classifier panel (PAM50), a test first reported in 2009 (J. Clin. Oncol. 2009;27:1160-7) that has since been commercialized as the Prosigna assay, available in Europe but not in the United States.
Using prespecified cutoffs on the PAM50 results for classifying patients as being at low, intermediate, and high risk for long term distant recurrences, the researchers tallied the rate of actual recurrences during a median follow-up of 11 years. The 15-year disease-free survival rate was 97.6% among low-risk patients, 90.9% in intermediate-risk patients, and 82.5% in high-risk patients, Dr. Gnant reported. The between-group differences were statistically significant.
The findings suggest that high-risk patients might be good candidates for extended adjuvant therapy, while low-risk patients, with a recurrence risk of less than 2% at 5-10 years and at 10-15 years following primary therapy "can be spared the side effects of extended adjuvant therapy," he said. The PAM50 risk of recurrence score "adds prognostic information beyond established clinicopathological factors."
The second analysis reported at the meeting retrospectively used medical records and specimens collected in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, which enrolled more than 6,000 postmenopausal women with localized invasive breast cancer (Lancet Oncology 2008;9:45-53). The researchers evaluated the prognostic efficacy of five different clinical, genetic, or histochemical test panels for predicting risk of distant recurrences during a median 10 years follow-up in 891 of the enrolled patients.
All five assessment panels yielded similar prognostic information during the first 5 years of follow-up. During the next 5 years, the strongest prognostic information came via the Clinical Treatment Score, which takes into account a patient’s nodal status, tumor grade and size, patient’s age, and treatment received, said Ivana Sestak, Ph.D., a statistician and epidemiologist at the University of London. The two most important prognostic features in this panel are tumor size and nodal status, she noted. Two other assessment panels – the PAM50 genetic panel and the Breast Cancer Index, a genetic test first described in 2011 – also provided statistically significant and clinically meaningful additional prediction of distant recurrences during 5-10 years of follow-up (Br. J. Cancer 2011;104:1762-9).
The other two tests Dr. Sestak and her associates evaluated did not add further prognostic information beyond what the Clinical Treatment Score provided. The uninformative tests were a set of four immunohistochemical markers (to estrogen, progesterone, HER2, and ki67), and the Oncotype Dx recurrence score – a 21-gene panel test marketed by Genomic Health.
"The PAM50 risk of recurrence score and the Breast Cancer Index may be used to identify estrogen receptor–positive breast cancer patients who are at increased risk of late recurrence and who may benefit from extended adjuvant hormonal therapy beyond 5 years," she concluded. But "none of these scores were developed to dictate treatment," she cautioned.
These findings, together with the PAM50 analysis from the ABCSG 8 study, solidify PAM50’s position as a validated prognostic tool, Dr. Gnant said.
In addition to PAM50 and the Breast Cancer Index, a third genetic test recently shown effective for predicting long-term recurrence risk in similar patients is the EndoPredict (Ann. Oncol. 2013;24:640-7).
All three assays can now be considered validated for longer-term prognosis in patients with endocrine-responsive, lymph node–negative breast cancer, Dr. Symmans said.
The conference was sponsored by the European Society for Medical Oncology.
Dr. Gnant disclosed ties to Amgen, Pfizer, Novartis, GlaxoSmithKline, Bayer, Sandoz, AstraZeneca, Genomic Health, NanoString Technologies, Sanofi-Aventis, and Roche. Dr. Sestak had no disclosures. Dr. Symmans is cofounder of, and has equity in, Nuvera Biosciences. Dr. Dubsky disclosed ties to AstraZeneca, Novartis, Sividon Diagnostica, and Pfizer.
Twitter: @mitchelzoler
The Breast Cancer Index and the PAM50 and EndoPredict tests were all developed as prognostic assays. They were not designed to, nor have they been demonstrated to, predict patient sensitivity to an endocrine treatment or to help select a class of endocrine agent to use in therapy. Despite these limitations, the data presented on all three tests suggest that they perform well for discriminating recurrence risk among patients with hormone-receptor positive, lymph-node negative breast cancer. So far, there is not good evidence that they can predict outcomes in lymph-node positive patients.
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Mitchel L. Zoler/IMNG Medical Media
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The patients with the greatest potential for stopping treatment after 5 years are those who also have HER2-negative disease and grade 1 or 2 disease, similar to the women enrolled in the ABCSG 8 trial.
Another attractive feature of these tests is that they can be performed by local pathology laboratories, precluding the need to send specimens to distant testing sites. The pathology community has been waiting a long time to more fully participate in the genomic diagnostic/personalized medicine arena.
The next step is to confirm the reproducibility of these tests when used by a variety of labs, essentially guaranteeing quality control. You need a critical mass of labs working together and using these tests to be sure that everyone gets clinically valid and reproducible results. I expect this to happen during the next year.
Dr. W. Fraser Symmans is professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston. He said that he is a c-founder of, and has equity in, Nuvera Biosciences. He made these comments as an invited discussant for the reports at the meeting and in an interview.
The Breast Cancer Index and the PAM50 and EndoPredict tests were all developed as prognostic assays. They were not designed to, nor have they been demonstrated to, predict patient sensitivity to an endocrine treatment or to help select a class of endocrine agent to use in therapy. Despite these limitations, the data presented on all three tests suggest that they perform well for discriminating recurrence risk among patients with hormone-receptor positive, lymph-node negative breast cancer. So far, there is not good evidence that they can predict outcomes in lymph-node positive patients.
|
Mitchel L. Zoler/IMNG Medical Media
|
The patients with the greatest potential for stopping treatment after 5 years are those who also have HER2-negative disease and grade 1 or 2 disease, similar to the women enrolled in the ABCSG 8 trial.
Another attractive feature of these tests is that they can be performed by local pathology laboratories, precluding the need to send specimens to distant testing sites. The pathology community has been waiting a long time to more fully participate in the genomic diagnostic/personalized medicine arena.
The next step is to confirm the reproducibility of these tests when used by a variety of labs, essentially guaranteeing quality control. You need a critical mass of labs working together and using these tests to be sure that everyone gets clinically valid and reproducible results. I expect this to happen during the next year.
Dr. W. Fraser Symmans is professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston. He said that he is a c-founder of, and has equity in, Nuvera Biosciences. He made these comments as an invited discussant for the reports at the meeting and in an interview.
The Breast Cancer Index and the PAM50 and EndoPredict tests were all developed as prognostic assays. They were not designed to, nor have they been demonstrated to, predict patient sensitivity to an endocrine treatment or to help select a class of endocrine agent to use in therapy. Despite these limitations, the data presented on all three tests suggest that they perform well for discriminating recurrence risk among patients with hormone-receptor positive, lymph-node negative breast cancer. So far, there is not good evidence that they can predict outcomes in lymph-node positive patients.
|
Mitchel L. Zoler/IMNG Medical Media
|
The patients with the greatest potential for stopping treatment after 5 years are those who also have HER2-negative disease and grade 1 or 2 disease, similar to the women enrolled in the ABCSG 8 trial.
Another attractive feature of these tests is that they can be performed by local pathology laboratories, precluding the need to send specimens to distant testing sites. The pathology community has been waiting a long time to more fully participate in the genomic diagnostic/personalized medicine arena.
The next step is to confirm the reproducibility of these tests when used by a variety of labs, essentially guaranteeing quality control. You need a critical mass of labs working together and using these tests to be sure that everyone gets clinically valid and reproducible results. I expect this to happen during the next year.
Dr. W. Fraser Symmans is professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston. He said that he is a c-founder of, and has equity in, Nuvera Biosciences. He made these comments as an invited discussant for the reports at the meeting and in an interview.
BRUSSELS – A pair of genetic tests each showed the ability to aid long-term prognosis estimates in patients with estrogen receptor–positive breast cancer, based on results from two retrospective analyses reported at IMPAKT 2013 Breast Cancer Conference.
The new results mean that a total of three different genetic tests have now shown added prognostic utility in retrospective analyses, bringing the field closer to actually using these tests in routine practice. The tests would prove particularly useful for patients with estrogen receptor–positive, node-negative breast cancer by helping to find those who are at low risk for long-term metastatic disease and who could safely stop treatment after 5 years of hormonal therapy, said Dr. Michael Gnant, professor of surgery at the University of Vienna.
But other experts stressed that it’s premature to start routinely using these tests.
"We’re getting to a point where we can offer to our patients genomic assays that are clinically validated and with demonstrated utility," Dr. W. Fraser Symmans said during the meeting. But, he added, while oncologists are "on the brink" of using the tests routinely, "we need to confirm reproducibility among labs, and that the test works in that setting," said Dr. Symmans, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.
None of the three genetic test panels were designed to predict late recurrences, noted Dr. Peter C. Dubsky, a surgeon at the University of Vienna and a collaborator with Dr. Gnant. "These data will need further validation before actually being incorporated into clinical decision-making concerning adjuvant endocrine therapy beyond 5 years," Dr. Dubsky said in a written statement.
The analysis reported by Dr. Gnant and Dr. Dubsky included formalin-fixed and paraffin-embedded tumor specimens from 1,478 patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 trial, which had the primary goal of assessing two different 5-year treatment strategies in more than 3,700 postmenopausal women with estrogen receptor–positive breast cancer (J. Clin. Oncol. 2012;30:722-8).
Dr. Gnant, Dr. Dubsky, and their associates assessed the 1,478 specimens with the Prediction Analysis of Microarray test using a 58-gene classifier panel (PAM50), a test first reported in 2009 (J. Clin. Oncol. 2009;27:1160-7) that has since been commercialized as the Prosigna assay, available in Europe but not in the United States.
Using prespecified cutoffs on the PAM50 results for classifying patients as being at low, intermediate, and high risk for long term distant recurrences, the researchers tallied the rate of actual recurrences during a median follow-up of 11 years. The 15-year disease-free survival rate was 97.6% among low-risk patients, 90.9% in intermediate-risk patients, and 82.5% in high-risk patients, Dr. Gnant reported. The between-group differences were statistically significant.
The findings suggest that high-risk patients might be good candidates for extended adjuvant therapy, while low-risk patients, with a recurrence risk of less than 2% at 5-10 years and at 10-15 years following primary therapy "can be spared the side effects of extended adjuvant therapy," he said. The PAM50 risk of recurrence score "adds prognostic information beyond established clinicopathological factors."
The second analysis reported at the meeting retrospectively used medical records and specimens collected in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, which enrolled more than 6,000 postmenopausal women with localized invasive breast cancer (Lancet Oncology 2008;9:45-53). The researchers evaluated the prognostic efficacy of five different clinical, genetic, or histochemical test panels for predicting risk of distant recurrences during a median 10 years follow-up in 891 of the enrolled patients.
All five assessment panels yielded similar prognostic information during the first 5 years of follow-up. During the next 5 years, the strongest prognostic information came via the Clinical Treatment Score, which takes into account a patient’s nodal status, tumor grade and size, patient’s age, and treatment received, said Ivana Sestak, Ph.D., a statistician and epidemiologist at the University of London. The two most important prognostic features in this panel are tumor size and nodal status, she noted. Two other assessment panels – the PAM50 genetic panel and the Breast Cancer Index, a genetic test first described in 2011 – also provided statistically significant and clinically meaningful additional prediction of distant recurrences during 5-10 years of follow-up (Br. J. Cancer 2011;104:1762-9).
The other two tests Dr. Sestak and her associates evaluated did not add further prognostic information beyond what the Clinical Treatment Score provided. The uninformative tests were a set of four immunohistochemical markers (to estrogen, progesterone, HER2, and ki67), and the Oncotype Dx recurrence score – a 21-gene panel test marketed by Genomic Health.
"The PAM50 risk of recurrence score and the Breast Cancer Index may be used to identify estrogen receptor–positive breast cancer patients who are at increased risk of late recurrence and who may benefit from extended adjuvant hormonal therapy beyond 5 years," she concluded. But "none of these scores were developed to dictate treatment," she cautioned.
These findings, together with the PAM50 analysis from the ABCSG 8 study, solidify PAM50’s position as a validated prognostic tool, Dr. Gnant said.
In addition to PAM50 and the Breast Cancer Index, a third genetic test recently shown effective for predicting long-term recurrence risk in similar patients is the EndoPredict (Ann. Oncol. 2013;24:640-7).
All three assays can now be considered validated for longer-term prognosis in patients with endocrine-responsive, lymph node–negative breast cancer, Dr. Symmans said.
The conference was sponsored by the European Society for Medical Oncology.
Dr. Gnant disclosed ties to Amgen, Pfizer, Novartis, GlaxoSmithKline, Bayer, Sandoz, AstraZeneca, Genomic Health, NanoString Technologies, Sanofi-Aventis, and Roche. Dr. Sestak had no disclosures. Dr. Symmans is cofounder of, and has equity in, Nuvera Biosciences. Dr. Dubsky disclosed ties to AstraZeneca, Novartis, Sividon Diagnostica, and Pfizer.
Twitter: @mitchelzoler
BRUSSELS – A pair of genetic tests each showed the ability to aid long-term prognosis estimates in patients with estrogen receptor–positive breast cancer, based on results from two retrospective analyses reported at IMPAKT 2013 Breast Cancer Conference.
The new results mean that a total of three different genetic tests have now shown added prognostic utility in retrospective analyses, bringing the field closer to actually using these tests in routine practice. The tests would prove particularly useful for patients with estrogen receptor–positive, node-negative breast cancer by helping to find those who are at low risk for long-term metastatic disease and who could safely stop treatment after 5 years of hormonal therapy, said Dr. Michael Gnant, professor of surgery at the University of Vienna.
But other experts stressed that it’s premature to start routinely using these tests.
"We’re getting to a point where we can offer to our patients genomic assays that are clinically validated and with demonstrated utility," Dr. W. Fraser Symmans said during the meeting. But, he added, while oncologists are "on the brink" of using the tests routinely, "we need to confirm reproducibility among labs, and that the test works in that setting," said Dr. Symmans, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.
None of the three genetic test panels were designed to predict late recurrences, noted Dr. Peter C. Dubsky, a surgeon at the University of Vienna and a collaborator with Dr. Gnant. "These data will need further validation before actually being incorporated into clinical decision-making concerning adjuvant endocrine therapy beyond 5 years," Dr. Dubsky said in a written statement.
The analysis reported by Dr. Gnant and Dr. Dubsky included formalin-fixed and paraffin-embedded tumor specimens from 1,478 patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 trial, which had the primary goal of assessing two different 5-year treatment strategies in more than 3,700 postmenopausal women with estrogen receptor–positive breast cancer (J. Clin. Oncol. 2012;30:722-8).
Dr. Gnant, Dr. Dubsky, and their associates assessed the 1,478 specimens with the Prediction Analysis of Microarray test using a 58-gene classifier panel (PAM50), a test first reported in 2009 (J. Clin. Oncol. 2009;27:1160-7) that has since been commercialized as the Prosigna assay, available in Europe but not in the United States.
Using prespecified cutoffs on the PAM50 results for classifying patients as being at low, intermediate, and high risk for long term distant recurrences, the researchers tallied the rate of actual recurrences during a median follow-up of 11 years. The 15-year disease-free survival rate was 97.6% among low-risk patients, 90.9% in intermediate-risk patients, and 82.5% in high-risk patients, Dr. Gnant reported. The between-group differences were statistically significant.
The findings suggest that high-risk patients might be good candidates for extended adjuvant therapy, while low-risk patients, with a recurrence risk of less than 2% at 5-10 years and at 10-15 years following primary therapy "can be spared the side effects of extended adjuvant therapy," he said. The PAM50 risk of recurrence score "adds prognostic information beyond established clinicopathological factors."
The second analysis reported at the meeting retrospectively used medical records and specimens collected in the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, which enrolled more than 6,000 postmenopausal women with localized invasive breast cancer (Lancet Oncology 2008;9:45-53). The researchers evaluated the prognostic efficacy of five different clinical, genetic, or histochemical test panels for predicting risk of distant recurrences during a median 10 years follow-up in 891 of the enrolled patients.
All five assessment panels yielded similar prognostic information during the first 5 years of follow-up. During the next 5 years, the strongest prognostic information came via the Clinical Treatment Score, which takes into account a patient’s nodal status, tumor grade and size, patient’s age, and treatment received, said Ivana Sestak, Ph.D., a statistician and epidemiologist at the University of London. The two most important prognostic features in this panel are tumor size and nodal status, she noted. Two other assessment panels – the PAM50 genetic panel and the Breast Cancer Index, a genetic test first described in 2011 – also provided statistically significant and clinically meaningful additional prediction of distant recurrences during 5-10 years of follow-up (Br. J. Cancer 2011;104:1762-9).
The other two tests Dr. Sestak and her associates evaluated did not add further prognostic information beyond what the Clinical Treatment Score provided. The uninformative tests were a set of four immunohistochemical markers (to estrogen, progesterone, HER2, and ki67), and the Oncotype Dx recurrence score – a 21-gene panel test marketed by Genomic Health.
"The PAM50 risk of recurrence score and the Breast Cancer Index may be used to identify estrogen receptor–positive breast cancer patients who are at increased risk of late recurrence and who may benefit from extended adjuvant hormonal therapy beyond 5 years," she concluded. But "none of these scores were developed to dictate treatment," she cautioned.
These findings, together with the PAM50 analysis from the ABCSG 8 study, solidify PAM50’s position as a validated prognostic tool, Dr. Gnant said.
In addition to PAM50 and the Breast Cancer Index, a third genetic test recently shown effective for predicting long-term recurrence risk in similar patients is the EndoPredict (Ann. Oncol. 2013;24:640-7).
All three assays can now be considered validated for longer-term prognosis in patients with endocrine-responsive, lymph node–negative breast cancer, Dr. Symmans said.
The conference was sponsored by the European Society for Medical Oncology.
Dr. Gnant disclosed ties to Amgen, Pfizer, Novartis, GlaxoSmithKline, Bayer, Sandoz, AstraZeneca, Genomic Health, NanoString Technologies, Sanofi-Aventis, and Roche. Dr. Sestak had no disclosures. Dr. Symmans is cofounder of, and has equity in, Nuvera Biosciences. Dr. Dubsky disclosed ties to AstraZeneca, Novartis, Sividon Diagnostica, and Pfizer.
Twitter: @mitchelzoler
AT IMPAKT 2013 BREAST CANCER CONFERENCE
Major finding: Low-risk patients by the PAM50 test had 97.6% 15-year disease-free survival compared with 82.5% in high-risk patients.
Data source: A retrospective analysis of 1,478 women enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 trial.
Disclosures: Dr. Gnant disclosed ties to Amgen, Pfizer, Novartis, GlaxoSmithKline, Bayer, Sandoz, AstraZeneca, Genomic Health, NanoString Technologies, Sanofi-Aventis, and Roche. Dr. Sestak had no disclosures. Dr. Symmans is cofounder of, and has equity in, Nuvera Biosciences. Dr. Dubsky disclosed ties to AstraZeneca, Novartis, Sividon Diagnostica, and Pfizer.
