Genetic biomarkers may be best bet for augmenting mammography screening

SEATTLE – Biomarkers may soon join other modalities for the early detection of breast cancer and identification of women at high risk for the disease, Susan L. Neuhausen, Ph.D., told attendees of the Global Biomarkers Consortium.

“There is an urgent need for biomarkers for breast cancer,” she maintained, citing its high prevalence and considerable mortality, coupled with better outcomes and lesser treatment requirements when it is caught early.

“I really think that for a lot of these biomarkers [in development], maybe their best use will be to augment mammographic screening, especially in the short term as they are being developed,” she speculated. Ultimately, “the hope – similar to PSA [prostate-specific antigen], where you can use it to detect cancer as well as use it as a marker of recurrence – is that these biomarkers of early detection will be developed to have the same attributes.”

Genetic biomarkers

“To me, the current best biomarker is actually a genetic biomarker,” said Dr. Neuhausen, who is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research, Population Sciences, and also coleader of the cancer control and population sciences program, Comprehensive Cancer Center, at the Beckman Research Institute, City of Hope, in Duarte, Calif.

Identifying the breast cancer susceptibility genes BRCA 1 and BRCA 2 paved the way for targeted chemoprevention and prophylactic surgery, which have been highly effective in reducing the incidence of breast cancer as well as ovarian cancer. However, mutations in these genes account for no more than approximately 5% of all breast cancers.

“There has been identification of additional moderate- to high-risk genes, and the strategies that work to prevent cancer in BRCA 1 and 2 carriers are the same that can used for these other high-risk genes,” Dr. Neuhausen noted. For example, mutations of partner and localizer of BRCA2 (PALB2) have been linked to heightened breast cancer risk (N Engl J Med. 2014;371:497-506). Additionally, many companies now offer multigene clinical risk panels.

“The problem or the issue at the current time is that we really don’t know what the risk of cancer in unaffected women who are carrying mutations in these genes is,” she commented. “The good news is there is a large European, United States, and Canadian study that is actually going to be screening for mutations in a total of about 25,000 women, so that similar to what’s been done in BRCA 1 and 2, we will actually have better risk estimates that one can then use for these women.”

A U.S. genome-wide association research effort, the Breast Cancer Surveillance Consortium (BCSC), has thus far identified about 100 loci linked to an increased risk of developing breast cancer, according to Dr. Neuhausen. “On an individual level, these really don’t account for much risk. However, if you combine them, they actually do,” she said.

Applied clinically, a polygenic risk score incorporating 77 single-nucleotide polymorphisms can stratify women into quintiles of risk (J Natl Cancer Inst. 2015;107(5):djv036). Among women without a family history of the disease, lifetime risk ranges from 5.2% for those in the lowest quintile to 16.6% for those in the highest.

Moreover, adding the polygenic risk score to the commonly used BCSC model increases the area under the curve from 0.66 to 0.69 for breast cancer risk prediction. It also results in reclassification of some women, in particular, identifying an additional 3% as having a greater than 3% risk of developing the disease over 5 years. “So this actually does have good discrimination and is something that can be useful moving forward,” Dr. Neuhausen commented.

“We have these low-, moderate-, and high-risk genes, and they really all need to be incorporated into models. There is research ongoing to try to incorporate all of them into models along with lifestyle factors and mammography, family history, that kind of thing,” she said. “But I really think that these genetic markers are very important because rather than early detection, if we can prevent breast cancer, that’s actually the real goal.”

Other biomarkers

A variety of other, nongenetic biomarkers for early breast cancer detection and risk stratification are generally less far along in development, but several have shown promise, according to Dr. Neuhausen.

In the realm of proteomics, a three–amino acid profile detectable in saliva that exploits the hypermetabolic and hypercatabolic nature of cancer was found to have an area under the curve of 0.916 for differentiating women with early breast cancer from unaffected peers (Clin Chim Acta. 2015;447:23-31). “It was only a very small study and they really need to look further, but I think it was an intriguing idea,” she commented.

Infrared spectroscopy of plasma identified a protein fingerprint that had roughly 90% sensitivity and 80% specificity for detecting breast cancer in a cohort that included women with the disease, women with benign breast conditions, and healthy women (BMC Cancer. 2015;15:408). And a pair of proteins in serum—HSP27 and 14-3-3 sigma—accurately distinguished breast cancer cases from controls in a Chinese population (Proteomics. 2003;3:433-9).

One study has suggested how proteomic biomarkers might be integrated with conventional modalities, showing that a five-protein signature in serum (dtectDx Breast, Provista) performed well among women younger than age 50 years for differentiating benign breast lesions from invasive breast cancer in those with a BI-RADS 3 or 4 mammogram (J Clin Oncol. 2014;32(26 Suppl 20). However, the signature had a fairly high false-positive rate, Dr. Neuhausen noted.

As for yet other types of biomarkers, a panel of circulating cell-free methylated DNA of eight tumor suppressor genes was found to have sensitivity and specificity exceeding 90% for differentiating between samples from breast cancer patients and from unaffected women (PLoS One. 2011;6:e16080).MicroRNA profiles of breast cancer have been identified, but findings have generally been inconsistent across studies (Breast Cancer. 2015;7:59-79). Somatic mutations in p53 and PI3KCA, present in about a third of breast cancers, currently have issues when applied to screening. “Those kinds of things are maybe better for determining response to treatment and that kind of thing. Are they ready for early detection? Not really,” Dr. Neuhausen said.

The situation is similar for DNA copy number, although intriguingly, a recent study of a prenatal test looking for fetal copy number aberrations in maternal plasma incidentally discovered maternal cell-free DNA that had copy number changes (JAMA Oncol. 2015 June 5.doi: 10.1001/jamaoncol.2015.1883). Imaging ultimately found various cancers in three women out of about 4,000 tested.

Dr. Neuhausen disclosed that she had no relevant conflicts of interest.

SEATTLE – Biomarkers may soon join other modalities for the early detection of breast cancer and identification of women at high risk for the disease, Susan L. Neuhausen, Ph.D., told attendees of the Global Biomarkers Consortium.

“There is an urgent need for biomarkers for breast cancer,” she maintained, citing its high prevalence and considerable mortality, coupled with better outcomes and lesser treatment requirements when it is caught early.

“I really think that for a lot of these biomarkers [in development], maybe their best use will be to augment mammographic screening, especially in the short term as they are being developed,” she speculated. Ultimately, “the hope – similar to PSA [prostate-specific antigen], where you can use it to detect cancer as well as use it as a marker of recurrence – is that these biomarkers of early detection will be developed to have the same attributes.”

Genetic biomarkers

“To me, the current best biomarker is actually a genetic biomarker,” said Dr. Neuhausen, who is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research, Population Sciences, and also coleader of the cancer control and population sciences program, Comprehensive Cancer Center, at the Beckman Research Institute, City of Hope, in Duarte, Calif.

Identifying the breast cancer susceptibility genes BRCA 1 and BRCA 2 paved the way for targeted chemoprevention and prophylactic surgery, which have been highly effective in reducing the incidence of breast cancer as well as ovarian cancer. However, mutations in these genes account for no more than approximately 5% of all breast cancers.

“There has been identification of additional moderate- to high-risk genes, and the strategies that work to prevent cancer in BRCA 1 and 2 carriers are the same that can used for these other high-risk genes,” Dr. Neuhausen noted. For example, mutations of partner and localizer of BRCA2 (PALB2) have been linked to heightened breast cancer risk (N Engl J Med. 2014;371:497-506). Additionally, many companies now offer multigene clinical risk panels.

“The problem or the issue at the current time is that we really don’t know what the risk of cancer in unaffected women who are carrying mutations in these genes is,” she commented. “The good news is there is a large European, United States, and Canadian study that is actually going to be screening for mutations in a total of about 25,000 women, so that similar to what’s been done in BRCA 1 and 2, we will actually have better risk estimates that one can then use for these women.”

A U.S. genome-wide association research effort, the Breast Cancer Surveillance Consortium (BCSC), has thus far identified about 100 loci linked to an increased risk of developing breast cancer, according to Dr. Neuhausen. “On an individual level, these really don’t account for much risk. However, if you combine them, they actually do,” she said.

Applied clinically, a polygenic risk score incorporating 77 single-nucleotide polymorphisms can stratify women into quintiles of risk (J Natl Cancer Inst. 2015;107(5):djv036). Among women without a family history of the disease, lifetime risk ranges from 5.2% for those in the lowest quintile to 16.6% for those in the highest.

Moreover, adding the polygenic risk score to the commonly used BCSC model increases the area under the curve from 0.66 to 0.69 for breast cancer risk prediction. It also results in reclassification of some women, in particular, identifying an additional 3% as having a greater than 3% risk of developing the disease over 5 years. “So this actually does have good discrimination and is something that can be useful moving forward,” Dr. Neuhausen commented.

“We have these low-, moderate-, and high-risk genes, and they really all need to be incorporated into models. There is research ongoing to try to incorporate all of them into models along with lifestyle factors and mammography, family history, that kind of thing,” she said. “But I really think that these genetic markers are very important because rather than early detection, if we can prevent breast cancer, that’s actually the real goal.”

Other biomarkers

A variety of other, nongenetic biomarkers for early breast cancer detection and risk stratification are generally less far along in development, but several have shown promise, according to Dr. Neuhausen.

In the realm of proteomics, a three–amino acid profile detectable in saliva that exploits the hypermetabolic and hypercatabolic nature of cancer was found to have an area under the curve of 0.916 for differentiating women with early breast cancer from unaffected peers (Clin Chim Acta. 2015;447:23-31). “It was only a very small study and they really need to look further, but I think it was an intriguing idea,” she commented.

Infrared spectroscopy of plasma identified a protein fingerprint that had roughly 90% sensitivity and 80% specificity for detecting breast cancer in a cohort that included women with the disease, women with benign breast conditions, and healthy women (BMC Cancer. 2015;15:408). And a pair of proteins in serum—HSP27 and 14-3-3 sigma—accurately distinguished breast cancer cases from controls in a Chinese population (Proteomics. 2003;3:433-9).

One study has suggested how proteomic biomarkers might be integrated with conventional modalities, showing that a five-protein signature in serum (dtectDx Breast, Provista) performed well among women younger than age 50 years for differentiating benign breast lesions from invasive breast cancer in those with a BI-RADS 3 or 4 mammogram (J Clin Oncol. 2014;32(26 Suppl 20). However, the signature had a fairly high false-positive rate, Dr. Neuhausen noted.

As for yet other types of biomarkers, a panel of circulating cell-free methylated DNA of eight tumor suppressor genes was found to have sensitivity and specificity exceeding 90% for differentiating between samples from breast cancer patients and from unaffected women (PLoS One. 2011;6:e16080).MicroRNA profiles of breast cancer have been identified, but findings have generally been inconsistent across studies (Breast Cancer. 2015;7:59-79). Somatic mutations in p53 and PI3KCA, present in about a third of breast cancers, currently have issues when applied to screening. “Those kinds of things are maybe better for determining response to treatment and that kind of thing. Are they ready for early detection? Not really,” Dr. Neuhausen said.

The situation is similar for DNA copy number, although intriguingly, a recent study of a prenatal test looking for fetal copy number aberrations in maternal plasma incidentally discovered maternal cell-free DNA that had copy number changes (JAMA Oncol. 2015 June 5.doi: 10.1001/jamaoncol.2015.1883). Imaging ultimately found various cancers in three women out of about 4,000 tested.

Dr. Neuhausen disclosed that she had no relevant conflicts of interest.

SEATTLE – Biomarkers may soon join other modalities for the early detection of breast cancer and identification of women at high risk for the disease, Susan L. Neuhausen, Ph.D., told attendees of the Global Biomarkers Consortium.

“There is an urgent need for biomarkers for breast cancer,” she maintained, citing its high prevalence and considerable mortality, coupled with better outcomes and lesser treatment requirements when it is caught early.

“I really think that for a lot of these biomarkers [in development], maybe their best use will be to augment mammographic screening, especially in the short term as they are being developed,” she speculated. Ultimately, “the hope – similar to PSA [prostate-specific antigen], where you can use it to detect cancer as well as use it as a marker of recurrence – is that these biomarkers of early detection will be developed to have the same attributes.”

Genetic biomarkers

“To me, the current best biomarker is actually a genetic biomarker,” said Dr. Neuhausen, who is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research, Population Sciences, and also coleader of the cancer control and population sciences program, Comprehensive Cancer Center, at the Beckman Research Institute, City of Hope, in Duarte, Calif.

Identifying the breast cancer susceptibility genes BRCA 1 and BRCA 2 paved the way for targeted chemoprevention and prophylactic surgery, which have been highly effective in reducing the incidence of breast cancer as well as ovarian cancer. However, mutations in these genes account for no more than approximately 5% of all breast cancers.

“There has been identification of additional moderate- to high-risk genes, and the strategies that work to prevent cancer in BRCA 1 and 2 carriers are the same that can used for these other high-risk genes,” Dr. Neuhausen noted. For example, mutations of partner and localizer of BRCA2 (PALB2) have been linked to heightened breast cancer risk (N Engl J Med. 2014;371:497-506). Additionally, many companies now offer multigene clinical risk panels.

“The problem or the issue at the current time is that we really don’t know what the risk of cancer in unaffected women who are carrying mutations in these genes is,” she commented. “The good news is there is a large European, United States, and Canadian study that is actually going to be screening for mutations in a total of about 25,000 women, so that similar to what’s been done in BRCA 1 and 2, we will actually have better risk estimates that one can then use for these women.”

A U.S. genome-wide association research effort, the Breast Cancer Surveillance Consortium (BCSC), has thus far identified about 100 loci linked to an increased risk of developing breast cancer, according to Dr. Neuhausen. “On an individual level, these really don’t account for much risk. However, if you combine them, they actually do,” she said.

Applied clinically, a polygenic risk score incorporating 77 single-nucleotide polymorphisms can stratify women into quintiles of risk (J Natl Cancer Inst. 2015;107(5):djv036). Among women without a family history of the disease, lifetime risk ranges from 5.2% for those in the lowest quintile to 16.6% for those in the highest.

Moreover, adding the polygenic risk score to the commonly used BCSC model increases the area under the curve from 0.66 to 0.69 for breast cancer risk prediction. It also results in reclassification of some women, in particular, identifying an additional 3% as having a greater than 3% risk of developing the disease over 5 years. “So this actually does have good discrimination and is something that can be useful moving forward,” Dr. Neuhausen commented.

“We have these low-, moderate-, and high-risk genes, and they really all need to be incorporated into models. There is research ongoing to try to incorporate all of them into models along with lifestyle factors and mammography, family history, that kind of thing,” she said. “But I really think that these genetic markers are very important because rather than early detection, if we can prevent breast cancer, that’s actually the real goal.”

Other biomarkers

A variety of other, nongenetic biomarkers for early breast cancer detection and risk stratification are generally less far along in development, but several have shown promise, according to Dr. Neuhausen.

In the realm of proteomics, a three–amino acid profile detectable in saliva that exploits the hypermetabolic and hypercatabolic nature of cancer was found to have an area under the curve of 0.916 for differentiating women with early breast cancer from unaffected peers (Clin Chim Acta. 2015;447:23-31). “It was only a very small study and they really need to look further, but I think it was an intriguing idea,” she commented.

Infrared spectroscopy of plasma identified a protein fingerprint that had roughly 90% sensitivity and 80% specificity for detecting breast cancer in a cohort that included women with the disease, women with benign breast conditions, and healthy women (BMC Cancer. 2015;15:408). And a pair of proteins in serum—HSP27 and 14-3-3 sigma—accurately distinguished breast cancer cases from controls in a Chinese population (Proteomics. 2003;3:433-9).

One study has suggested how proteomic biomarkers might be integrated with conventional modalities, showing that a five-protein signature in serum (dtectDx Breast, Provista) performed well among women younger than age 50 years for differentiating benign breast lesions from invasive breast cancer in those with a BI-RADS 3 or 4 mammogram (J Clin Oncol. 2014;32(26 Suppl 20). However, the signature had a fairly high false-positive rate, Dr. Neuhausen noted.

As for yet other types of biomarkers, a panel of circulating cell-free methylated DNA of eight tumor suppressor genes was found to have sensitivity and specificity exceeding 90% for differentiating between samples from breast cancer patients and from unaffected women (PLoS One. 2011;6:e16080).MicroRNA profiles of breast cancer have been identified, but findings have generally been inconsistent across studies (Breast Cancer. 2015;7:59-79). Somatic mutations in p53 and PI3KCA, present in about a third of breast cancers, currently have issues when applied to screening. “Those kinds of things are maybe better for determining response to treatment and that kind of thing. Are they ready for early detection? Not really,” Dr. Neuhausen said.

The situation is similar for DNA copy number, although intriguingly, a recent study of a prenatal test looking for fetal copy number aberrations in maternal plasma incidentally discovered maternal cell-free DNA that had copy number changes (JAMA Oncol. 2015 June 5.doi: 10.1001/jamaoncol.2015.1883). Imaging ultimately found various cancers in three women out of about 4,000 tested.

Dr. Neuhausen disclosed that she had no relevant conflicts of interest.