Breast Cancer

The probability of long-term amenorrhea is similarly high in all premenopausal breast cancer patients age 35 years and older who undergo chemotherapy, regardless of whether they carry a BRCA1 or BRCA2 mutation.

Age at treatment and use of tamoxifen were important predictors of chemotherapy-induced amenorrhea in a multicenter survey of 1,954 premenopausal women aged 26-47 with invasive breast cancers and BRCA1 or BRCA2 mutations. In the absence of chemotherapy, however, tamoxifen alone was not associated with the onset of long-term amenorrhea.

The findings indicate that all women are at risk of chemotherapy-induced amenorrhea and BRCA1 or BRCA2 status per se should not be an indication for referral to a fertility clinic, according to Dr. Adriana Valentini of the Women’s College Research Institute, Toronto, and her colleagues in the Hereditary Breast Cancer Clinical Study Group.

Breast cancer patients who wish to preserve fertility should be aware of the synergistic impact of chemotherapy and tamoxifen on inducing long-term amenorrhea and possibly menopause, the researchers said. The study was published online Aug. 26 in the Journal of Clinical Oncology.

The researchers compared age of amenorrhea onset after breast cancer diagnosis for women who were and were not treated with chemotherapy, alone or with tamoxifen. Chemotherapy-induced amenorrhea was defined as 2 or more years of amenorrhea, with no resumption of menses, commencing within 2 years of initiating chemotherapy (J. Clin. Oncol. 2013 Aug. 26 [doi:10.1200/JCO.2012.47.7893]).

Patients were selected from a database of 13,004 BRCA1 and BRCA2 mutation carriers and 2,451 noncarriers at one of 62 participating centers in seven countries. The women sought testing for BRCA1 and BRCA2 mutations because of a personal or family history of breast or ovarian cancer. They were diagnosed with invasive breast cancer between 26 and 47 years of age and were premenopausal at the time of diagnosis.

In total, 1,954 BRCA carriers with breast cancer were eligible; 1,506 (77%) carried a BRCA1 mutation, 436 (22%) carried a BRCA2 mutation, and 12 (0.6%) carried both mutations.

Of the 1,954 carrier patients, 1,426 received chemotherapy and 35% of them experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea.

The study also included 167 noncarrier women with breast cancer as a comparison group; 100 of these women (59%) received chemotherapy, and 49% developed chemotherapy-induced amenorrhea.

The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed at or before age 30 years, 33% for women diagnosed at age 31-44 years, and 79% for women diagnosed after age 45 years (P trend greater than or equal to .001).

Tamoxifen was give to 478 carrier patients, and 410 (86%) received both tamoxifen and chemotherapy. Their probability of induced amenorrhea was 52%, compared with 29% for those who did not receive tamoxifen (P less than or equal to .001).

The probability of chemotherapy-induced amenorrhea was significantly higher for BRCA2 carriers than for BRCA1 carriers (46.8% v 32.7%; P less than or equal to .001). By age 38 years, 50% of BRCA2 carriers were expected to experience amenorrhea after chemotherapy, compared with the age of 40 years expected for BRCA1 carriers.

Among all women who reached age 56 years, the mean age of menopause was 45.4 years for those who received chemotherapy and resumed menses, and 49 years for those who did not receive chemotherapy (P less than or equal to .001), a difference of 3.6 years.

Among women who had a BRCA1 mutation and reached age 56 years, the mean age of menopause was 45.5 years for those who received chemotherapy and 48.7 years for those who did not receive chemotherapy (P less than or equal to .001).

Among women who had a BRCA2 mutation and reached age 56 years, the mean age of menopause was 45.2 years for those who received chemotherapy and 49.9 years for those who did not receive chemotherapy (P less than or equal to .003).

The study was supported by the Canadian Breast Cancer Research Alliance, the Canadian Cancer Research Society Research Initiative, Fonds de Recherche en Sante´ du Que´ bec, and National Institutes of Health Grant No. R01 CA74415. The authors reported having no potential conflicts of interest.

mdales@frontlinemedcom.com

The probability of long-term amenorrhea is similarly high in all premenopausal breast cancer patients age 35 years and older who undergo chemotherapy, regardless of whether they carry a BRCA1 or BRCA2 mutation.

Age at treatment and use of tamoxifen were important predictors of chemotherapy-induced amenorrhea in a multicenter survey of 1,954 premenopausal women aged 26-47 with invasive breast cancers and BRCA1 or BRCA2 mutations. In the absence of chemotherapy, however, tamoxifen alone was not associated with the onset of long-term amenorrhea.

The findings indicate that all women are at risk of chemotherapy-induced amenorrhea and BRCA1 or BRCA2 status per se should not be an indication for referral to a fertility clinic, according to Dr. Adriana Valentini of the Women’s College Research Institute, Toronto, and her colleagues in the Hereditary Breast Cancer Clinical Study Group.

Breast cancer patients who wish to preserve fertility should be aware of the synergistic impact of chemotherapy and tamoxifen on inducing long-term amenorrhea and possibly menopause, the researchers said. The study was published online Aug. 26 in the Journal of Clinical Oncology.

The researchers compared age of amenorrhea onset after breast cancer diagnosis for women who were and were not treated with chemotherapy, alone or with tamoxifen. Chemotherapy-induced amenorrhea was defined as 2 or more years of amenorrhea, with no resumption of menses, commencing within 2 years of initiating chemotherapy (J. Clin. Oncol. 2013 Aug. 26 [doi:10.1200/JCO.2012.47.7893]).

Patients were selected from a database of 13,004 BRCA1 and BRCA2 mutation carriers and 2,451 noncarriers at one of 62 participating centers in seven countries. The women sought testing for BRCA1 and BRCA2 mutations because of a personal or family history of breast or ovarian cancer. They were diagnosed with invasive breast cancer between 26 and 47 years of age and were premenopausal at the time of diagnosis.

In total, 1,954 BRCA carriers with breast cancer were eligible; 1,506 (77%) carried a BRCA1 mutation, 436 (22%) carried a BRCA2 mutation, and 12 (0.6%) carried both mutations.

Of the 1,954 carrier patients, 1,426 received chemotherapy and 35% of them experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea.

The study also included 167 noncarrier women with breast cancer as a comparison group; 100 of these women (59%) received chemotherapy, and 49% developed chemotherapy-induced amenorrhea.

The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed at or before age 30 years, 33% for women diagnosed at age 31-44 years, and 79% for women diagnosed after age 45 years (P trend greater than or equal to .001).

Tamoxifen was give to 478 carrier patients, and 410 (86%) received both tamoxifen and chemotherapy. Their probability of induced amenorrhea was 52%, compared with 29% for those who did not receive tamoxifen (P less than or equal to .001).

The probability of chemotherapy-induced amenorrhea was significantly higher for BRCA2 carriers than for BRCA1 carriers (46.8% v 32.7%; P less than or equal to .001). By age 38 years, 50% of BRCA2 carriers were expected to experience amenorrhea after chemotherapy, compared with the age of 40 years expected for BRCA1 carriers.

Among all women who reached age 56 years, the mean age of menopause was 45.4 years for those who received chemotherapy and resumed menses, and 49 years for those who did not receive chemotherapy (P less than or equal to .001), a difference of 3.6 years.

Among women who had a BRCA1 mutation and reached age 56 years, the mean age of menopause was 45.5 years for those who received chemotherapy and 48.7 years for those who did not receive chemotherapy (P less than or equal to .001).

Among women who had a BRCA2 mutation and reached age 56 years, the mean age of menopause was 45.2 years for those who received chemotherapy and 49.9 years for those who did not receive chemotherapy (P less than or equal to .003).

The study was supported by the Canadian Breast Cancer Research Alliance, the Canadian Cancer Research Society Research Initiative, Fonds de Recherche en Sante´ du Que´ bec, and National Institutes of Health Grant No. R01 CA74415. The authors reported having no potential conflicts of interest.

mdales@frontlinemedcom.com

The probability of long-term amenorrhea is similarly high in all premenopausal breast cancer patients age 35 years and older who undergo chemotherapy, regardless of whether they carry a BRCA1 or BRCA2 mutation.

Age at treatment and use of tamoxifen were important predictors of chemotherapy-induced amenorrhea in a multicenter survey of 1,954 premenopausal women aged 26-47 with invasive breast cancers and BRCA1 or BRCA2 mutations. In the absence of chemotherapy, however, tamoxifen alone was not associated with the onset of long-term amenorrhea.

The findings indicate that all women are at risk of chemotherapy-induced amenorrhea and BRCA1 or BRCA2 status per se should not be an indication for referral to a fertility clinic, according to Dr. Adriana Valentini of the Women’s College Research Institute, Toronto, and her colleagues in the Hereditary Breast Cancer Clinical Study Group.

Breast cancer patients who wish to preserve fertility should be aware of the synergistic impact of chemotherapy and tamoxifen on inducing long-term amenorrhea and possibly menopause, the researchers said. The study was published online Aug. 26 in the Journal of Clinical Oncology.

The researchers compared age of amenorrhea onset after breast cancer diagnosis for women who were and were not treated with chemotherapy, alone or with tamoxifen. Chemotherapy-induced amenorrhea was defined as 2 or more years of amenorrhea, with no resumption of menses, commencing within 2 years of initiating chemotherapy (J. Clin. Oncol. 2013 Aug. 26 [doi:10.1200/JCO.2012.47.7893]).

Patients were selected from a database of 13,004 BRCA1 and BRCA2 mutation carriers and 2,451 noncarriers at one of 62 participating centers in seven countries. The women sought testing for BRCA1 and BRCA2 mutations because of a personal or family history of breast or ovarian cancer. They were diagnosed with invasive breast cancer between 26 and 47 years of age and were premenopausal at the time of diagnosis.

In total, 1,954 BRCA carriers with breast cancer were eligible; 1,506 (77%) carried a BRCA1 mutation, 436 (22%) carried a BRCA2 mutation, and 12 (0.6%) carried both mutations.

Of the 1,954 carrier patients, 1,426 received chemotherapy and 35% of them experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea.

The study also included 167 noncarrier women with breast cancer as a comparison group; 100 of these women (59%) received chemotherapy, and 49% developed chemotherapy-induced amenorrhea.

The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed at or before age 30 years, 33% for women diagnosed at age 31-44 years, and 79% for women diagnosed after age 45 years (P trend greater than or equal to .001).

Tamoxifen was give to 478 carrier patients, and 410 (86%) received both tamoxifen and chemotherapy. Their probability of induced amenorrhea was 52%, compared with 29% for those who did not receive tamoxifen (P less than or equal to .001).

The probability of chemotherapy-induced amenorrhea was significantly higher for BRCA2 carriers than for BRCA1 carriers (46.8% v 32.7%; P less than or equal to .001). By age 38 years, 50% of BRCA2 carriers were expected to experience amenorrhea after chemotherapy, compared with the age of 40 years expected for BRCA1 carriers.

Among all women who reached age 56 years, the mean age of menopause was 45.4 years for those who received chemotherapy and resumed menses, and 49 years for those who did not receive chemotherapy (P less than or equal to .001), a difference of 3.6 years.

Among women who had a BRCA1 mutation and reached age 56 years, the mean age of menopause was 45.5 years for those who received chemotherapy and 48.7 years for those who did not receive chemotherapy (P less than or equal to .001).

Among women who had a BRCA2 mutation and reached age 56 years, the mean age of menopause was 45.2 years for those who received chemotherapy and 49.9 years for those who did not receive chemotherapy (P less than or equal to .003).

The study was supported by the Canadian Breast Cancer Research Alliance, the Canadian Cancer Research Society Research Initiative, Fonds de Recherche en Sante´ du Que´ bec, and National Institutes of Health Grant No. R01 CA74415. The authors reported having no potential conflicts of interest.

mdales@frontlinemedcom.com

Overall survival rates at 10 years after diagnosis were similarly good in women with and without BRCA1 mutations if they had stage I-III node-negative breast cancers that were smaller than 2 cm, based on a retrospective study of Polish women who were under age 50 years at diagnosis.

Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted hazard ratio, 4.1; 95% confidence interval, 1.8-8.9). Among BRCA1 carriers with 2 cm or smaller breast tumors, the 10-year survival rate was 84.1%, compared with 89.9% for the node-negative patients and 68.6% for the node-positive patients, according to Dr. Tomasz Huzarski of Pomeranian Medical University, Szczecin, Poland, and the members of the Polish Hereditary Breast Cancer Consortium.

Their study also showed that mortality rates were lower in BRCA1 carriers who had prophylactic oophorectomies. Compared with BRCA1 carriers who had intact ovaries, carriers who had an oophorectomy had a mortality reduction of 70% (adjusted HR, 0.30; 95% CI, 0.12-0.75).

The findings were gleaned from the medical records of 3,345 Polish women who were age 50 years or less when diagnosed from 1996 to 2006 with stage I-III breast cancer. In Poland, three founder mutations (5382insC, C61G, 4153delA) represent over 90% of the BRCA1 mutations, and young women diagnosed with breast cancers at one of 17 affiliated clinical centers there are screened for those BRCA1 mutations. The records indicated that 233 (7%) of the women with a first cancer diagnosis of stage I-III breast cancer had a BRCA1 mutation.

Based on BRCA1 status alone, the 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4%-86.4%); for noncarriers, it was 82.2% (95% CI, 80.5%-83.7%). The difference was not statistically significant, the authors wrote in an article published online in the Journal of Clinical Oncology (J. Clin. Oncol. 2013 Aug. 12 [doi:10.1200/JCO.2012.45.3571]).

In a multivariate analysis, however, mortality differed significantly for BRCA1 carriers and noncarriers (HR, 1.81; 95% CI, 1.26-2.61; P = .002). Of the 233 BRCA1-positive patients, 101 (43.6%) comprised a high-risk group who had cancers that were node positive and/or at least 5 cm or more in size. Their 10-year survival was 68.2% (95% CI, 58.2%-78.6%).

"The effect of oophorectomy on survival was profound and was statistically significant for BRCA1 carriers," the Dr. Huzarski and his coworkers wrote. A preventive oophorectomy was performed in 115 of the 233 carriers. There were 13 deaths, all resulting from breast cancer, in the 115 women. Among the 113 women (data were missing for 5 women) who did not have an oophorectomy, there were 28 deaths: 22 from breast cancer and 6 from breast or ovarian cancer. Overall, 28 (68%) of the 41 deaths occurred in women with intact ovaries.

As the study was limited to women in Poland, the authors cautioned that the results may not generalizable to women with other BRCA1 mutations or ethnicities. Additionally, these were early-onset cases only and the survival rates may not accurately reflect those of women diagnosed with cancer at a later age.

"It is important that these observations be replicated in other populations; if they are, oophorectomy should be considered a standard of care for women with breast cancer and a BRCA1 mutation," they wrote.

Dr. Huzarski and his associates reported having no financial conflicts of interest.

mdales@frontlinemedcom.com

Overall survival rates at 10 years after diagnosis were similarly good in women with and without BRCA1 mutations if they had stage I-III node-negative breast cancers that were smaller than 2 cm, based on a retrospective study of Polish women who were under age 50 years at diagnosis.

Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted hazard ratio, 4.1; 95% confidence interval, 1.8-8.9). Among BRCA1 carriers with 2 cm or smaller breast tumors, the 10-year survival rate was 84.1%, compared with 89.9% for the node-negative patients and 68.6% for the node-positive patients, according to Dr. Tomasz Huzarski of Pomeranian Medical University, Szczecin, Poland, and the members of the Polish Hereditary Breast Cancer Consortium.

Their study also showed that mortality rates were lower in BRCA1 carriers who had prophylactic oophorectomies. Compared with BRCA1 carriers who had intact ovaries, carriers who had an oophorectomy had a mortality reduction of 70% (adjusted HR, 0.30; 95% CI, 0.12-0.75).

The findings were gleaned from the medical records of 3,345 Polish women who were age 50 years or less when diagnosed from 1996 to 2006 with stage I-III breast cancer. In Poland, three founder mutations (5382insC, C61G, 4153delA) represent over 90% of the BRCA1 mutations, and young women diagnosed with breast cancers at one of 17 affiliated clinical centers there are screened for those BRCA1 mutations. The records indicated that 233 (7%) of the women with a first cancer diagnosis of stage I-III breast cancer had a BRCA1 mutation.

Based on BRCA1 status alone, the 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4%-86.4%); for noncarriers, it was 82.2% (95% CI, 80.5%-83.7%). The difference was not statistically significant, the authors wrote in an article published online in the Journal of Clinical Oncology (J. Clin. Oncol. 2013 Aug. 12 [doi:10.1200/JCO.2012.45.3571]).

In a multivariate analysis, however, mortality differed significantly for BRCA1 carriers and noncarriers (HR, 1.81; 95% CI, 1.26-2.61; P = .002). Of the 233 BRCA1-positive patients, 101 (43.6%) comprised a high-risk group who had cancers that were node positive and/or at least 5 cm or more in size. Their 10-year survival was 68.2% (95% CI, 58.2%-78.6%).

"The effect of oophorectomy on survival was profound and was statistically significant for BRCA1 carriers," the Dr. Huzarski and his coworkers wrote. A preventive oophorectomy was performed in 115 of the 233 carriers. There were 13 deaths, all resulting from breast cancer, in the 115 women. Among the 113 women (data were missing for 5 women) who did not have an oophorectomy, there were 28 deaths: 22 from breast cancer and 6 from breast or ovarian cancer. Overall, 28 (68%) of the 41 deaths occurred in women with intact ovaries.

As the study was limited to women in Poland, the authors cautioned that the results may not generalizable to women with other BRCA1 mutations or ethnicities. Additionally, these were early-onset cases only and the survival rates may not accurately reflect those of women diagnosed with cancer at a later age.

"It is important that these observations be replicated in other populations; if they are, oophorectomy should be considered a standard of care for women with breast cancer and a BRCA1 mutation," they wrote.

Dr. Huzarski and his associates reported having no financial conflicts of interest.

mdales@frontlinemedcom.com

Overall survival rates at 10 years after diagnosis were similarly good in women with and without BRCA1 mutations if they had stage I-III node-negative breast cancers that were smaller than 2 cm, based on a retrospective study of Polish women who were under age 50 years at diagnosis.

Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted hazard ratio, 4.1; 95% confidence interval, 1.8-8.9). Among BRCA1 carriers with 2 cm or smaller breast tumors, the 10-year survival rate was 84.1%, compared with 89.9% for the node-negative patients and 68.6% for the node-positive patients, according to Dr. Tomasz Huzarski of Pomeranian Medical University, Szczecin, Poland, and the members of the Polish Hereditary Breast Cancer Consortium.

Their study also showed that mortality rates were lower in BRCA1 carriers who had prophylactic oophorectomies. Compared with BRCA1 carriers who had intact ovaries, carriers who had an oophorectomy had a mortality reduction of 70% (adjusted HR, 0.30; 95% CI, 0.12-0.75).

The findings were gleaned from the medical records of 3,345 Polish women who were age 50 years or less when diagnosed from 1996 to 2006 with stage I-III breast cancer. In Poland, three founder mutations (5382insC, C61G, 4153delA) represent over 90% of the BRCA1 mutations, and young women diagnosed with breast cancers at one of 17 affiliated clinical centers there are screened for those BRCA1 mutations. The records indicated that 233 (7%) of the women with a first cancer diagnosis of stage I-III breast cancer had a BRCA1 mutation.

Based on BRCA1 status alone, the 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4%-86.4%); for noncarriers, it was 82.2% (95% CI, 80.5%-83.7%). The difference was not statistically significant, the authors wrote in an article published online in the Journal of Clinical Oncology (J. Clin. Oncol. 2013 Aug. 12 [doi:10.1200/JCO.2012.45.3571]).

In a multivariate analysis, however, mortality differed significantly for BRCA1 carriers and noncarriers (HR, 1.81; 95% CI, 1.26-2.61; P = .002). Of the 233 BRCA1-positive patients, 101 (43.6%) comprised a high-risk group who had cancers that were node positive and/or at least 5 cm or more in size. Their 10-year survival was 68.2% (95% CI, 58.2%-78.6%).

"The effect of oophorectomy on survival was profound and was statistically significant for BRCA1 carriers," the Dr. Huzarski and his coworkers wrote. A preventive oophorectomy was performed in 115 of the 233 carriers. There were 13 deaths, all resulting from breast cancer, in the 115 women. Among the 113 women (data were missing for 5 women) who did not have an oophorectomy, there were 28 deaths: 22 from breast cancer and 6 from breast or ovarian cancer. Overall, 28 (68%) of the 41 deaths occurred in women with intact ovaries.

As the study was limited to women in Poland, the authors cautioned that the results may not generalizable to women with other BRCA1 mutations or ethnicities. Additionally, these were early-onset cases only and the survival rates may not accurately reflect those of women diagnosed with cancer at a later age.

"It is important that these observations be replicated in other populations; if they are, oophorectomy should be considered a standard of care for women with breast cancer and a BRCA1 mutation," they wrote.

Dr. Huzarski and his associates reported having no financial conflicts of interest.

mdales@frontlinemedcom.com

Dr. Bernard Fisher, the surgeon whose research played a key role in the shift from radical mastectomy to less aggressive procedures for early-stage breast cancers, turns 95 this month. As director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Dr. Fisher championed the role of the randomized clinical trial. Yet, his career was nearly destroyed by allegations of scientific misconduct regarding falsified data from one of the surgeons in his study. Ultimately, he was exonerated, and resumed his research career which included establishing the role of tamoxifen for lowering breast cancer risk in high-risk women. To read an article on Dr. Fisher written for The Atlantic, click here.

Dr. Bernard Fisher, the surgeon whose research played a key role in the shift from radical mastectomy to less aggressive procedures for early-stage breast cancers, turns 95 this month. As director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Dr. Fisher championed the role of the randomized clinical trial. Yet, his career was nearly destroyed by allegations of scientific misconduct regarding falsified data from one of the surgeons in his study. Ultimately, he was exonerated, and resumed his research career which included establishing the role of tamoxifen for lowering breast cancer risk in high-risk women. To read an article on Dr. Fisher written for The Atlantic, click here.

Dr. Bernard Fisher, the surgeon whose research played a key role in the shift from radical mastectomy to less aggressive procedures for early-stage breast cancers, turns 95 this month. As director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), Dr. Fisher championed the role of the randomized clinical trial. Yet, his career was nearly destroyed by allegations of scientific misconduct regarding falsified data from one of the surgeons in his study. Ultimately, he was exonerated, and resumed his research career which included establishing the role of tamoxifen for lowering breast cancer risk in high-risk women. To read an article on Dr. Fisher written for The Atlantic, click here.

The long-term use of calcium-channel blockers is associated with a doubling of the risk of both invasive ductal carcinoma and invasive lobular carcinoma of the breast, according to a report published online Aug. 5 in JAMA Internal Medicine.

This and other findings from a large population-based case-control study require confirmation in future research, because this is the first report of such a strong adverse long-term impact of calcium-channel blockers (CCBs) on breast cancer risk, said Dr. Christopher I. Li of the division of public health sciences, Fred Hutchinson Cancer Research Center, Seattle, and his associates.

The investigators found no such association between breast cancer and any of the other commonly used antihypertensive agents, even if they were taken for long durations.

The study results are relevant to public health, given that antihypertensive drugs are the most commonly prescribed class of medication in the United States, the researchers noted.

Previous studies of a possible link between breast cancer risk on the one hand and antihypertensive agents in general, and CCBs in particular, on the other hand, have produced inconsistent results. Most have included relatively few cases of breast cancer, have not assessed longer durations of use, and have inadequately examined the more recently introduced forms of the drugs.

Dr. Li and his colleagues averted these drawbacks by assessing postmenopausal women who had taken all the major classes of antihypertensive drugs for long durations, in a large enough sample to include many cases of the two most common histologic subtypes of breast cancer: invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC).

They identified through a tumor registry 1,960 women aged 55-74 years who were diagnosed as having a primary IDC or ILC during January 2000 to December 2008 in the greater metropolitan Seattle area. These cases were matched for age and area of residence with 891 cancer-free women who served as controls. The two groups had similar annual household incomes and medical histories of hypertension, heart disease, and hypercholesterolemia.

Overall use, current use, former use, and short-term use of antihypertensive drugs were not associated with the risk of either IDC or ILC.

Only the long-term use of calcium-channel blockers (10 years or more) was related to increased risk of breast cancer, with an OR of 2.4 for IDC and an OR of 2.6 for ILC, the investigators said (JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9071]).

This association remained robust when the data were analyzed according to the tumor’s estrogen-receptor status: The ORs were 2.3 for ER-positive IDC, 3.1 for ER-negative IDC, and 2.6 for ER-positive ILC.

No other drug categories showed significant associations with breast cancer risk. "With respect to diuretic use, risks associated with thiazide and nonthiazide diuretic use were also assessed separately, but neither was associated with breast cancer risk," they said.

A sensitivity analysis limited to women in both study groups who had hypertension and were currently using antihypertensive medications produced similar results. This indicates that the underlying condition itself does not explain the association with breast cancer, and thus confounding by indication was adequately controlled for.

"There was also some indication that current use of ACE inhibitors for 10 years or longer was associated with reduced risks of both IDC (OR, 0.7) and ILC (OR, 0.6), though the risk estimate for IDC was within the limits of chance," they said.

This finding must be interpreted with caution and requires confirmation in future research that includes a large number of long-term users of ACE inhibitors, Dr. Li and his associates added.

The U.S. National Cancer Institute and the U.S. Department of Defense supported the study. No relevant financial conflicts of interest were reported.

The long-term use of calcium-channel blockers is associated with a doubling of the risk of both invasive ductal carcinoma and invasive lobular carcinoma of the breast, according to a report published online Aug. 5 in JAMA Internal Medicine.

This and other findings from a large population-based case-control study require confirmation in future research, because this is the first report of such a strong adverse long-term impact of calcium-channel blockers (CCBs) on breast cancer risk, said Dr. Christopher I. Li of the division of public health sciences, Fred Hutchinson Cancer Research Center, Seattle, and his associates.

The investigators found no such association between breast cancer and any of the other commonly used antihypertensive agents, even if they were taken for long durations.

The study results are relevant to public health, given that antihypertensive drugs are the most commonly prescribed class of medication in the United States, the researchers noted.

Previous studies of a possible link between breast cancer risk on the one hand and antihypertensive agents in general, and CCBs in particular, on the other hand, have produced inconsistent results. Most have included relatively few cases of breast cancer, have not assessed longer durations of use, and have inadequately examined the more recently introduced forms of the drugs.

Dr. Li and his colleagues averted these drawbacks by assessing postmenopausal women who had taken all the major classes of antihypertensive drugs for long durations, in a large enough sample to include many cases of the two most common histologic subtypes of breast cancer: invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC).

They identified through a tumor registry 1,960 women aged 55-74 years who were diagnosed as having a primary IDC or ILC during January 2000 to December 2008 in the greater metropolitan Seattle area. These cases were matched for age and area of residence with 891 cancer-free women who served as controls. The two groups had similar annual household incomes and medical histories of hypertension, heart disease, and hypercholesterolemia.

Overall use, current use, former use, and short-term use of antihypertensive drugs were not associated with the risk of either IDC or ILC.

Only the long-term use of calcium-channel blockers (10 years or more) was related to increased risk of breast cancer, with an OR of 2.4 for IDC and an OR of 2.6 for ILC, the investigators said (JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9071]).

This association remained robust when the data were analyzed according to the tumor’s estrogen-receptor status: The ORs were 2.3 for ER-positive IDC, 3.1 for ER-negative IDC, and 2.6 for ER-positive ILC.

No other drug categories showed significant associations with breast cancer risk. "With respect to diuretic use, risks associated with thiazide and nonthiazide diuretic use were also assessed separately, but neither was associated with breast cancer risk," they said.

A sensitivity analysis limited to women in both study groups who had hypertension and were currently using antihypertensive medications produced similar results. This indicates that the underlying condition itself does not explain the association with breast cancer, and thus confounding by indication was adequately controlled for.

"There was also some indication that current use of ACE inhibitors for 10 years or longer was associated with reduced risks of both IDC (OR, 0.7) and ILC (OR, 0.6), though the risk estimate for IDC was within the limits of chance," they said.

This finding must be interpreted with caution and requires confirmation in future research that includes a large number of long-term users of ACE inhibitors, Dr. Li and his associates added.

The U.S. National Cancer Institute and the U.S. Department of Defense supported the study. No relevant financial conflicts of interest were reported.

The long-term use of calcium-channel blockers is associated with a doubling of the risk of both invasive ductal carcinoma and invasive lobular carcinoma of the breast, according to a report published online Aug. 5 in JAMA Internal Medicine.

This and other findings from a large population-based case-control study require confirmation in future research, because this is the first report of such a strong adverse long-term impact of calcium-channel blockers (CCBs) on breast cancer risk, said Dr. Christopher I. Li of the division of public health sciences, Fred Hutchinson Cancer Research Center, Seattle, and his associates.

The investigators found no such association between breast cancer and any of the other commonly used antihypertensive agents, even if they were taken for long durations.

The study results are relevant to public health, given that antihypertensive drugs are the most commonly prescribed class of medication in the United States, the researchers noted.

Previous studies of a possible link between breast cancer risk on the one hand and antihypertensive agents in general, and CCBs in particular, on the other hand, have produced inconsistent results. Most have included relatively few cases of breast cancer, have not assessed longer durations of use, and have inadequately examined the more recently introduced forms of the drugs.

Dr. Li and his colleagues averted these drawbacks by assessing postmenopausal women who had taken all the major classes of antihypertensive drugs for long durations, in a large enough sample to include many cases of the two most common histologic subtypes of breast cancer: invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC).

They identified through a tumor registry 1,960 women aged 55-74 years who were diagnosed as having a primary IDC or ILC during January 2000 to December 2008 in the greater metropolitan Seattle area. These cases were matched for age and area of residence with 891 cancer-free women who served as controls. The two groups had similar annual household incomes and medical histories of hypertension, heart disease, and hypercholesterolemia.

Overall use, current use, former use, and short-term use of antihypertensive drugs were not associated with the risk of either IDC or ILC.

Only the long-term use of calcium-channel blockers (10 years or more) was related to increased risk of breast cancer, with an OR of 2.4 for IDC and an OR of 2.6 for ILC, the investigators said (JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9071]).

This association remained robust when the data were analyzed according to the tumor’s estrogen-receptor status: The ORs were 2.3 for ER-positive IDC, 3.1 for ER-negative IDC, and 2.6 for ER-positive ILC.

No other drug categories showed significant associations with breast cancer risk. "With respect to diuretic use, risks associated with thiazide and nonthiazide diuretic use were also assessed separately, but neither was associated with breast cancer risk," they said.

A sensitivity analysis limited to women in both study groups who had hypertension and were currently using antihypertensive medications produced similar results. This indicates that the underlying condition itself does not explain the association with breast cancer, and thus confounding by indication was adequately controlled for.

"There was also some indication that current use of ACE inhibitors for 10 years or longer was associated with reduced risks of both IDC (OR, 0.7) and ILC (OR, 0.6), though the risk estimate for IDC was within the limits of chance," they said.

This finding must be interpreted with caution and requires confirmation in future research that includes a large number of long-term users of ACE inhibitors, Dr. Li and his associates added.

The U.S. National Cancer Institute and the U.S. Department of Defense supported the study. No relevant financial conflicts of interest were reported.

Being less than 40 years old does not significantly impact survival in women with HER2-positive breast cancer, according to a retrospective analysis of a large, randomized breast cancer study.

"Our finding that age is neither a clear prognostic factor for early recurrence nor a predictive factor for benefit of trastuzumab in women with HER2-positive breast cancer may have important implications for care and future research. Most prior research suggesting that age is an independent prognostic factor has not taken HER2 status into account," noted Dr. Ann H. Partridge and her colleagues.

Younger women are more likely to present with aggressive breast tumors and advanced disease; young age at diagnosis is an independent risk factor for recurrence and death. Few studies have been conducted to evaluate if the finding remains the same among women with HER2-positive (human epidermal growth factor receptor 2–positive) tumors, according to Dr. Partridge, an oncologist at the Dana-Farber Cancer Institute in Boston, and her colleagues.

They performed a retrospective analysis of data from the HERA [Herceptin Adjuvant] study, an open-label, phase III randomized trial that found significantly improved disease-free survival in HER2-positive breast cancer patients who received a year of trastuzumab following adjuvant chemotherapy (N. Engl. J. Med. 2005;353:1659-72).

Among 1,698 women randomly assigned to observation in the trial, there was no significant difference in disease-free survival (HR 1.18; 95% CI, 0.90-1.54) or overall survival (HR 1.01; 95% CI, 0.60-1.69) in women aged 40 years or younger, compared with women over age 40 years (J. Clin. Oncol. 2013;31:2692-8).

This was also true among the 1,703 women randomly assigned to trastuzumab. Disease-free survival (HR 1.11; 95% CI, 0.81-1.51) and overall survival (HR 1.18; 95% CI, 0.66-2.09) were comparable in younger women, compared with those over 40 years of age. Interaction between age group and treatment effect was not statistically significant for either parameter (DFS P = 0.89; OS P = 0.55).

Overall, 722 women (21%) were 40 years of age or younger at study entry.

"Our findings suggest that as breast cancer continues to be better characterized molecularly, and therapies such as trastuzumab are developed to target molecular subtypes, the importance of age with regard to prognosis will continue to diminish, if not disappear," they wrote.

The short follow-up was a limitation of the study. "Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes," they noted.

Dr. Partridge is a consultant for Genentech, maker of trastuzumab. Another author is an employee of, and holds stock in, Roche, the parent company of Genentech. All but one of the six other investigators have ties to the two companies

aotto@frontlinemedcom.com

Being less than 40 years old does not significantly impact survival in women with HER2-positive breast cancer, according to a retrospective analysis of a large, randomized breast cancer study.

"Our finding that age is neither a clear prognostic factor for early recurrence nor a predictive factor for benefit of trastuzumab in women with HER2-positive breast cancer may have important implications for care and future research. Most prior research suggesting that age is an independent prognostic factor has not taken HER2 status into account," noted Dr. Ann H. Partridge and her colleagues.

Younger women are more likely to present with aggressive breast tumors and advanced disease; young age at diagnosis is an independent risk factor for recurrence and death. Few studies have been conducted to evaluate if the finding remains the same among women with HER2-positive (human epidermal growth factor receptor 2–positive) tumors, according to Dr. Partridge, an oncologist at the Dana-Farber Cancer Institute in Boston, and her colleagues.

They performed a retrospective analysis of data from the HERA [Herceptin Adjuvant] study, an open-label, phase III randomized trial that found significantly improved disease-free survival in HER2-positive breast cancer patients who received a year of trastuzumab following adjuvant chemotherapy (N. Engl. J. Med. 2005;353:1659-72).

Among 1,698 women randomly assigned to observation in the trial, there was no significant difference in disease-free survival (HR 1.18; 95% CI, 0.90-1.54) or overall survival (HR 1.01; 95% CI, 0.60-1.69) in women aged 40 years or younger, compared with women over age 40 years (J. Clin. Oncol. 2013;31:2692-8).

This was also true among the 1,703 women randomly assigned to trastuzumab. Disease-free survival (HR 1.11; 95% CI, 0.81-1.51) and overall survival (HR 1.18; 95% CI, 0.66-2.09) were comparable in younger women, compared with those over 40 years of age. Interaction between age group and treatment effect was not statistically significant for either parameter (DFS P = 0.89; OS P = 0.55).

Overall, 722 women (21%) were 40 years of age or younger at study entry.

"Our findings suggest that as breast cancer continues to be better characterized molecularly, and therapies such as trastuzumab are developed to target molecular subtypes, the importance of age with regard to prognosis will continue to diminish, if not disappear," they wrote.

The short follow-up was a limitation of the study. "Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes," they noted.

Dr. Partridge is a consultant for Genentech, maker of trastuzumab. Another author is an employee of, and holds stock in, Roche, the parent company of Genentech. All but one of the six other investigators have ties to the two companies

aotto@frontlinemedcom.com

Being less than 40 years old does not significantly impact survival in women with HER2-positive breast cancer, according to a retrospective analysis of a large, randomized breast cancer study.

"Our finding that age is neither a clear prognostic factor for early recurrence nor a predictive factor for benefit of trastuzumab in women with HER2-positive breast cancer may have important implications for care and future research. Most prior research suggesting that age is an independent prognostic factor has not taken HER2 status into account," noted Dr. Ann H. Partridge and her colleagues.

Younger women are more likely to present with aggressive breast tumors and advanced disease; young age at diagnosis is an independent risk factor for recurrence and death. Few studies have been conducted to evaluate if the finding remains the same among women with HER2-positive (human epidermal growth factor receptor 2–positive) tumors, according to Dr. Partridge, an oncologist at the Dana-Farber Cancer Institute in Boston, and her colleagues.

They performed a retrospective analysis of data from the HERA [Herceptin Adjuvant] study, an open-label, phase III randomized trial that found significantly improved disease-free survival in HER2-positive breast cancer patients who received a year of trastuzumab following adjuvant chemotherapy (N. Engl. J. Med. 2005;353:1659-72).

Among 1,698 women randomly assigned to observation in the trial, there was no significant difference in disease-free survival (HR 1.18; 95% CI, 0.90-1.54) or overall survival (HR 1.01; 95% CI, 0.60-1.69) in women aged 40 years or younger, compared with women over age 40 years (J. Clin. Oncol. 2013;31:2692-8).

This was also true among the 1,703 women randomly assigned to trastuzumab. Disease-free survival (HR 1.11; 95% CI, 0.81-1.51) and overall survival (HR 1.18; 95% CI, 0.66-2.09) were comparable in younger women, compared with those over 40 years of age. Interaction between age group and treatment effect was not statistically significant for either parameter (DFS P = 0.89; OS P = 0.55).

Overall, 722 women (21%) were 40 years of age or younger at study entry.

"Our findings suggest that as breast cancer continues to be better characterized molecularly, and therapies such as trastuzumab are developed to target molecular subtypes, the importance of age with regard to prognosis will continue to diminish, if not disappear," they wrote.

The short follow-up was a limitation of the study. "Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes," they noted.

Dr. Partridge is a consultant for Genentech, maker of trastuzumab. Another author is an employee of, and holds stock in, Roche, the parent company of Genentech. All but one of the six other investigators have ties to the two companies

aotto@frontlinemedcom.com

The likelihood of nodal metastases is increased in breast cancer patients whose tumors have breast cancer stem and progenitor cells with defects in PI3/Akt signaling.

The findings, drawn from an analysis of surgical specimens, "support embarking on a new way of approaching breast cancer diagnosis and treatment planning" and have potential implications for targeted treatment with PI3/Akt inhibitors currently being tested in clinical trials, Dr. Cory A. Donovan and his colleagues at the Oregon Health and Science University, Portland reported online July 24 in JAMA Surgery.

The researchers evaluated malignant and benign stem cells from 30 fresh surgical specimens of ductal breast cancers. Nine of the 10 specimens with mutations in breast cancer stem and progenitor cells (BCSCs) were associated with axillary lymph node micro- or macrometastases. Just 4 of the 20 tumors without mutations were associated with axillary lymph node metastases, the investigators said (JAMA Surg. 2013 July 17 [doi:10.1001/jamasurg.2013.3028]).

The tumor specimens were collected from patients with stage IA through IIIB cancers via cell sorting and were subjected to whole genomic amplification and subsequent screening for oncogene mutations. The 10 tumors with BCSC defects had AKT1, HRAS, or PIK3CA mutations.

"Three different mutations (E545k, N345k, and H1047R) were detected in PIK3CA, a single mutation was detected in AKT1, and a single mutation was detected in HRAS," the investigators wrote.

No difference in CD44 positivity was observed between BCSCs with and without mutations.

"When the presence of any BCSC mutation correlated with patient and breast cancer characteristics, no statistically significant correlations were found with patient age at diagnosis, tumor size, tumor histologic grade, estrogen receptor expression, progesterone receptor expression, or ERBB2 status. However, a statistically significant correlation was observed between the presence of BCSC mutations and axillary lymph node metastases. This significance was more pronounced when micrometastatic disease was included," they said.

At a mean follow-up of 29 months, disease had progressed after treatment in 3 of the 10 patients with BCSC mutations. Two patients died of disease; one had brain metastases. Conversely, there was no evidence of disease at a mean follow-up of 19 months in the patients with BCSCs without mutations.

Since 20% of patients without BCSC mutations had axillary lymph node metastases, it appears that a PI3K/Akt mutation in BCSC is not a requirement for metastases, but the link between PI3K and metastatic potential demonstrated in this study suggests that "micrometastases harboring PI3K/Akt mutations may carry a different risk for distant metastatic disease," Dr. Donovan and his associates noted.

"Longer patient follow-up periods and a larger sample size will determine if this subset of patients demonstrates an increased risk and may benefit from specifically designed use of adjuvant chemotherapy," the researchers added.

The existing evidence regarding the prognostic significance of specific PI3K/Akt signaling pathway mutations is conflicting, likely because of the variability of the mutations, the heterogeneity of the tumors, and the complexity of the pathway. Although the findings in BCSCs in the current study are consistent with others showing that PIK3CA and AKT mutations in breast cancers are associated with factors that may indicate poor prognosis and decreased survival, other studies have demonstrated improved survival, lower tumor grades, and increased rates of estrogen receptor positivity in patients with tumors that have PIK3CA mutations, they said.

"Our study findings indicate that the answer to this controversy may lie in identifying mutations in BCSCs, as well as mutations in the tumor as a whole," they said, adding that the findings support an evaluation of BCSCs along with overall breast cancer assessment.

"The analysis of BCSCs can generate specific information about tumor growth and metastatic potential that may not be obtained from analysis of the tumor progeny cells alone. Simultaneous molecular analyses of both the tumor and BCSCs may better identify patients who are likely to benefit from specific therapeutic regimens. Similarly, simultaneous BCSC and tumor analysis may increase the number of patients who might benefit from treatment but be missed by tumor analysis alone," Dr. Donovan and his coworkers said.

P13K/Akt signaling pathway inhibitors are currently being evaluated in clinical trials and could prove useful for the treatment of patients with BCSC mutations, they noted, adding that this may be true even in cases without PIK/Akt mutation.

"The use of BCSC-specific and tumor-targeted chemotherapeutic agents may prove to be synergistic with each other, providing a novel therapeutic approach," they said.

This study was supported by a grant from the Janet E. Bowen Foundation. The authors reported having no disclosures.

The likelihood of nodal metastases is increased in breast cancer patients whose tumors have breast cancer stem and progenitor cells with defects in PI3/Akt signaling.

The findings, drawn from an analysis of surgical specimens, "support embarking on a new way of approaching breast cancer diagnosis and treatment planning" and have potential implications for targeted treatment with PI3/Akt inhibitors currently being tested in clinical trials, Dr. Cory A. Donovan and his colleagues at the Oregon Health and Science University, Portland reported online July 24 in JAMA Surgery.

The researchers evaluated malignant and benign stem cells from 30 fresh surgical specimens of ductal breast cancers. Nine of the 10 specimens with mutations in breast cancer stem and progenitor cells (BCSCs) were associated with axillary lymph node micro- or macrometastases. Just 4 of the 20 tumors without mutations were associated with axillary lymph node metastases, the investigators said (JAMA Surg. 2013 July 17 [doi:10.1001/jamasurg.2013.3028]).

The tumor specimens were collected from patients with stage IA through IIIB cancers via cell sorting and were subjected to whole genomic amplification and subsequent screening for oncogene mutations. The 10 tumors with BCSC defects had AKT1, HRAS, or PIK3CA mutations.

"Three different mutations (E545k, N345k, and H1047R) were detected in PIK3CA, a single mutation was detected in AKT1, and a single mutation was detected in HRAS," the investigators wrote.

No difference in CD44 positivity was observed between BCSCs with and without mutations.

"When the presence of any BCSC mutation correlated with patient and breast cancer characteristics, no statistically significant correlations were found with patient age at diagnosis, tumor size, tumor histologic grade, estrogen receptor expression, progesterone receptor expression, or ERBB2 status. However, a statistically significant correlation was observed between the presence of BCSC mutations and axillary lymph node metastases. This significance was more pronounced when micrometastatic disease was included," they said.

At a mean follow-up of 29 months, disease had progressed after treatment in 3 of the 10 patients with BCSC mutations. Two patients died of disease; one had brain metastases. Conversely, there was no evidence of disease at a mean follow-up of 19 months in the patients with BCSCs without mutations.

Since 20% of patients without BCSC mutations had axillary lymph node metastases, it appears that a PI3K/Akt mutation in BCSC is not a requirement for metastases, but the link between PI3K and metastatic potential demonstrated in this study suggests that "micrometastases harboring PI3K/Akt mutations may carry a different risk for distant metastatic disease," Dr. Donovan and his associates noted.

"Longer patient follow-up periods and a larger sample size will determine if this subset of patients demonstrates an increased risk and may benefit from specifically designed use of adjuvant chemotherapy," the researchers added.

The existing evidence regarding the prognostic significance of specific PI3K/Akt signaling pathway mutations is conflicting, likely because of the variability of the mutations, the heterogeneity of the tumors, and the complexity of the pathway. Although the findings in BCSCs in the current study are consistent with others showing that PIK3CA and AKT mutations in breast cancers are associated with factors that may indicate poor prognosis and decreased survival, other studies have demonstrated improved survival, lower tumor grades, and increased rates of estrogen receptor positivity in patients with tumors that have PIK3CA mutations, they said.

"Our study findings indicate that the answer to this controversy may lie in identifying mutations in BCSCs, as well as mutations in the tumor as a whole," they said, adding that the findings support an evaluation of BCSCs along with overall breast cancer assessment.

"The analysis of BCSCs can generate specific information about tumor growth and metastatic potential that may not be obtained from analysis of the tumor progeny cells alone. Simultaneous molecular analyses of both the tumor and BCSCs may better identify patients who are likely to benefit from specific therapeutic regimens. Similarly, simultaneous BCSC and tumor analysis may increase the number of patients who might benefit from treatment but be missed by tumor analysis alone," Dr. Donovan and his coworkers said.

P13K/Akt signaling pathway inhibitors are currently being evaluated in clinical trials and could prove useful for the treatment of patients with BCSC mutations, they noted, adding that this may be true even in cases without PIK/Akt mutation.

"The use of BCSC-specific and tumor-targeted chemotherapeutic agents may prove to be synergistic with each other, providing a novel therapeutic approach," they said.

This study was supported by a grant from the Janet E. Bowen Foundation. The authors reported having no disclosures.

The likelihood of nodal metastases is increased in breast cancer patients whose tumors have breast cancer stem and progenitor cells with defects in PI3/Akt signaling.

The findings, drawn from an analysis of surgical specimens, "support embarking on a new way of approaching breast cancer diagnosis and treatment planning" and have potential implications for targeted treatment with PI3/Akt inhibitors currently being tested in clinical trials, Dr. Cory A. Donovan and his colleagues at the Oregon Health and Science University, Portland reported online July 24 in JAMA Surgery.

The researchers evaluated malignant and benign stem cells from 30 fresh surgical specimens of ductal breast cancers. Nine of the 10 specimens with mutations in breast cancer stem and progenitor cells (BCSCs) were associated with axillary lymph node micro- or macrometastases. Just 4 of the 20 tumors without mutations were associated with axillary lymph node metastases, the investigators said (JAMA Surg. 2013 July 17 [doi:10.1001/jamasurg.2013.3028]).

The tumor specimens were collected from patients with stage IA through IIIB cancers via cell sorting and were subjected to whole genomic amplification and subsequent screening for oncogene mutations. The 10 tumors with BCSC defects had AKT1, HRAS, or PIK3CA mutations.

"Three different mutations (E545k, N345k, and H1047R) were detected in PIK3CA, a single mutation was detected in AKT1, and a single mutation was detected in HRAS," the investigators wrote.

No difference in CD44 positivity was observed between BCSCs with and without mutations.

"When the presence of any BCSC mutation correlated with patient and breast cancer characteristics, no statistically significant correlations were found with patient age at diagnosis, tumor size, tumor histologic grade, estrogen receptor expression, progesterone receptor expression, or ERBB2 status. However, a statistically significant correlation was observed between the presence of BCSC mutations and axillary lymph node metastases. This significance was more pronounced when micrometastatic disease was included," they said.

At a mean follow-up of 29 months, disease had progressed after treatment in 3 of the 10 patients with BCSC mutations. Two patients died of disease; one had brain metastases. Conversely, there was no evidence of disease at a mean follow-up of 19 months in the patients with BCSCs without mutations.

Since 20% of patients without BCSC mutations had axillary lymph node metastases, it appears that a PI3K/Akt mutation in BCSC is not a requirement for metastases, but the link between PI3K and metastatic potential demonstrated in this study suggests that "micrometastases harboring PI3K/Akt mutations may carry a different risk for distant metastatic disease," Dr. Donovan and his associates noted.

"Longer patient follow-up periods and a larger sample size will determine if this subset of patients demonstrates an increased risk and may benefit from specifically designed use of adjuvant chemotherapy," the researchers added.

The existing evidence regarding the prognostic significance of specific PI3K/Akt signaling pathway mutations is conflicting, likely because of the variability of the mutations, the heterogeneity of the tumors, and the complexity of the pathway. Although the findings in BCSCs in the current study are consistent with others showing that PIK3CA and AKT mutations in breast cancers are associated with factors that may indicate poor prognosis and decreased survival, other studies have demonstrated improved survival, lower tumor grades, and increased rates of estrogen receptor positivity in patients with tumors that have PIK3CA mutations, they said.

"Our study findings indicate that the answer to this controversy may lie in identifying mutations in BCSCs, as well as mutations in the tumor as a whole," they said, adding that the findings support an evaluation of BCSCs along with overall breast cancer assessment.

"The analysis of BCSCs can generate specific information about tumor growth and metastatic potential that may not be obtained from analysis of the tumor progeny cells alone. Simultaneous molecular analyses of both the tumor and BCSCs may better identify patients who are likely to benefit from specific therapeutic regimens. Similarly, simultaneous BCSC and tumor analysis may increase the number of patients who might benefit from treatment but be missed by tumor analysis alone," Dr. Donovan and his coworkers said.

P13K/Akt signaling pathway inhibitors are currently being evaluated in clinical trials and could prove useful for the treatment of patients with BCSC mutations, they noted, adding that this may be true even in cases without PIK/Akt mutation.

"The use of BCSC-specific and tumor-targeted chemotherapeutic agents may prove to be synergistic with each other, providing a novel therapeutic approach," they said.

This study was supported by a grant from the Janet E. Bowen Foundation. The authors reported having no disclosures.

The disparity between black women and white women in breast cancer survival has not changed appreciably since the early 1990s, and it appears to be related primarily to differences between the two racial groups at presentation rather than to treatment differences, according to a report in the July 24/31 issue of JAMA.

These are the findings of a large, population-based study using an innovative statistical approach to tease out the complex interactions among demographic, clinical, and treatment differences between the races.

"Our results suggest that it may be difficult to eliminate the racial disparity in survival ... unless differences in presentation can be reduced," said Dr. Jeffrey H. Silber of the Center for Outcomes Research at Children’s Hospital of Philadelphia and his associates.

The researchers analyzed information from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess the racial disparity in 5-year breast cancer survival among women older than 65 years at diagnosis in 1991-2005.To do so, they used rigorous matching methods in three sequential analyses to compare 7,375 black patients with white control subjects selected from a pool of 99,898 white patients.

The black women first were compared with white women who had similar demographic traits (age, year of diagnosis, and SEER site), then with white patients who had similar clinical presentations (comorbidities, tumor stage, and other tumor factors), and finally with white patients who had similar treatment (specifics of surgery, radiotherapy, and chemotherapy).

"The three matched white groups sequentially remove aspects of the [racial] disparity while leaving other aspects in place, so as to develop an understanding of how the disparity occurs," the investigators noted (JAMA 2013;310:389-97).

There were four major findings:

First, 5-year breast cancer survival improved somewhat in both races over time, but the disparity between black women and white women remained constant.

Second, when the women were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life. In other words, compared with white women of the same age, year of diagnosis, and geographical location, black women still had a significantly lower 5-year breast cancer survival. Thus, demographic differences explain only a small part of the racial disparity.

Third, when the women were matched for clinical traits at presentation, this disparity in 5-year survival dropped to 4.4%, which represents approximately 1 year. This is a smaller but still significant difference between black women and white women who present with the same clinical picture.

Fourth, when the women were matched for treatment factors, this disparity only decreased slightly. "Hence, treatment differences explained only 0.81% of the 12.9% difference in 5-year survival," Dr. Silber and his associates said.

Most of the disparity in survival could be attributed to the poorer health of black women at presentation. Black women were markedly less likely than were white women to have seen a primary care provider during the preceding year and were significantly less likely to have undergone recent screening for breast cancer, colon cancer, or high cholesterol.

Black women also were significantly more likely than white women to have comorbid conditions. "Some of the effectiveness of cancer treatment ... may be blunted by other health problems" or by the treatment of those health problems, the investigators said.

Finally, black women were more likely than were white women to present with advanced breast cancer and worse biological features, such as larger tumor size and less favorable receptor status. The mean interval between diagnosis and the first treatment also was significantly longer for black women than for white women, they added.

This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.

The disparity between black women and white women in breast cancer survival has not changed appreciably since the early 1990s, and it appears to be related primarily to differences between the two racial groups at presentation rather than to treatment differences, according to a report in the July 24/31 issue of JAMA.

These are the findings of a large, population-based study using an innovative statistical approach to tease out the complex interactions among demographic, clinical, and treatment differences between the races.

"Our results suggest that it may be difficult to eliminate the racial disparity in survival ... unless differences in presentation can be reduced," said Dr. Jeffrey H. Silber of the Center for Outcomes Research at Children’s Hospital of Philadelphia and his associates.

The researchers analyzed information from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess the racial disparity in 5-year breast cancer survival among women older than 65 years at diagnosis in 1991-2005.To do so, they used rigorous matching methods in three sequential analyses to compare 7,375 black patients with white control subjects selected from a pool of 99,898 white patients.

The black women first were compared with white women who had similar demographic traits (age, year of diagnosis, and SEER site), then with white patients who had similar clinical presentations (comorbidities, tumor stage, and other tumor factors), and finally with white patients who had similar treatment (specifics of surgery, radiotherapy, and chemotherapy).

"The three matched white groups sequentially remove aspects of the [racial] disparity while leaving other aspects in place, so as to develop an understanding of how the disparity occurs," the investigators noted (JAMA 2013;310:389-97).

There were four major findings:

First, 5-year breast cancer survival improved somewhat in both races over time, but the disparity between black women and white women remained constant.

Second, when the women were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life. In other words, compared with white women of the same age, year of diagnosis, and geographical location, black women still had a significantly lower 5-year breast cancer survival. Thus, demographic differences explain only a small part of the racial disparity.

Third, when the women were matched for clinical traits at presentation, this disparity in 5-year survival dropped to 4.4%, which represents approximately 1 year. This is a smaller but still significant difference between black women and white women who present with the same clinical picture.

Fourth, when the women were matched for treatment factors, this disparity only decreased slightly. "Hence, treatment differences explained only 0.81% of the 12.9% difference in 5-year survival," Dr. Silber and his associates said.

Most of the disparity in survival could be attributed to the poorer health of black women at presentation. Black women were markedly less likely than were white women to have seen a primary care provider during the preceding year and were significantly less likely to have undergone recent screening for breast cancer, colon cancer, or high cholesterol.

Black women also were significantly more likely than white women to have comorbid conditions. "Some of the effectiveness of cancer treatment ... may be blunted by other health problems" or by the treatment of those health problems, the investigators said.

Finally, black women were more likely than were white women to present with advanced breast cancer and worse biological features, such as larger tumor size and less favorable receptor status. The mean interval between diagnosis and the first treatment also was significantly longer for black women than for white women, they added.

This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.

The disparity between black women and white women in breast cancer survival has not changed appreciably since the early 1990s, and it appears to be related primarily to differences between the two racial groups at presentation rather than to treatment differences, according to a report in the July 24/31 issue of JAMA.

These are the findings of a large, population-based study using an innovative statistical approach to tease out the complex interactions among demographic, clinical, and treatment differences between the races.

"Our results suggest that it may be difficult to eliminate the racial disparity in survival ... unless differences in presentation can be reduced," said Dr. Jeffrey H. Silber of the Center for Outcomes Research at Children’s Hospital of Philadelphia and his associates.

The researchers analyzed information from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess the racial disparity in 5-year breast cancer survival among women older than 65 years at diagnosis in 1991-2005.To do so, they used rigorous matching methods in three sequential analyses to compare 7,375 black patients with white control subjects selected from a pool of 99,898 white patients.

The black women first were compared with white women who had similar demographic traits (age, year of diagnosis, and SEER site), then with white patients who had similar clinical presentations (comorbidities, tumor stage, and other tumor factors), and finally with white patients who had similar treatment (specifics of surgery, radiotherapy, and chemotherapy).

"The three matched white groups sequentially remove aspects of the [racial] disparity while leaving other aspects in place, so as to develop an understanding of how the disparity occurs," the investigators noted (JAMA 2013;310:389-97).

There were four major findings:

First, 5-year breast cancer survival improved somewhat in both races over time, but the disparity between black women and white women remained constant.

Second, when the women were matched for demographic characteristics at presentation, 5-year survival was 68.8% for white women and 55.9% for black women, an absolute difference of nearly 13%, which represents approximately 3 years of life. In other words, compared with white women of the same age, year of diagnosis, and geographical location, black women still had a significantly lower 5-year breast cancer survival. Thus, demographic differences explain only a small part of the racial disparity.

Third, when the women were matched for clinical traits at presentation, this disparity in 5-year survival dropped to 4.4%, which represents approximately 1 year. This is a smaller but still significant difference between black women and white women who present with the same clinical picture.

Fourth, when the women were matched for treatment factors, this disparity only decreased slightly. "Hence, treatment differences explained only 0.81% of the 12.9% difference in 5-year survival," Dr. Silber and his associates said.

Most of the disparity in survival could be attributed to the poorer health of black women at presentation. Black women were markedly less likely than were white women to have seen a primary care provider during the preceding year and were significantly less likely to have undergone recent screening for breast cancer, colon cancer, or high cholesterol.

Black women also were significantly more likely than white women to have comorbid conditions. "Some of the effectiveness of cancer treatment ... may be blunted by other health problems" or by the treatment of those health problems, the investigators said.

Finally, black women were more likely than were white women to present with advanced breast cancer and worse biological features, such as larger tumor size and less favorable receptor status. The mean interval between diagnosis and the first treatment also was significantly longer for black women than for white women, they added.

This study was supported by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, and the National Science Foundation. No relevant conflicts of interest were reported.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – Upamostat, an investigational oral inhibitor of urokinase-type plasminogen activator, did not add to the efficacy of capecitabine monotherapy when given as first-line therapy to unselected patients with HER2-negative metastatic breast cancer, based on the results of a phase II trial.

The 132 women studied were assigned evenly to capecitabine monotherapy or to capecitabine plus upamostat. Median progression-free survival, the trial’s primary endpoint, was statistically indistinguishable at about 8 months in each group.

Courtesy Fox Chase Cancer Center

However, upamostat was associated with a 4-month gain in this outcome in the subset of patients who had previously received chemotherapy in the adjuvant or neoadjuvant setting, an unplanned exploratory analysis found.

"Treatment with prior chemotherapy potentially defines a more homogeneous subpopulation in this study. Also, prior chemotherapy could possibly identify a population with more aggressive disease due to higher expression of uPA [urokinase-type plasminogen activator]," said lead author Dr. Lori J. Goldstein of the Fox Chase Cancer Center in Philadelphia. "This would be in line with the treatment effects seen in the group who progressed early after initial diagnosis."

"Future studies with upamostat should target a more homogeneous patient population and incorporate biomarker-specific strategies for patient characterization and selection," Dr. Goldstein recommended.

Adding upamostat to chemotherapy, for nearly 3 years in some cases, was generally safe and well tolerated. The only increase in adverse events was in the incidence of hand-foot syndrome.

"Upamostat can safely be given over extended periods of time. [The study] is also the first proof of activity of an anti-uPA inhibitor in breast cancer therapy," Dr. Goldstein said at the annual meeting of the American Society of Clinical Oncology.

Part of the plasminogen activation system, uPA promotes tumor cell invasion, migration, and proliferation, Dr. Goldstein explained, giving some background to the research.

"As the uPA system is quantitatively more expressed in tumor cells and tumor-associated stromal cells, it is an interesting target for cancer therapy. uPA and PAI-1 [plasminogen activator inhibitor-1] are both ASCO-recommended prognostic and predictive biomarkers for early-stage breast cancer," she said.

Among all the patients enrolled in the trial, median progression-free survival was 8.3 months with the upamostat-capecitabine combination and 7.5 months with capecitabine alone, a nonsignificant difference. The estimated 6-month rates of progression-free survival were 56% and 50%.

Archival tumor specimens were not available for uPA and PAI-1 testing, according to Dr. Goldstein. And testing of serial plasma samples for a variety of biomarkers – uPA, PAI-1, CAIX (a marker associated with poorer prognostic features), and the fibrin degradation product D-dimer – failed to show any differences between groups.

In unplanned exploratory analyses, median progression-free survival among patients who had received prior adjuvant or neoadjuvant chemotherapy was 8.3 months with upamostat-capecitabine combination therapy and 4.3 months with capecitabine monotherapy.

The combination therapy also seemed to have an edge among patients who had experienced their recurrence within 3 years from initial diagnosis (5.6 vs. 2.7 months), Dr. Goldstein reported.

The upamostat-capecitabine group had a higher rate of any-grade hand-foot syndrome (77% vs. 46%), possibly related to a longer duration of treatment, whereas rates of other toxicities were similar.

"The pharmacokinetic analyses demonstrated no drug-drug interactions between upamostat and capecitabine," she noted.

Dr. Goldstein disclosed that she receives research funding from the U.S. Department of Defense and Wilex. The trial was sponsored by Wilex, the maker of upamostat.

CHICAGO – Upamostat, an investigational oral inhibitor of urokinase-type plasminogen activator, did not add to the efficacy of capecitabine monotherapy when given as first-line therapy to unselected patients with HER2-negative metastatic breast cancer, based on the results of a phase II trial.

The 132 women studied were assigned evenly to capecitabine monotherapy or to capecitabine plus upamostat. Median progression-free survival, the trial’s primary endpoint, was statistically indistinguishable at about 8 months in each group.

Courtesy Fox Chase Cancer Center

However, upamostat was associated with a 4-month gain in this outcome in the subset of patients who had previously received chemotherapy in the adjuvant or neoadjuvant setting, an unplanned exploratory analysis found.

"Treatment with prior chemotherapy potentially defines a more homogeneous subpopulation in this study. Also, prior chemotherapy could possibly identify a population with more aggressive disease due to higher expression of uPA [urokinase-type plasminogen activator]," said lead author Dr. Lori J. Goldstein of the Fox Chase Cancer Center in Philadelphia. "This would be in line with the treatment effects seen in the group who progressed early after initial diagnosis."

"Future studies with upamostat should target a more homogeneous patient population and incorporate biomarker-specific strategies for patient characterization and selection," Dr. Goldstein recommended.

Adding upamostat to chemotherapy, for nearly 3 years in some cases, was generally safe and well tolerated. The only increase in adverse events was in the incidence of hand-foot syndrome.

"Upamostat can safely be given over extended periods of time. [The study] is also the first proof of activity of an anti-uPA inhibitor in breast cancer therapy," Dr. Goldstein said at the annual meeting of the American Society of Clinical Oncology.

Part of the plasminogen activation system, uPA promotes tumor cell invasion, migration, and proliferation, Dr. Goldstein explained, giving some background to the research.

"As the uPA system is quantitatively more expressed in tumor cells and tumor-associated stromal cells, it is an interesting target for cancer therapy. uPA and PAI-1 [plasminogen activator inhibitor-1] are both ASCO-recommended prognostic and predictive biomarkers for early-stage breast cancer," she said.

Among all the patients enrolled in the trial, median progression-free survival was 8.3 months with the upamostat-capecitabine combination and 7.5 months with capecitabine alone, a nonsignificant difference. The estimated 6-month rates of progression-free survival were 56% and 50%.

Archival tumor specimens were not available for uPA and PAI-1 testing, according to Dr. Goldstein. And testing of serial plasma samples for a variety of biomarkers – uPA, PAI-1, CAIX (a marker associated with poorer prognostic features), and the fibrin degradation product D-dimer – failed to show any differences between groups.

In unplanned exploratory analyses, median progression-free survival among patients who had received prior adjuvant or neoadjuvant chemotherapy was 8.3 months with upamostat-capecitabine combination therapy and 4.3 months with capecitabine monotherapy.

The combination therapy also seemed to have an edge among patients who had experienced their recurrence within 3 years from initial diagnosis (5.6 vs. 2.7 months), Dr. Goldstein reported.

The upamostat-capecitabine group had a higher rate of any-grade hand-foot syndrome (77% vs. 46%), possibly related to a longer duration of treatment, whereas rates of other toxicities were similar.

"The pharmacokinetic analyses demonstrated no drug-drug interactions between upamostat and capecitabine," she noted.

Dr. Goldstein disclosed that she receives research funding from the U.S. Department of Defense and Wilex. The trial was sponsored by Wilex, the maker of upamostat.

CHICAGO – Upamostat, an investigational oral inhibitor of urokinase-type plasminogen activator, did not add to the efficacy of capecitabine monotherapy when given as first-line therapy to unselected patients with HER2-negative metastatic breast cancer, based on the results of a phase II trial.

The 132 women studied were assigned evenly to capecitabine monotherapy or to capecitabine plus upamostat. Median progression-free survival, the trial’s primary endpoint, was statistically indistinguishable at about 8 months in each group.

Courtesy Fox Chase Cancer Center

However, upamostat was associated with a 4-month gain in this outcome in the subset of patients who had previously received chemotherapy in the adjuvant or neoadjuvant setting, an unplanned exploratory analysis found.

"Treatment with prior chemotherapy potentially defines a more homogeneous subpopulation in this study. Also, prior chemotherapy could possibly identify a population with more aggressive disease due to higher expression of uPA [urokinase-type plasminogen activator]," said lead author Dr. Lori J. Goldstein of the Fox Chase Cancer Center in Philadelphia. "This would be in line with the treatment effects seen in the group who progressed early after initial diagnosis."

"Future studies with upamostat should target a more homogeneous patient population and incorporate biomarker-specific strategies for patient characterization and selection," Dr. Goldstein recommended.

Adding upamostat to chemotherapy, for nearly 3 years in some cases, was generally safe and well tolerated. The only increase in adverse events was in the incidence of hand-foot syndrome.

"Upamostat can safely be given over extended periods of time. [The study] is also the first proof of activity of an anti-uPA inhibitor in breast cancer therapy," Dr. Goldstein said at the annual meeting of the American Society of Clinical Oncology.

Part of the plasminogen activation system, uPA promotes tumor cell invasion, migration, and proliferation, Dr. Goldstein explained, giving some background to the research.

"As the uPA system is quantitatively more expressed in tumor cells and tumor-associated stromal cells, it is an interesting target for cancer therapy. uPA and PAI-1 [plasminogen activator inhibitor-1] are both ASCO-recommended prognostic and predictive biomarkers for early-stage breast cancer," she said.

Among all the patients enrolled in the trial, median progression-free survival was 8.3 months with the upamostat-capecitabine combination and 7.5 months with capecitabine alone, a nonsignificant difference. The estimated 6-month rates of progression-free survival were 56% and 50%.

Archival tumor specimens were not available for uPA and PAI-1 testing, according to Dr. Goldstein. And testing of serial plasma samples for a variety of biomarkers – uPA, PAI-1, CAIX (a marker associated with poorer prognostic features), and the fibrin degradation product D-dimer – failed to show any differences between groups.

In unplanned exploratory analyses, median progression-free survival among patients who had received prior adjuvant or neoadjuvant chemotherapy was 8.3 months with upamostat-capecitabine combination therapy and 4.3 months with capecitabine monotherapy.

The combination therapy also seemed to have an edge among patients who had experienced their recurrence within 3 years from initial diagnosis (5.6 vs. 2.7 months), Dr. Goldstein reported.

The upamostat-capecitabine group had a higher rate of any-grade hand-foot syndrome (77% vs. 46%), possibly related to a longer duration of treatment, whereas rates of other toxicities were similar.

"The pharmacokinetic analyses demonstrated no drug-drug interactions between upamostat and capecitabine," she noted.

Dr. Goldstein disclosed that she receives research funding from the U.S. Department of Defense and Wilex. The trial was sponsored by Wilex, the maker of upamostat.