Breast Cancer

SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.

SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.

SAN ANTONIO – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD, of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium.

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study, failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study. Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601, a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Axillary dissection can be avoided in patients with early breast cancer and limited sentinel node involvement, investigators reported at the San Antonio Breast Cancer Symposium.

Both disease-free survival (DFS) and overall survival (OS) were similar in a population of patients with cT1-T2 N0M0 breast cancer and sentinel node micrometastases who underwent axillary dissection (AD), compared with those who did not. Complications associated with axillary surgery can be avoided in this population, without any adverse effect on survival.

“Our findings are fully consistent with those of the Z0011 trial, which after 10 years found no differences between the AD and no-AD groups for any endpoint in patients with moderate disease burden in the axilla undergoing conservative breast surgery,” said study author Viviana Galimberti, MD, of the European Institute of Oncology in Milan.

In the ACOSOG Z0011, trial, the use of sentinel node biopsy alone was not inferior to AD in patients with limited sentinel node metastasis treated with breast conservation and systemic therapy.

“We also suggest that non-AD is acceptable treatment in patients scheduled for mastectomy,” Dr. Galimberti said.

For patients with breast cancer and metastases in the sentinel nodes, AD has been the standard of care, but for those with limited sentinel node involvement, it was hypothesized that AD might not be necessary.

The phase 3 IBCSG 23-01 study was a multicenter, randomized, noninferiority trial that compared DFS in breast cancer patients with one or more micrometastases (greater than or equal to 2 mm) in the sentinel nodes who were randomized to either AD or no axillary dissection (no-AD). The 5-year results, which were published in 2013 in the Lancet Oncology (2013 Jun;14[7]:e251-2) showed no difference in DFS between the two groups.

At the meeting, Dr. Galimberti reported on outcomes after an extended median follow-up of 9.8 years. A cohort of 934 women (931 evaluable) were enrolled from 27 centers from 2001 to 2010 and randomized to either AD or no AD (467 in the no-AD group and 464 in the AD group).

The results were similar to those reported at 5 years. The 10-year DFS rates were similar for both cohorts; 77% for non-AD vs. 75% for AD (hazard ratio [no-AD vs. AD], 0.85; 95% confidence interval, 0.65-1.11; log-rank P = .23; noninferiority P = .002).

The rate of axillary failure in the no-AD group was low, Dr. Galimberti pointed out, at 1.7% and 0.8% among women who underwent breast-conserving surgery. There were nine ipsilateral axillary events in the no-AD group vs. three in the AD group, and 45 deaths in the no-AD group vs. 58 in the AD group. The 10-year OS was 91% (95% CI, 88%-94%) in the no-AD group and 88% (95% CI, 85%-92%) in the AD group (HR [no-AD vs. AD], 0.77; 95% CI, 0.56-1.07; log-rank P = .19).

There was no difference between groups for the main endpoint of DFS or the secondary endpoint of OS, said Dr. Galimberti.

In subgroup analyses, which included tumor size, estrogen-receptor status, progesterone-receptor status, tumor grade, and type of surgery, there were no subgroups identified that benefited from AD over no-AD.

“Our data fully support the change in clinical practice that started after the early published results,” Dr Galimberti concluded. “No AD is now standard treatment in early breast cancer when the sentinel node is only minimally involved.”

The study received no outside funding and the authors had no disclosures.

SOURCE: Galimberti et al. SABCS Abstract GS5-02

SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.

However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium

High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).

In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).

The researchers of this trial also found that pCR was a surrogate for long-term outcome.

“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.

The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.

Of the cancer genes, only ERBB2 was predictive of pCR.

A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.

The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.

Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).

After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.

“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”

SOURCE: Sotiriou et al. SABCS Abstract GS1-04

SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.

However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium

High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).

In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).

The researchers of this trial also found that pCR was a surrogate for long-term outcome.

“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.

The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.

Of the cancer genes, only ERBB2 was predictive of pCR.

A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.

The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.

Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).

After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.

“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”

SOURCE: Sotiriou et al. SABCS Abstract GS1-04

SAN ANTONIO – Among patients receiving trastuzumab plus lapatinib neoadjuvant therapy for HER2-positive early breast cancer, amplification of ERBB2 was predictive of a pathologic complete response (pCR), according to findings presented at the San Antonio Breast Cancer Symposium.

However, ERBB2 mRNA expression and PAM50-enriched HER2 better predicted pCR, said lead study author Cristos Sotiriou, MD, of the Breast Cancer Translational Research Laboratory at the Institut Jules Bordet in Belgium

High genomic instability was associated with a higher pCR rate in patients with estrogen receptor–positive tumors, but copy number alterations (CNAs) were not associated with event-free survival (EFS).

In the large phase 3 NeoALTTO trial, lapatinib combined with trastuzumab in the neoadjuvant setting nearly doubled the pCR rate as compared with either agent used alone. The 3-year EFS was also improved with dual HER2 blockage versus single HER2 therapy (84% for the combination, hazard ratio, 0.78; P = .33 vs. 78% for lapatinib alone and 76% for trastuzumab alone, HR, 1.06; P = .81 for both).

The researchers of this trial also found that pCR was a surrogate for long-term outcome.

“Expression of ERBB2, ESR1, and immune signatures were the main drivers of pCR,” said Dr. Sotiriou.

The main goal of the current study was to investigate the relevance of CNAs for pCR and EFS in this population. A total of 455 patients were enrolled in the NeoALTTO study, and of this cohort, 270 had tumor content that was sufficient to assay for CNAs. Tumor-infiltrating lymphocytes and gene expression were also obtained and the genome instability index was calculated, and 184 samples were included in the final analysis.

Of the cancer genes, only ERBB2 was predictive of pCR.

A total of 159 recurrent CNA regions were identified. ERBB2 amplification was associated with high pCR (P = .0007), but less than ERBB2 expression, and it lost its significance after correcting for ERBB2 expression.

The genome instability index (GII) was defined as the “median absolute deviation of the normalized copy number” and independent of ERBB2 amplification, the pCR rate increased with the GII (P = .03.

Amplification of two regions on 6q23-24 was significantly associated with higher pCR (P = .00005 and P = .00087). One of the segments harbored 39 genes, some with an expression level that was also predictive of pCR. The 6q23-24 segment was associated with pCR in estrogen receptor–positive tumors only (interaction test P = .04).

After multiple testing correction, there were no amplified regions or genes found to be predictive of EFS.

“A novel amplified region on 6q23-24 was shown to be predictive of pCR, in particular for estrogen receptor–positive tumors,” said Dr. Sotiriou. “This may warrant further investigation.”

SOURCE: Sotiriou et al. SABCS Abstract GS1-04

SAN ANTONIO – A biological risk signature can help guide decisions about use of adjuvant radiation therapy in patients with ductal carcinoma in situ (DCIS), suggests a validation study reported at the San Antonio Breast Cancer Symposium.

Radiation therapy reduces the 10-year risk of any ipsilateral recurrence in this population by about 50% as established in a large overview of trials (J Natl Cancer Inst Monogr. 2010;2010:162-77), noted lead investigator Fredrik Wärnberg, MD, PhD, of Uppsala Academic Hospital, Uppsala University, Sweden. But factors such as tumor size, grade, and margins have not been helpful in identifying patients most likely to benefit.

Study details

Main results from the SweDCIS trial, previously reported (J Clin Oncol. 2014;32:3613-8), showed that adjuvant radiation therapy reduced recurrences, yielding a 12% absolute reduction in risk of ipsilateral recurrence (10% for in situ recurrences and 2% for invasive recurrences).

For the validation study, Dr. Wärnberg and his colleagues were able to obtain tissue and biological signature results, blinded to patient outcome, for 56% of the original trial population. About half of patients each were determined to have low risk scores and elevated risk scores.

Among the 506 patients with clear margins, the score, analyzed as a continuous variable, was associated with risk of any (in situ or invasive) ipsilateral recurrence during follow-up (hazard ratio, 1.49 per 5-unit increase; P = .038).

In a multivariate model, receipt of radiation therapy was associated with a 52% relative reduction in 10-year risk of any ipsilateral recurrence for those with a low-risk score (HR, 0.48; P = .04) and a greater 69% relative reduction for those with an elevated risk score (HR, 0.31; P less than .001).

Radiation therapy did not significantly reduce the risk of ipsilateral invasive recurrence in the low risk group (HR, 0.84; P = .70), but it did in the elevated risk group (HR, 0.24; P = .012).

These findings essentially mirrored those of a 2015 validation study in a separate cohort of 526 patients from Uppsala University Hospital and the University of Massachusetts, according to Dr. Wärnberg. “We found highly consistent data with these two different sets,” he said.

Analyses additionally showed that radiation therapy reduced the 10-year risk of an invasive breast cancer recurrence by an absolute 1% for patients with low risk scores (not significant) but by an absolute 9% for patients with elevated risk scores (P = .012).

Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.

SOURCE: Warnberg et al., SABCS Abstract GS5-08

SAN ANTONIO – A biological risk signature can help guide decisions about use of adjuvant radiation therapy in patients with ductal carcinoma in situ (DCIS), suggests a validation study reported at the San Antonio Breast Cancer Symposium.

Radiation therapy reduces the 10-year risk of any ipsilateral recurrence in this population by about 50% as established in a large overview of trials (J Natl Cancer Inst Monogr. 2010;2010:162-77), noted lead investigator Fredrik Wärnberg, MD, PhD, of Uppsala Academic Hospital, Uppsala University, Sweden. But factors such as tumor size, grade, and margins have not been helpful in identifying patients most likely to benefit.

Study details

Main results from the SweDCIS trial, previously reported (J Clin Oncol. 2014;32:3613-8), showed that adjuvant radiation therapy reduced recurrences, yielding a 12% absolute reduction in risk of ipsilateral recurrence (10% for in situ recurrences and 2% for invasive recurrences).

For the validation study, Dr. Wärnberg and his colleagues were able to obtain tissue and biological signature results, blinded to patient outcome, for 56% of the original trial population. About half of patients each were determined to have low risk scores and elevated risk scores.

Among the 506 patients with clear margins, the score, analyzed as a continuous variable, was associated with risk of any (in situ or invasive) ipsilateral recurrence during follow-up (hazard ratio, 1.49 per 5-unit increase; P = .038).

In a multivariate model, receipt of radiation therapy was associated with a 52% relative reduction in 10-year risk of any ipsilateral recurrence for those with a low-risk score (HR, 0.48; P = .04) and a greater 69% relative reduction for those with an elevated risk score (HR, 0.31; P less than .001).

Radiation therapy did not significantly reduce the risk of ipsilateral invasive recurrence in the low risk group (HR, 0.84; P = .70), but it did in the elevated risk group (HR, 0.24; P = .012).

These findings essentially mirrored those of a 2015 validation study in a separate cohort of 526 patients from Uppsala University Hospital and the University of Massachusetts, according to Dr. Wärnberg. “We found highly consistent data with these two different sets,” he said.

Analyses additionally showed that radiation therapy reduced the 10-year risk of an invasive breast cancer recurrence by an absolute 1% for patients with low risk scores (not significant) but by an absolute 9% for patients with elevated risk scores (P = .012).

Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.

SOURCE: Warnberg et al., SABCS Abstract GS5-08

SAN ANTONIO – A biological risk signature can help guide decisions about use of adjuvant radiation therapy in patients with ductal carcinoma in situ (DCIS), suggests a validation study reported at the San Antonio Breast Cancer Symposium.

Radiation therapy reduces the 10-year risk of any ipsilateral recurrence in this population by about 50% as established in a large overview of trials (J Natl Cancer Inst Monogr. 2010;2010:162-77), noted lead investigator Fredrik Wärnberg, MD, PhD, of Uppsala Academic Hospital, Uppsala University, Sweden. But factors such as tumor size, grade, and margins have not been helpful in identifying patients most likely to benefit.

Study details

Main results from the SweDCIS trial, previously reported (J Clin Oncol. 2014;32:3613-8), showed that adjuvant radiation therapy reduced recurrences, yielding a 12% absolute reduction in risk of ipsilateral recurrence (10% for in situ recurrences and 2% for invasive recurrences).

For the validation study, Dr. Wärnberg and his colleagues were able to obtain tissue and biological signature results, blinded to patient outcome, for 56% of the original trial population. About half of patients each were determined to have low risk scores and elevated risk scores.

Among the 506 patients with clear margins, the score, analyzed as a continuous variable, was associated with risk of any (in situ or invasive) ipsilateral recurrence during follow-up (hazard ratio, 1.49 per 5-unit increase; P = .038).

In a multivariate model, receipt of radiation therapy was associated with a 52% relative reduction in 10-year risk of any ipsilateral recurrence for those with a low-risk score (HR, 0.48; P = .04) and a greater 69% relative reduction for those with an elevated risk score (HR, 0.31; P less than .001).

Radiation therapy did not significantly reduce the risk of ipsilateral invasive recurrence in the low risk group (HR, 0.84; P = .70), but it did in the elevated risk group (HR, 0.24; P = .012).

These findings essentially mirrored those of a 2015 validation study in a separate cohort of 526 patients from Uppsala University Hospital and the University of Massachusetts, according to Dr. Wärnberg. “We found highly consistent data with these two different sets,” he said.

Analyses additionally showed that radiation therapy reduced the 10-year risk of an invasive breast cancer recurrence by an absolute 1% for patients with low risk scores (not significant) but by an absolute 9% for patients with elevated risk scores (P = .012).

Dr. Wärnberg disclosed that he had no relevant conflicts of interest. The study was funded in part by PreludeDx.

SOURCE: Warnberg et al., SABCS Abstract GS5-08

REPORTING FROM SABCS 2017

SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10,  and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

[email protected]

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

REPORTING FROM SABCS 2017

SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10,  and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

[email protected]

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

REPORTING FROM SABCS 2017

SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10,  and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

[email protected]

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

SAN ANTONIO – Postmenopausal women may be able to lower their risk of invasive breast cancer by simply losing some weight, according to an analysis of the large prospective Women’s Health Initiative Observational Study.

“While obesity is an established risk factor for postmenopausal breast cancer, studies of weight loss and breast cancer provide inconsistent results. It’s been very, very difficult to show that losing weight changes breast cancer incidence,” said lead investigator Rowan T. Chlebowski, MD, PhD, research professor in the department of medical oncology and therapeutics research at City of Hope in Duarte, Calif. “Consequently, the current public health message is limited to ‘avoid body fatness’ [N Engl J Med. 2016;375:794-8]. That’s not a very strong public health message.”

Susan London/Frontline Medical News

Parsing the findings

“I hope that you can present this to general doctors rather than oncologists because those are the ones seeing healthy women, by and large,” said press briefing moderator C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. “But in my patients, I’ve always suggested that they lose weight. Most of them with breast cancer are overweight, it seems. And I always had to do it because of diabetes and other factors. Now we can do it because we have a breast cancer endpoint that also suggests that losing weight will help with that as well.”

Susan London/Frontline Medical News

Study details

The Women’s Health Initiative Observational Study recruited 93,676 postmenopausal women aged 50-79 years from 40 U.S. clinical centers during 1993-1998. The women had measurements taken of height and weight at baseline and at year 3 for calculation of BMI, and were asked about intentionality of any weight loss during that period.

Analyses were based on 61,335 women who had normal or higher body weight and were cancer free at baseline, survived at least 3 years, and had adequate data.

Overall, about 13.3% of women lost at least 5% of their body weight between baseline and year 3; 7.9% did so intentionally, losing an average of 19.6 pounds, and 5.5% did so unintentionally, losing an average of 16.9 pounds.

“We used the 5% decrease because this level has been shown to change some biochemical markers potentially associated with cancer. And it has been shown in a different study population, a randomized trial, to reduce the frequency of diabetes,” Dr. Chlebowski noted.

“There was nothing that the study did to induce the weight loss. And based on a partial look at the data, it doesn’t look like many of the women went to some kind of program to lose weight. So it was probably self-directed weight loss,” he noted. “Interestingly, the body mass index of this group was 29.9, so they were on the verge of going into obesity. We wondered in retrospect whether that was a motivating factor for them.”

In multivariate analysis, relative to peers having a stable weight over time, the women losing at least 5% of their weight had a lower risk of breast cancer (hazard ratio, 0.88; 95% confidence interval, 0.78-0.98; P = .02).

Findings were unchanged after further adjustment for mammography frequency. In addition, risk reduction was statistically indistinguishable whether the weight loss was intentional or not (P = .2 for interaction), and whether women were normal weight, overweight, or obese at baseline (P = .4 for interaction).

The 19.6% of women who had a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall, but they did have a significantly elevated risk of triple-negative breast cancer (HR, 1.54; 95% CI, 1.16-2.05). “We really don’t have a good explanation for this,” Dr. Chlebowski said.

Tackling the global obesity epidemic by conventional means to reduce cancer risk is an uphill battle, he concluded. “We are going to be looking for possible mediating factors. If you can find the mediating factors, pharmacologic intervention would have a much greater chance of success.”

Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.

SOURCE: Chlebowski et al., SABCS 2017 Abstract GS5-07

SAN ANTONIO – Postmenopausal women may be able to lower their risk of invasive breast cancer by simply losing some weight, according to an analysis of the large prospective Women’s Health Initiative Observational Study.

“While obesity is an established risk factor for postmenopausal breast cancer, studies of weight loss and breast cancer provide inconsistent results. It’s been very, very difficult to show that losing weight changes breast cancer incidence,” said lead investigator Rowan T. Chlebowski, MD, PhD, research professor in the department of medical oncology and therapeutics research at City of Hope in Duarte, Calif. “Consequently, the current public health message is limited to ‘avoid body fatness’ [N Engl J Med. 2016;375:794-8]. That’s not a very strong public health message.”

Susan London/Frontline Medical News

Parsing the findings

“I hope that you can present this to general doctors rather than oncologists because those are the ones seeing healthy women, by and large,” said press briefing moderator C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. “But in my patients, I’ve always suggested that they lose weight. Most of them with breast cancer are overweight, it seems. And I always had to do it because of diabetes and other factors. Now we can do it because we have a breast cancer endpoint that also suggests that losing weight will help with that as well.”

Susan London/Frontline Medical News

Study details

The Women’s Health Initiative Observational Study recruited 93,676 postmenopausal women aged 50-79 years from 40 U.S. clinical centers during 1993-1998. The women had measurements taken of height and weight at baseline and at year 3 for calculation of BMI, and were asked about intentionality of any weight loss during that period.

Analyses were based on 61,335 women who had normal or higher body weight and were cancer free at baseline, survived at least 3 years, and had adequate data.

Overall, about 13.3% of women lost at least 5% of their body weight between baseline and year 3; 7.9% did so intentionally, losing an average of 19.6 pounds, and 5.5% did so unintentionally, losing an average of 16.9 pounds.

“We used the 5% decrease because this level has been shown to change some biochemical markers potentially associated with cancer. And it has been shown in a different study population, a randomized trial, to reduce the frequency of diabetes,” Dr. Chlebowski noted.

“There was nothing that the study did to induce the weight loss. And based on a partial look at the data, it doesn’t look like many of the women went to some kind of program to lose weight. So it was probably self-directed weight loss,” he noted. “Interestingly, the body mass index of this group was 29.9, so they were on the verge of going into obesity. We wondered in retrospect whether that was a motivating factor for them.”

In multivariate analysis, relative to peers having a stable weight over time, the women losing at least 5% of their weight had a lower risk of breast cancer (hazard ratio, 0.88; 95% confidence interval, 0.78-0.98; P = .02).

Findings were unchanged after further adjustment for mammography frequency. In addition, risk reduction was statistically indistinguishable whether the weight loss was intentional or not (P = .2 for interaction), and whether women were normal weight, overweight, or obese at baseline (P = .4 for interaction).

The 19.6% of women who had a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall, but they did have a significantly elevated risk of triple-negative breast cancer (HR, 1.54; 95% CI, 1.16-2.05). “We really don’t have a good explanation for this,” Dr. Chlebowski said.

Tackling the global obesity epidemic by conventional means to reduce cancer risk is an uphill battle, he concluded. “We are going to be looking for possible mediating factors. If you can find the mediating factors, pharmacologic intervention would have a much greater chance of success.”

Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.

SOURCE: Chlebowski et al., SABCS 2017 Abstract GS5-07

SAN ANTONIO – Postmenopausal women may be able to lower their risk of invasive breast cancer by simply losing some weight, according to an analysis of the large prospective Women’s Health Initiative Observational Study.

“While obesity is an established risk factor for postmenopausal breast cancer, studies of weight loss and breast cancer provide inconsistent results. It’s been very, very difficult to show that losing weight changes breast cancer incidence,” said lead investigator Rowan T. Chlebowski, MD, PhD, research professor in the department of medical oncology and therapeutics research at City of Hope in Duarte, Calif. “Consequently, the current public health message is limited to ‘avoid body fatness’ [N Engl J Med. 2016;375:794-8]. That’s not a very strong public health message.”

Susan London/Frontline Medical News

Parsing the findings

“I hope that you can present this to general doctors rather than oncologists because those are the ones seeing healthy women, by and large,” said press briefing moderator C. Kent Osborne, MD, codirector of SABCS and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston. “But in my patients, I’ve always suggested that they lose weight. Most of them with breast cancer are overweight, it seems. And I always had to do it because of diabetes and other factors. Now we can do it because we have a breast cancer endpoint that also suggests that losing weight will help with that as well.”

Susan London/Frontline Medical News

Study details

The Women’s Health Initiative Observational Study recruited 93,676 postmenopausal women aged 50-79 years from 40 U.S. clinical centers during 1993-1998. The women had measurements taken of height and weight at baseline and at year 3 for calculation of BMI, and were asked about intentionality of any weight loss during that period.

Analyses were based on 61,335 women who had normal or higher body weight and were cancer free at baseline, survived at least 3 years, and had adequate data.

Overall, about 13.3% of women lost at least 5% of their body weight between baseline and year 3; 7.9% did so intentionally, losing an average of 19.6 pounds, and 5.5% did so unintentionally, losing an average of 16.9 pounds.

“We used the 5% decrease because this level has been shown to change some biochemical markers potentially associated with cancer. And it has been shown in a different study population, a randomized trial, to reduce the frequency of diabetes,” Dr. Chlebowski noted.

“There was nothing that the study did to induce the weight loss. And based on a partial look at the data, it doesn’t look like many of the women went to some kind of program to lose weight. So it was probably self-directed weight loss,” he noted. “Interestingly, the body mass index of this group was 29.9, so they were on the verge of going into obesity. We wondered in retrospect whether that was a motivating factor for them.”

In multivariate analysis, relative to peers having a stable weight over time, the women losing at least 5% of their weight had a lower risk of breast cancer (hazard ratio, 0.88; 95% confidence interval, 0.78-0.98; P = .02).

Findings were unchanged after further adjustment for mammography frequency. In addition, risk reduction was statistically indistinguishable whether the weight loss was intentional or not (P = .2 for interaction), and whether women were normal weight, overweight, or obese at baseline (P = .4 for interaction).

The 19.6% of women who had a weight gain of at least 5% did not have a significantly elevated risk of breast cancer overall, but they did have a significantly elevated risk of triple-negative breast cancer (HR, 1.54; 95% CI, 1.16-2.05). “We really don’t have a good explanation for this,” Dr. Chlebowski said.

Tackling the global obesity epidemic by conventional means to reduce cancer risk is an uphill battle, he concluded. “We are going to be looking for possible mediating factors. If you can find the mediating factors, pharmacologic intervention would have a much greater chance of success.”

Dr. Chlebowski disclosed that he had no relevant conflicts of interest. Research was supported by the National Heart, Lung and Blood Institute; National Institutes of Health; Department of Health and Human Services; and American Institute for Cancer Research.

SOURCE: Chlebowski et al., SABCS 2017 Abstract GS5-07

SAN ANTONIO – Undergoing axillary lymph node dissection (ALND) is more likely to result in arm swelling and decreased range of arm motion in young breast cancer patients, as compared with having a sentinel lymph node biopsy (SLNB), according to new findings.

In a large prospective cohort study that included 1,302 breast cancer patients aged 40 or younger, the incidence of arm swelling 1 year after diagnosis among women who underwent breast-conserving surgery was 6% for the SLNB group versus 24% for those who had ALND. Among patients who had a mastectomy, the rates were similar; 6% versus 23% for SLNB or ALND, respectively.

“Young breast cancer survivors report high rates of arm morbidity in the first year of follow-up,” said lead author Anne Kuijer, MD, of Dana-Farber Cancer Institute/Brigham and Women’s Hospital in Boston. “Axillary node dissection, increased BMI [body mass index] and socioeconomic status were all independently associated with an increased risk of arm swelling,” she said at the San Antonio Breast Cancer Symposium.

She noted that patients who received mastectomy with radiation therapy were twice as likely to have decreased range of motion at 1 year, compared with patients treated with breast-conserving treatment.

In this study, the authors evaluated the incidence of arm morbidity associated with both ALND and SLNB in patients who were enrolled in the Young Women’s Breast Cancer Study. This multicenter prospective cohort study was designed to explore biological, medical, and psychosocial issues experienced by young breast cancer patients.

Within this large cohort, 55% had undergone an SLNB only, and 41% an ALND. The remaining patients did not undergo either procedure.

The primary endpoint of this study was to examine the incidence of patient-reported arm swelling or decreased range of motion at 1 year after their breast cancer diagnosis. Patients used the Cancer Rehabilitation Evaluation System (CARES-SF) to measure their symptoms.

Overall, at 1 year, 13% of the cohort reported arm swelling, and 40% reported decreased range of motion in the ipsilateral arm.

Several factors were associated with a higher risk of arm morbidity. Patients with a BMI of greater than 25 were more likely to report arm swelling vs. those with lower BMI (odds ratio, 1.7; P = .03) as well as have less range of motion (OR, 1.5; P = .05). Women who reported feeling financially comfortable were 40% less likely to report swelling (P = .02) and 90% less likely to report decreased range of motion (P = .67).

In addition, those who underwent ALND were 3.4 times more likely to report swelling, compared with women who had SLNB, but it was not associated with a reduction in range of motion.

One limitation of the study is that the cohort included patients who had received treatment at large cancer centers in the Northeast, suggesting that they may have been of higher socioeconomic status and may have led more active lifestyles, compared with the general population. Another limitation is that arm morbidity was self-reported and not objectively measured.

“I think our findings highlight opportunities for preoperative counseling, early referral of patients to physical therapy, and identification of resources for support of those at increased risk,” said Dr. Kuijer.

SOURCE: Kuijer et al. SABCS Abstract GS5-03

SAN ANTONIO – Undergoing axillary lymph node dissection (ALND) is more likely to result in arm swelling and decreased range of arm motion in young breast cancer patients, as compared with having a sentinel lymph node biopsy (SLNB), according to new findings.

In a large prospective cohort study that included 1,302 breast cancer patients aged 40 or younger, the incidence of arm swelling 1 year after diagnosis among women who underwent breast-conserving surgery was 6% for the SLNB group versus 24% for those who had ALND. Among patients who had a mastectomy, the rates were similar; 6% versus 23% for SLNB or ALND, respectively.

“Young breast cancer survivors report high rates of arm morbidity in the first year of follow-up,” said lead author Anne Kuijer, MD, of Dana-Farber Cancer Institute/Brigham and Women’s Hospital in Boston. “Axillary node dissection, increased BMI [body mass index] and socioeconomic status were all independently associated with an increased risk of arm swelling,” she said at the San Antonio Breast Cancer Symposium.

She noted that patients who received mastectomy with radiation therapy were twice as likely to have decreased range of motion at 1 year, compared with patients treated with breast-conserving treatment.

In this study, the authors evaluated the incidence of arm morbidity associated with both ALND and SLNB in patients who were enrolled in the Young Women’s Breast Cancer Study. This multicenter prospective cohort study was designed to explore biological, medical, and psychosocial issues experienced by young breast cancer patients.

Within this large cohort, 55% had undergone an SLNB only, and 41% an ALND. The remaining patients did not undergo either procedure.

The primary endpoint of this study was to examine the incidence of patient-reported arm swelling or decreased range of motion at 1 year after their breast cancer diagnosis. Patients used the Cancer Rehabilitation Evaluation System (CARES-SF) to measure their symptoms.

Overall, at 1 year, 13% of the cohort reported arm swelling, and 40% reported decreased range of motion in the ipsilateral arm.

Several factors were associated with a higher risk of arm morbidity. Patients with a BMI of greater than 25 were more likely to report arm swelling vs. those with lower BMI (odds ratio, 1.7; P = .03) as well as have less range of motion (OR, 1.5; P = .05). Women who reported feeling financially comfortable were 40% less likely to report swelling (P = .02) and 90% less likely to report decreased range of motion (P = .67).

In addition, those who underwent ALND were 3.4 times more likely to report swelling, compared with women who had SLNB, but it was not associated with a reduction in range of motion.

One limitation of the study is that the cohort included patients who had received treatment at large cancer centers in the Northeast, suggesting that they may have been of higher socioeconomic status and may have led more active lifestyles, compared with the general population. Another limitation is that arm morbidity was self-reported and not objectively measured.

“I think our findings highlight opportunities for preoperative counseling, early referral of patients to physical therapy, and identification of resources for support of those at increased risk,” said Dr. Kuijer.

SOURCE: Kuijer et al. SABCS Abstract GS5-03

SAN ANTONIO – Undergoing axillary lymph node dissection (ALND) is more likely to result in arm swelling and decreased range of arm motion in young breast cancer patients, as compared with having a sentinel lymph node biopsy (SLNB), according to new findings.

In a large prospective cohort study that included 1,302 breast cancer patients aged 40 or younger, the incidence of arm swelling 1 year after diagnosis among women who underwent breast-conserving surgery was 6% for the SLNB group versus 24% for those who had ALND. Among patients who had a mastectomy, the rates were similar; 6% versus 23% for SLNB or ALND, respectively.

“Young breast cancer survivors report high rates of arm morbidity in the first year of follow-up,” said lead author Anne Kuijer, MD, of Dana-Farber Cancer Institute/Brigham and Women’s Hospital in Boston. “Axillary node dissection, increased BMI [body mass index] and socioeconomic status were all independently associated with an increased risk of arm swelling,” she said at the San Antonio Breast Cancer Symposium.

She noted that patients who received mastectomy with radiation therapy were twice as likely to have decreased range of motion at 1 year, compared with patients treated with breast-conserving treatment.

In this study, the authors evaluated the incidence of arm morbidity associated with both ALND and SLNB in patients who were enrolled in the Young Women’s Breast Cancer Study. This multicenter prospective cohort study was designed to explore biological, medical, and psychosocial issues experienced by young breast cancer patients.

Within this large cohort, 55% had undergone an SLNB only, and 41% an ALND. The remaining patients did not undergo either procedure.

The primary endpoint of this study was to examine the incidence of patient-reported arm swelling or decreased range of motion at 1 year after their breast cancer diagnosis. Patients used the Cancer Rehabilitation Evaluation System (CARES-SF) to measure their symptoms.

Overall, at 1 year, 13% of the cohort reported arm swelling, and 40% reported decreased range of motion in the ipsilateral arm.

Several factors were associated with a higher risk of arm morbidity. Patients with a BMI of greater than 25 were more likely to report arm swelling vs. those with lower BMI (odds ratio, 1.7; P = .03) as well as have less range of motion (OR, 1.5; P = .05). Women who reported feeling financially comfortable were 40% less likely to report swelling (P = .02) and 90% less likely to report decreased range of motion (P = .67).

In addition, those who underwent ALND were 3.4 times more likely to report swelling, compared with women who had SLNB, but it was not associated with a reduction in range of motion.

One limitation of the study is that the cohort included patients who had received treatment at large cancer centers in the Northeast, suggesting that they may have been of higher socioeconomic status and may have led more active lifestyles, compared with the general population. Another limitation is that arm morbidity was self-reported and not objectively measured.

“I think our findings highlight opportunities for preoperative counseling, early referral of patients to physical therapy, and identification of resources for support of those at increased risk,” said Dr. Kuijer.

SOURCE: Kuijer et al. SABCS Abstract GS5-03

SAN ANTONIO – Dr. William A. Gradishar and Dr. Hope S. Rugo reflect on some familiar questions at the conclusion of the San Antonio Breast Cancer Symposium: Should young, high-risk women receive ovarian suppression? What is the optimal duration for trastuzumab therapy? What about extended aromatase inhibitor therapy? But new questions were considered as well, based on results presented at the 40th annual symposium.

Will combining a checkpoint inhibitor with trastuzumab help overcome trastuzumab resistance?

Are CDK 4/6 inhibitors here to stay?

Does acupuncture relieve joint pain in women on adjuvant aromatase inhibitor treatment?

The potential approval of a few novel agents in 2018 – an antibody-drug conjugate and a new PARP inhibitor – were also discussed in the video roundtable.

Dr. William A. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago. He had no disclosures to report. Dr. Hope S. Rugo is professor of medicine at the University of California, San Francisco. She disclosed that she receives research funding (institutional) from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, and Merck.

SAN ANTONIO – Dr. William A. Gradishar and Dr. Hope S. Rugo reflect on some familiar questions at the conclusion of the San Antonio Breast Cancer Symposium: Should young, high-risk women receive ovarian suppression? What is the optimal duration for trastuzumab therapy? What about extended aromatase inhibitor therapy? But new questions were considered as well, based on results presented at the 40th annual symposium.

Will combining a checkpoint inhibitor with trastuzumab help overcome trastuzumab resistance?

Are CDK 4/6 inhibitors here to stay?

Does acupuncture relieve joint pain in women on adjuvant aromatase inhibitor treatment?

The potential approval of a few novel agents in 2018 – an antibody-drug conjugate and a new PARP inhibitor – were also discussed in the video roundtable.

Dr. William A. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago. He had no disclosures to report. Dr. Hope S. Rugo is professor of medicine at the University of California, San Francisco. She disclosed that she receives research funding (institutional) from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, and Merck.

SAN ANTONIO – Dr. William A. Gradishar and Dr. Hope S. Rugo reflect on some familiar questions at the conclusion of the San Antonio Breast Cancer Symposium: Should young, high-risk women receive ovarian suppression? What is the optimal duration for trastuzumab therapy? What about extended aromatase inhibitor therapy? But new questions were considered as well, based on results presented at the 40th annual symposium.

Will combining a checkpoint inhibitor with trastuzumab help overcome trastuzumab resistance?

Are CDK 4/6 inhibitors here to stay?

Does acupuncture relieve joint pain in women on adjuvant aromatase inhibitor treatment?

The potential approval of a few novel agents in 2018 – an antibody-drug conjugate and a new PARP inhibitor – were also discussed in the video roundtable.

Dr. William A. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago. He had no disclosures to report. Dr. Hope S. Rugo is professor of medicine at the University of California, San Francisco. She disclosed that she receives research funding (institutional) from Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, and Merck.

SAN ANTONIO – Treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6) appears to have the same efficacy in older breast cancer patients, as compared to younger ones, according to new findings presented at the San Antonio Breast Cancer Symposium.

Women aged 65 years and older with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer who received CDK4/6 inhibitors achieved a rate of progression-free survival (PFS) similar to that which has been reported in younger patients. Importantly, combining a CDK4/6 inhibitor with endocrine therapy led to superior PFS as compared to endocrine therapy alone.

However, older patients appeared to be less tolerant of associated adverse events and were more likely to discontinue treatment for that reason.

“Older patients with breast cancer benefit from treatment with CDK4/6 inhibitors ... for HR-positive, HER2-negative, metastatic breast cancer,” said the study’s lead author, Harpreet Singh, MD, scientific liaison for the FDA’s Cancer in Older Adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, at the Food and Drug Administration.

“The severity of adverse events and rates of dose modifications and interruptions were higher in those 65 years of age and older and those 70 years and older,” Dr. Singh said. “Rates of selected adverse events were similar across pooled trials.”

Breast cancer is a disease of aging, and 72,000 breast cancers occur annually in women aged 70 years or older, she explained. “Most cancers in older women are lower risk tumors and most older patients will die of other causes, but approximately 40% of breast cancer related deaths are in women over the age of 70.

“But the accrual of older individuals in trials has been a persistent challenge,” said Dr. Singh. “Older patients traditionally have been underrepresented in oncology clinical trials, so pooling outcomes of older patients across clinical trials in the same drug class allows us to gain insight into how these patients may benefit.”

In the current study, which was an FDA-conducted review of FDA registration trials over a 10 year period, the authors found that fewer than 60% of new cases of breast cancer are diagnosed in women under the age of 65 years.

“But these women make up about 80% of the clinical trial populations even though they are only 57% of cases,” said Dr. Singh.

Only 17% of clinical trial populations comprised individuals aged 65-74 years – even though patients aged 75 years and older make up about 20% of new cases, they comprise only 4% of the clinical trial population.

The FDA has issued several guidances that encourage investigators to enroll older women into trials but does not require them to. Only 22% of patients over 70 received adjuvant or neoadjuvant therapy compared to close to 50% of younger patients, and as a result, very little is known about the safety and efficacy of these agents in older adults.

To assess the efficacy and safety of CDK4/6 inhibitors in an older population, Dr. Singh and her colleagues pooled and analyzed data from prospective, randomized, controlled trials that evaluated three different CDK4/6 inhibitors in combination with an aromatase inhibitor, as the first-line treatment for postmenopausal patients with HR-positive metastatic breast cancer. The cohort included 1,334 patients, (intention-to-treat population, 1,992), of whom 42% were aged 65 years or older, and 24% were 70 years or older.

The primary endpoint was PFS in patients aged 70 years and older, and in control groups.

For patients 70 years or older who received a CDK4/6 inhibitor in combination with an aromatase inhibitor, the estimated PFS was not reached (25.1 months, not reached), versus 16.8 months (13.7, 21.9) for those who received an aromatase inhibitor only.

For patients younger than 70 years of age, PFS also was superior among those who received a CDK4/6 inhibitor, compared with treatment with an aromatase inhibitor alone: 23.75(21.9, 25.4) months versus an estimated 13.8 months (12.9, 14.7).

There were no treatment differences across age subgroups and similar results with alternate age cut-offs (greater than 65 years, greater than 75 years, etc.).

When looking at safety, the authors found that older patients were more likely to stop treatment because of adverse events. Among those 70 years and older, 20% discontinued treatment as compared with 17% of those 65 years or older, and 8% of those under the age of 65 years. Virtually all patients in the three age groups experienced grade 1-2 events (younger than 65, 98%; greater than or equal to 65 years, 98%; greater than or equal to 70 years, 99%), and the majority experienced grade 3-4 events (76%, 83%, 85%, respectively), with the rate higher in the older age groups. More than three quarters of all patients experienced neutropenia (76%, 77%, 80%), and two-thirds or higher grade 3-4 neutropenia (65%, 69%, 72%). Adverse events leading to dose interruption and/or reduction were also higher in the older age groups (66%, 75%, 77%).

“But there are many signs of progress,” said Dr. Singh, referring to efforts in enrolling more older breast cancer patients in clinical trials. “There are ongoing efforts to modernize eligibility criteria which will include greater inclusion of older adults, and specifically, taking a rational approach to organ dysfunction and prior malignancies.”

The increased use of patient-reported outcomes will provide further information on the tolerability of therapy. “Also the acquisition of real-world data from more diverse oncology practices will help inform data on efficacy and safety of novel therapies in older adults,” concluded Dr. Singh.

SOURCE: Singh et al., SABCS 2017 Abstract GS5-06.

SAN ANTONIO – Treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6) appears to have the same efficacy in older breast cancer patients, as compared to younger ones, according to new findings presented at the San Antonio Breast Cancer Symposium.

Women aged 65 years and older with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer who received CDK4/6 inhibitors achieved a rate of progression-free survival (PFS) similar to that which has been reported in younger patients. Importantly, combining a CDK4/6 inhibitor with endocrine therapy led to superior PFS as compared to endocrine therapy alone.

However, older patients appeared to be less tolerant of associated adverse events and were more likely to discontinue treatment for that reason.

“Older patients with breast cancer benefit from treatment with CDK4/6 inhibitors ... for HR-positive, HER2-negative, metastatic breast cancer,” said the study’s lead author, Harpreet Singh, MD, scientific liaison for the FDA’s Cancer in Older Adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, at the Food and Drug Administration.

“The severity of adverse events and rates of dose modifications and interruptions were higher in those 65 years of age and older and those 70 years and older,” Dr. Singh said. “Rates of selected adverse events were similar across pooled trials.”

Breast cancer is a disease of aging, and 72,000 breast cancers occur annually in women aged 70 years or older, she explained. “Most cancers in older women are lower risk tumors and most older patients will die of other causes, but approximately 40% of breast cancer related deaths are in women over the age of 70.

“But the accrual of older individuals in trials has been a persistent challenge,” said Dr. Singh. “Older patients traditionally have been underrepresented in oncology clinical trials, so pooling outcomes of older patients across clinical trials in the same drug class allows us to gain insight into how these patients may benefit.”

In the current study, which was an FDA-conducted review of FDA registration trials over a 10 year period, the authors found that fewer than 60% of new cases of breast cancer are diagnosed in women under the age of 65 years.

“But these women make up about 80% of the clinical trial populations even though they are only 57% of cases,” said Dr. Singh.

Only 17% of clinical trial populations comprised individuals aged 65-74 years – even though patients aged 75 years and older make up about 20% of new cases, they comprise only 4% of the clinical trial population.

The FDA has issued several guidances that encourage investigators to enroll older women into trials but does not require them to. Only 22% of patients over 70 received adjuvant or neoadjuvant therapy compared to close to 50% of younger patients, and as a result, very little is known about the safety and efficacy of these agents in older adults.

To assess the efficacy and safety of CDK4/6 inhibitors in an older population, Dr. Singh and her colleagues pooled and analyzed data from prospective, randomized, controlled trials that evaluated three different CDK4/6 inhibitors in combination with an aromatase inhibitor, as the first-line treatment for postmenopausal patients with HR-positive metastatic breast cancer. The cohort included 1,334 patients, (intention-to-treat population, 1,992), of whom 42% were aged 65 years or older, and 24% were 70 years or older.

The primary endpoint was PFS in patients aged 70 years and older, and in control groups.

For patients 70 years or older who received a CDK4/6 inhibitor in combination with an aromatase inhibitor, the estimated PFS was not reached (25.1 months, not reached), versus 16.8 months (13.7, 21.9) for those who received an aromatase inhibitor only.

For patients younger than 70 years of age, PFS also was superior among those who received a CDK4/6 inhibitor, compared with treatment with an aromatase inhibitor alone: 23.75(21.9, 25.4) months versus an estimated 13.8 months (12.9, 14.7).

There were no treatment differences across age subgroups and similar results with alternate age cut-offs (greater than 65 years, greater than 75 years, etc.).

When looking at safety, the authors found that older patients were more likely to stop treatment because of adverse events. Among those 70 years and older, 20% discontinued treatment as compared with 17% of those 65 years or older, and 8% of those under the age of 65 years. Virtually all patients in the three age groups experienced grade 1-2 events (younger than 65, 98%; greater than or equal to 65 years, 98%; greater than or equal to 70 years, 99%), and the majority experienced grade 3-4 events (76%, 83%, 85%, respectively), with the rate higher in the older age groups. More than three quarters of all patients experienced neutropenia (76%, 77%, 80%), and two-thirds or higher grade 3-4 neutropenia (65%, 69%, 72%). Adverse events leading to dose interruption and/or reduction were also higher in the older age groups (66%, 75%, 77%).

“But there are many signs of progress,” said Dr. Singh, referring to efforts in enrolling more older breast cancer patients in clinical trials. “There are ongoing efforts to modernize eligibility criteria which will include greater inclusion of older adults, and specifically, taking a rational approach to organ dysfunction and prior malignancies.”

The increased use of patient-reported outcomes will provide further information on the tolerability of therapy. “Also the acquisition of real-world data from more diverse oncology practices will help inform data on efficacy and safety of novel therapies in older adults,” concluded Dr. Singh.

SOURCE: Singh et al., SABCS 2017 Abstract GS5-06.

SAN ANTONIO – Treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6) appears to have the same efficacy in older breast cancer patients, as compared to younger ones, according to new findings presented at the San Antonio Breast Cancer Symposium.

Women aged 65 years and older with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer who received CDK4/6 inhibitors achieved a rate of progression-free survival (PFS) similar to that which has been reported in younger patients. Importantly, combining a CDK4/6 inhibitor with endocrine therapy led to superior PFS as compared to endocrine therapy alone.

However, older patients appeared to be less tolerant of associated adverse events and were more likely to discontinue treatment for that reason.

“Older patients with breast cancer benefit from treatment with CDK4/6 inhibitors ... for HR-positive, HER2-negative, metastatic breast cancer,” said the study’s lead author, Harpreet Singh, MD, scientific liaison for the FDA’s Cancer in Older Adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, at the Food and Drug Administration.

“The severity of adverse events and rates of dose modifications and interruptions were higher in those 65 years of age and older and those 70 years and older,” Dr. Singh said. “Rates of selected adverse events were similar across pooled trials.”

Breast cancer is a disease of aging, and 72,000 breast cancers occur annually in women aged 70 years or older, she explained. “Most cancers in older women are lower risk tumors and most older patients will die of other causes, but approximately 40% of breast cancer related deaths are in women over the age of 70.

“But the accrual of older individuals in trials has been a persistent challenge,” said Dr. Singh. “Older patients traditionally have been underrepresented in oncology clinical trials, so pooling outcomes of older patients across clinical trials in the same drug class allows us to gain insight into how these patients may benefit.”

In the current study, which was an FDA-conducted review of FDA registration trials over a 10 year period, the authors found that fewer than 60% of new cases of breast cancer are diagnosed in women under the age of 65 years.

“But these women make up about 80% of the clinical trial populations even though they are only 57% of cases,” said Dr. Singh.

Only 17% of clinical trial populations comprised individuals aged 65-74 years – even though patients aged 75 years and older make up about 20% of new cases, they comprise only 4% of the clinical trial population.

The FDA has issued several guidances that encourage investigators to enroll older women into trials but does not require them to. Only 22% of patients over 70 received adjuvant or neoadjuvant therapy compared to close to 50% of younger patients, and as a result, very little is known about the safety and efficacy of these agents in older adults.

To assess the efficacy and safety of CDK4/6 inhibitors in an older population, Dr. Singh and her colleagues pooled and analyzed data from prospective, randomized, controlled trials that evaluated three different CDK4/6 inhibitors in combination with an aromatase inhibitor, as the first-line treatment for postmenopausal patients with HR-positive metastatic breast cancer. The cohort included 1,334 patients, (intention-to-treat population, 1,992), of whom 42% were aged 65 years or older, and 24% were 70 years or older.

The primary endpoint was PFS in patients aged 70 years and older, and in control groups.

For patients 70 years or older who received a CDK4/6 inhibitor in combination with an aromatase inhibitor, the estimated PFS was not reached (25.1 months, not reached), versus 16.8 months (13.7, 21.9) for those who received an aromatase inhibitor only.

For patients younger than 70 years of age, PFS also was superior among those who received a CDK4/6 inhibitor, compared with treatment with an aromatase inhibitor alone: 23.75(21.9, 25.4) months versus an estimated 13.8 months (12.9, 14.7).

There were no treatment differences across age subgroups and similar results with alternate age cut-offs (greater than 65 years, greater than 75 years, etc.).

When looking at safety, the authors found that older patients were more likely to stop treatment because of adverse events. Among those 70 years and older, 20% discontinued treatment as compared with 17% of those 65 years or older, and 8% of those under the age of 65 years. Virtually all patients in the three age groups experienced grade 1-2 events (younger than 65, 98%; greater than or equal to 65 years, 98%; greater than or equal to 70 years, 99%), and the majority experienced grade 3-4 events (76%, 83%, 85%, respectively), with the rate higher in the older age groups. More than three quarters of all patients experienced neutropenia (76%, 77%, 80%), and two-thirds or higher grade 3-4 neutropenia (65%, 69%, 72%). Adverse events leading to dose interruption and/or reduction were also higher in the older age groups (66%, 75%, 77%).

“But there are many signs of progress,” said Dr. Singh, referring to efforts in enrolling more older breast cancer patients in clinical trials. “There are ongoing efforts to modernize eligibility criteria which will include greater inclusion of older adults, and specifically, taking a rational approach to organ dysfunction and prior malignancies.”

The increased use of patient-reported outcomes will provide further information on the tolerability of therapy. “Also the acquisition of real-world data from more diverse oncology practices will help inform data on efficacy and safety of novel therapies in older adults,” concluded Dr. Singh.

SOURCE: Singh et al., SABCS 2017 Abstract GS5-06.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.

Susan London/Frontline Medical News

Predicting benefit

The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.

Study details

In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.

“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.

Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.

Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.

Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.

The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.

Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).

“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.

Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).

TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”

Improving efficacy

Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.

“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”

Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.

“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”

Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.

SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.

Susan London/Frontline Medical News

Predicting benefit

The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.

Study details

In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.

“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.

Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.

Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.

Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.

The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.

Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).

“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.

Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).

TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”

Improving efficacy

Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.

“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”

Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.

“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”

Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.

SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.

SAN ANTONIO – The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1), a trial reported at the San Antonio Breast Cancer Symposium suggests. But presence of immune cells in the tumor is a major additional determinant of benefit.

Susan London/Frontline Medical News

Predicting benefit

The trial is noteworthy for its efforts to identify the subset of patients most likely to benefit from immune checkpoint inhibition, according to press briefing moderator Virginia Kaklamani, MD, a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center, San Antonio, and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center.

Study details

In the PANACEA trial (additionally known as IBCSG 45-13 and BIG 4-13), the most common adverse event of any grade and type with the pembrolizumab-trastuzumab combination was fatigue, seen in 21% of patients, Dr. Loi reported. For immune-related adverse events specifically, 19.0% of patients experienced an event, 10.3% experienced an event of grade 3 or worse, and 6.9% stopped treatment because of these events.

“These frequencies are consistent with what has been reported in other solid tumor types with pembrolizumab,” she commented. There were no cardiac events reported.

Efficacy analyses were restricted largely to the PD-L1–positive cohort, given the lack of any response in the negative cohort.

Median duration of response in the positive cohort was 3.5 months, and median duration of disease control was 11.1 months. Five patients (10.8%) remain on treatment with no progression; three of them have completed 2 years of pembrolizumab.

Median progression-free and overall survival were 2.7 and 16.1 months, respectively; corresponding 12-month rates were 13% and 65%. “There is a tantalizing suggestion of a tail on the curve. ... Obviously, this requires further follow-up, and the numbers are small,” Dr. Loi commented.

The median baseline stromal TIL level in metastatic lesions was just 1%. “This is 20 times less than what we observe in primary HER2-positive breast cancers,” she pointed out.

Compared with the PD-L1–negative cohort, the PD-L1–positive cohort had higher TIL levels. Additionally, within that latter cohort, TIL level was higher among patients achieving response versus not (P = .006) and patients achieving disease control versus not (P = .0006).

“We then went on to try to identify a TIL cutoff that could enrich the population for responders. This has been done in other solid tumor types,” Dr. Loi explained.

Analyses in the PD-L1-positive cohort showed that TIL levels down to 5% predicted benefit. The 41% of patients having 5% or more TILs were dramatically more likely to have a response (39% vs. 5%) and disease control (47% vs. 5%).

TIL levels varied widely according to site of the metastasis, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

“At this stage, we are not sure which is the chicken and the egg: Patients could have disease in their lung and their lymph nodes because their immune system is better controlling their disease,” Dr. Loi commented. “How we treat these patients is still an open question. In patients with liver metastases, perhaps we need to be more aggressive with the primary or tumor-control anti-HER2 therapy.”

Improving efficacy

Going forward, one strategy for improving pembrolizumab efficacy in this patient population might be priming the immune response, according to Dr. Loi.

“In HER2 disease, it’s very clear that oncogenic signaling is the driver, so targeting HER2 potently also will help relieve tumor-mediated immune suppression,” she elaborated. “In this particular context, targeting HER2 well is the key. Whether you need the addition of a little bit of chemo or some radiation, all this needs to be studied.”

Another strategy for improving pembrolizumab efficacy might be moving the drug to earlier disease settings, Dr. Loi proposed.

“By the time you get to advanced stage and have had multiple treatments, you actually have low levels of T-cell infiltration in your metastatic lesion, for whatever reasons – tumor burden, immunosuppression, multiple lines of treatment. That all reduces your chance of responding to pembrolizumab, for example, as monotherapy,” she elaborated. “We don’t know yet if chemotherapy in addition to pembrolizumab could change that tumor microenvironment. But still, I think the earlier in lines you go, the more chance you are going to have of preexisting effective antitumor immunity that can be reactivated with the addition of pembrolizumab.”

Dr. Loi disclosed that her institution receives research funding from Novartis, Pfizer, Merck, Genentech/Roche, and Puma. Merck provided study drug and support for PANACEA.

SOURCE: Loi S et al. SABCS 2017 Abstract GS2-06.