FROM THE ASCO BREAST CANCER SYMPOSIUM 2015

SAN FRANCISCO – Using multiplatform profiling, potentially targetable biomarker aberrations were identified in a large sample of tumors taken from older breast cancer patients, reported researchers at the 2015 Breast Cancer Symposium.

In this cross sectional study, 1,189 tumors were collected from breast cancer patients between the ages of 70-97 years, and the samples were assayed for potential targetable biomarkers, and then the findings were compared with samples obtained from younger patients.

“Most of the differences we found were in triple negative patients, and they are related to PIK3CA mutations,” said study author Dr. Paula Pohlmann, from the Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington.

“Also, I am very puzzled that the BRCA1 mutations were not found in older triple negative patients, as compared with the younger patients,” she noted. “Even taking into account the limitations of the study, it was still interesting.”

ERBB2 mutations were identified in non-amplifed breast cancers and less frequently in amplified ones. “And another interesting point was that both PD-1 and PD-L1 positivity by immunohistochemistry were found in all groups, and not only triple negative,” said Dr. Pohlmann. “The checkpoints are similar for both older and younger populations.”

Dr. Pohlmann explained that while she expected to see the PD-1 and PD-L1 positivity, it is worth mentioning since all the treatments focusing on PD-1 and PD-L1 in breast cancer are with triple negative disease. “But we found this expression in Her2 positive and hormone receptor positive disease.”

However, she emphasized that this doesn’t mean that they are necessarily a target. “If they will respond to that therapy, we don’t know, that’s a different story, but the markers are there,” Dr. Pohlmann said.

In this study a total of 1,189 tumors were collected from breast cancer patients (male= 21/female = 1,168) who were aged 70 years and older. The tumors were analyzed (breast biopsy n = 512; metastatic site n = 677), and of 1,088 tumors with available immunohistochemistry (IHC) of ER, PR and IHC and/or in situ hybridization (ISH) of HER2, 613 (56%) were HR+/HER2-, 72 (7%) were HR+/HER2+, 346 (32%) were triple negative, and 57 (5%) were HR-/HER2+.

Overall, 39 of 47 genes that were sequenced carried mutations with frequencies ranging from 0.2% to 37%. The highest mutation rates were seen in PIK3CA (37%), TP53 (37%), BRCA2 (12%), PTEN (5.8%), AKT1 (4.2%), cMET (3.9%), ERBB2 (3.5%), BRCA1 (3.3%), and ATM (3.2%).

Among 13 patients with ERBB2 mutation, 3 had it amplified. PD-L1 expression on tumor cells was detected in 13% of tumors and PD-1 expression on tumor-infiltrating lymphocytes was seen in 46%, but the triple negative subtype had the highest expression: 20% and 60%, respectively.

The researchers also noted that TOPO1, TLE3, AR, TOP2A, and SPARC were overexpressed in 61%, 58%, 55%, 51%, and 37% of tumors, respectively. These observations suggest that there is potential sensitivity to irinotecan, taxanes, anthracyclines, and nab-paclitaxel.

In addition, TS, RRM1, and ERCC1 were under-expressed in 69%, 69%, and 53% of tumors, respectively, which suggests that there may be potential sensitivity to fluoropyrimidines, gemcitabine, and platinums

“This study provides key elements for the design of clinical trials focusing on geriatric patient population, particularly in the subgroup of triple negative breast cancer,” said Dr. Pohlmann. “In addition, ERBB2 abnormalities in older patients may also warrant further investigation.”

Dr. Charles E. Geyer, Jr., of Virginia Commonwealth University Massey Cancer Center, Richmond, in his discussion of the paper, pointed out that while there were some differences in the groups, it wasn’t clear that they are clinically significant differences. “The most interesting were PD-1 and PD-L1, which were in higher numbers than are being reported.”

But the data from this study suggest that focus needs to be on inclusion of geriatric patients in targeted therapy trials, he said.

He also noted that in general, patients frequently have some unrealistic expectations when it comes to genetic testing. “The advocacy often gets a little ahead of the science,” Dr. Geyer said.

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