Could proteins in a breast tumor help identify who is more likely to relapse despite tamoxifen treatment?

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Shc adapter proteins are secondary messenger proteins involved in several cellular pathways, including receptor tyrosine kinase signaling and apoptosis in response to stress.

The researchers had previously reported that high levels of tyrosine-phosphorylated Shc (PY-Shc), together with low levels of its inhibitory p66 Shc isoform, were strongly prognostic for a high risk of recurrence in both early, node-negative primary breast cancers and more advanced, node-positive primary breast cancers.

Abnormal activation of tyrosine kinases upstream of Shc signaling proteins has been implicated in resistance to tamoxifen, described in the abstract as the most widely prescribed drug for estrogen receptor-positive breast cancer. This led the researchers to hypothesize that Shc isoforms could identify patients at increased risk of relapse despite tamoxifen treatment.

In this observational cohort study, the researchers used immunohistochemical analyses to measure PY-Shc and p66 Shc in archived primary breast tumor samples. They studied a population-based cohort of 60 patients with 9 relapses and, for validation, an independent external cohort of 31 patients with 13 relapses. In both cohorts, all patients received tamoxifen as their sole systemic adjuvant treatment before relapse.

In univariate and multivariate analyses, the Shc proteins were very strong, independent predictors of treatment failure in both cohorts. In the population-based cohort, the interquartile hazard ratio was 8.3 (95% confidence interval [CI] 1.8 to 38; P = 0.007). In the validation cohort, the interquartile relative risk was 12.1 (95% CI 1.7 to 86; P = 0.013).

The findings suggest that PY-Shc and p66 Shc levels in primary tumors can identify patients at high risk of relapse despite tamoxifen treatment. With further validation, these measurements may help clinicians select alternative adjuvant treatment strategies.