Molecular subtype profiling of invasive breast cancers weakly positive for estrogen receptor

Abstract

The estrogen receptor (ER) is a key predictive biomarker in the treatment of breast cancer. There is uncertainty regarding the use of hormonal therapy in the setting of weakly positive ER by immunohistochemistry (IHC). We report intrinsic subtype classification on a cohort of ER weakly positive early-stage breast cancers. Consecutive cases of breast cancer treated by primary surgical resection were retrospectively identified from 4 centers that engage in routine external proficiency testing for breast biomarkers. ER-negative (Allred 0 and 2) and ER weakly positive (Allred 3-5) cases were included. Gene expression profiling was performed using qRT-PCR. Intrinsic subtype prediction was made based upon the PAM50 gene expression signature. 148 cases were included in the series: 60 cases originally diagnosed as ER weakly positive and 88 ER negative. Of the cases originally assessed as ER weakly positive, only 6 (10 %) were confirmed to be of luminal subtype by gene expression profiling; the remaining 90 % of cases were classified as basal-like or HER2-enriched subtypes. This was not significantly different than the fraction of luminal cases identified in the IHC ER-negative cohort (5 (5 %) luminal, 83(95 %) non-luminal). Recurrence-free, and overall, survival rates were similar in both groups (p = 0.4 and 0.5, respectively) despite adjuvant hormonal therapy prescribed in the majority (59 %) of weakly positive ER cases. Weak ER expression by IHC is a poor correlate of luminal subtype in invasive breast cancer. In the setting of highly sensitive and robust IHC methodology, cutoffs for ER status determination and subsequent systemic therapy should be revisited.

Basal biomarkers nestin and INPP4b identify intrinsic subtypes accurately in breast cancers that are weakly positive for oestrogen receptor

“…We based our current study on our previously published data in which we classified the intrinsic subtypes by PAM50 assay ( n = 55), with the addition of three new cases to this cohort. Applying the PAM50 assay showed that among the 58 weakly positive ER cases, 28 (48%) were assigned as basal‐like, 21 (36%) were classified as HER2‐enriched and only nine (16%) were classified as luminal subtype.…”

“…Weakly positive ER cases have also been reported by our group and others to be more clinically akin to ER‐negative than to ER strongly positive breast cancers, casting doubt on the current recommendations for diagnosis and treatment of this subgroup as a luminal subtype based on IHC assessment alone . Furthermore, the clinically problematic setting of weak ER positivity raises important questions about the benefit of hormonal therapies, with a missed opportunity to initiate more effective adjuvant treatments as chemotherapy …”

“…The current study utilized three TMAs. The first TMA was selected from a previous study that included 153 cases from 2010 to 2013, among which 62 cases were ER weakly positive (Allred 3–5) and 91 were ER‐negative (Allred 0, 2) by clinical IHC diagnostic testing . The additional two TMAs each consisted of 20 triple‐negative and 20 non‐triple‐negative cases that were identified in the period 2008–11 as part of an IHC quality control programme.…”

“…Oestrogen receptor staining reports the subtype as luminal when 1% or more of the breast tumour cells express ER by IHC. However, it has been shown that the IHC luminal subtype does not correspond entirely to the intrinsic luminal subtype as assigned by gene‐expression profile . Recent data published by our group and others have shown that nearly half of cases that are ER weakly positive (defined as 1–10% of nuclei expressing ER, and thus assigned as luminal by IHC) are classified as basal‐like when using gene‐expression profiling assay as a reference standard …”

Outcome for triple negative breast cancer in a retrospective cohort with an emphasis on response to platinum-based neoadjuvant therapy

“…In our institution, these are treated as ER negative disease, although some receive adjuvant endocrine therapy. Whether including these patients could skew our results is a legitimate question; however, molecular subtype analysis suggests that the majority of these cancers have the same profiles and clinical outcome as ER negative disease [72, 73]. …”