A Majority of Low (1-10%) ER Positive Breast Cancers Behave Like Hormone Receptor Negative Tumors

Abstract

Background: The 2010 guidelines by ASCO-CAP have mandated that breast cancer specimens with ≥1% positively staining cells by immunohistochemistry should be considered Estrogen Receptor (ER) positive. This has led to a subclass of low-ER positive (1-10%) breast cancers. We have examined the biology and clinical behavior of these low ER staining tumors.Methods: We have developed a probabilistic score of the “ER-positivity” by quantitative estimation of ER related gene transcripts from FFPE specimens. Immunohistochemistry for ER was done on 240 surgically excised tumors of primary breast cancer. Relative transcript abundance of 3 house-keeping genes and 6 ER related genes were determined by q-RT PCR. A logistic regression model using 3 ER associated genes provided the best probability function, and a cut-off value was derived by ROC analysis. 144 high ER (>10%), 75 ER negative and 21 low-ER (1-10%) tumors were evaluated using the probability score and the disease specific survival was compared.Results: Half of the low-ER positive tumors were assigned to the ER negative group based on the probability score; in contrast 95% of ER negative and 92% of the high ER positive tumors were assigned to the appropriate ER group (p<0.0001). The survival of the low-ER group was intermediate between that of the high ER positive and ER negative groups (p<0.05).Conclusion: Our results suggest that the newly lowered ASCO-CAP criteria for ER positivity, leads to the false categorization of biologically ER negative tumors as ER positive ones. This may have particular relevance to India, where we have a much higher proportion of ER negative tumors in general.

ER, PR and HER2 testing in breast cancer

“…7 Clinically the majority of these tumours were also found to behave more like ER negative tumours. 8 While the binary scoring system may be adequate, the percentage score may provide additional information in treatment decision making, as ER and/or PR levels have been demonstrated to be associated with patient outcome. Staining of >50% of tumour cells was viewed as indicating highly endocrine-responsive tumours.…”

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

“…For example, in ER+ tumors, not all cells express the receptor. Clinically, ER+ breast cancers can be qualified as such even if only 1% of cells express detectable levels of ER protein, though some low-expressing tumors may behave as ER-negative tumors in response to targeted therapies [29,30]. Similarly, HER2+ tumors can show regional variation in expression by immunohistochemistry and copy number per cell by fluorescence in situ hybridization, with positivity clinically defined as 10% of cells positive (CAP Guidelines) [31,32,12].…”

Prediction of Response to Aromatase Inhibitors in Breast Cancer

“…While the low cut-off setting is clinically justifiable to administer non-toxic treatment for a life-threatening disease, it also disposes for overtreatment. Indeed, the biology of tumours with low ER expression often resembles ER-negative tumours [68,69] and numerous studies have confirmed that level of tumour ER expression is associated with the likelihood of endocrine responsiveness. In context of response to AIs, this was most clearly shown in the P024 trial which compared neo-adjuvant Letrozole and Tamoxifen [61].…”

“…On one side, there is a relatively small group (up to ~20 %) of low risk patients with excellent prognosis, usually ER-rich, which do not need addition of cytotoxic therapy to adjuvant treatment [109,125,126,132]. On the other side of the range, tests may identify a group of ER+ve tumours with low expression of ER (up to ~10 % of ER+ve tumours) [68,69] and/or inconsistent with luminal phenotype [122]. Albeit these high-risk tumours are associated with poor response rates, some of these ER+ve tumours still may respond to AI treatment.…”

“…This suggests that the high proportion of nonluminal intrinsic subtypes observed by Dunbier et al [122,123] might be explained by the well-known differences between tumours with low-and high-expression of ER (as discussed in more details earlier in the oestrogen receptor section). If this is the case, then intrinsic sub-types testing may complement the binary ER assessment, especially when low threshold is set for ER-positivity [67,68].…”