Prescription of endocrine or HER2-targeted therapy for metastatic BC is still mainly determined by the biomarker status of the primary tumor, although previous studies have shown that receptor conversion is a relatively common phenomenon [3, 5–11]. These observations have been, however, considered to originate from technical limitations of the method rather than representing true changes in the tissue phenotype, and mostly disregarded. Still, limited accuracy and reproducibility of receptor assays does not explain cases where receptor expression changes from 0 to 100% and vice-versa. It seems that the whole issue is much more complicated with a possible role of intratumoral heterogeneity [13], receptor conversion is thought to be the a result of clonal selection or selective pressure of therapy [14].
The rate of discrepancy for estrogen receptor reported in the literature is 6–18%, for progesterone receptor it is 25–42%, and 4–17% for HER2 [3, 5–9, 11, 12] – Table 4. However, the studies are heterogeneous, especially with regard to the tissue samples studied and the processing technology used. Somewhat different results may be given by the fact that some authors also included only biopsies in the study, which may not be sufficiently objective.
Table 4
The reported rates for discordance of HR between primary and metastatic breast cancer [3, 5–9, 11, 12].
| | Rate of discrepancy (%) | Rate of discrepancy according to the direction of conversion (%) |
| ER | PR | HER2 | ER (+/-) | ER (-/+) | PR (+/-) | PR (-/+) | HER2 (+/-) | HER2 (-/+) | Total n |
| Nishimura (2011) | 10.3 | 25.8 | 14.4 | 8.2 | 2.1 | 19.6 | 6.2 | 3.1 | 11.3 | 97 |
| Amir (2012) | 16.0 | 40.0 | 10.0 | 11.7 | 4.3 | 36.2 | 4.3 | 2.1 | 6.4 | 94 |
| Ibrahim (2012) | 16.4 | 41.7 | 17.5 | 9.5 | 6.9 | 33.0 | 8.7 | 5.0 | 12.5 | 120 |
| Curtit (2013) | 17.0 | 29.0 | 4.0 | 12.3 | 4.7 | 22.1 | 7.2 | 2.6 | 0.9 | 235 |
| Dieci (2013) | 13.4 | 39.0 | 11.8 | 10.9 | 2.5 | 30.3 | 8.4 | 3.4 | 8.4 | 119 |
| Shin (2016) | 18.1 | 25.0 | 10.3 | 11.1 | 6.9 | 17.4 | 7.6 | 2.8 | 7.5 | 114 |
| Woo (2019) | 6.0 | 40.0 | 12.0 | 5.3 | 24.3 | 5.9 | 0.7 | 2.0 | 2.0 | 152 |
| Chen (2020) | 18.3 | 40.3 | 13.7 | 15.8 | 2.6 | 31.0 | 9.3 | 7.8 | 5.9 | 387 |
| Our study | 26.0 | 52.0 | 2.0 | 22.0 | 4.0 | 30.0 | 22.0 | 0 | 2.0 | 50 |
| ER - estrogen receptor; PR - progesterone receptor; HER2 - human epidermal growth factor receptor 2 |
Most studies agree that the discordance is significantly higher for PR when compared with ER and HER2 and also that the conversions occurred mostly as a switch from positive to negative receptor status when compared with that from negative to [3–9, 12, 15], while most studies consistently show more patients gaining HER2 expression than loosing it among the cases of HER2 expression discordance [3, 5, 6, 9, 10, 8].
Also in our cohort, positivity in the primary lesion and negativity in the recurrence site was a more frequent pattern than the opposite for ER and PR. Although, we observed conversion in HER2 receptor only in one case in our cohort, it was just conversion from negativity to positivity.
In their meta-analysis including 39 studies, Schrijver et al. [16] found that ER discordance was statistically significantly higher in metastases located in the central nervous system and bones compared with liver metastases, and PR discordance was higher in bone and liver metastases compared with CNS metastases. PR conversion from positivity to negativity occurred statistically significantly more often than from negativity to positivity.
Completely different results were reported by Woo et al. [11]. Although they showed, similarly to others, that negative conversion occurred more frequently than positive conversion in hormone receptors, they found no changes in ER, PR, or HER2 status in brain metastases. Also in lung metastases, no changes in ER status were observed. All primary triple-negative breast cancers remained triple-negative in the metastatic lesion in their cohort.
In contrast, Jung et al. [17] described discordances in ER, PR, and HER2 between primary tumor and resected brain metastases in more than 50% of the 37 Korean patients included in their study.
In our study, we observed the majority of conversions in brain metastases, where the transition to triple negativity was also substantially more common. However, we have not shown that the probability of conversion varies according to the location of the metastases.
Our study also confirms that endocrine therapy reduces the positivity of PR and ER receptors in metastatic tissue relatively to their original abundance in the primary lesion. In accordance with Chen et al., who reported a majority of conversions being from a positive to negative status, this may be largely attributed to selective killing of BC cells overexpressing ER or HER2 by endocrine or HER2-targeted therapy.
Hoefnagel et al. [4] hypothesized that their observation of decreased survival in patients converting to negative in their metastases may be because the endocrine treatment of stage IV disease was initiated based on the primary tumor characteristics, while the receptor-negative cells, that were actually constituting the metastases, are known to be fully resistant to endocrine treatment. Therefore, it would be important to know upfront which receptor-positive patients are likely to develop receptor-negative metastases. This would allow, for example, for a supplementation of their adjuvant hormonal therapy (to control their receptor-positive metastatic cells) with adjuvant chemotherapy. In their cohort, OS of patients showing conversion from positive to negative ER or PR, or from negative to positive ER or PR, or remaining receptor-negative was comparable, and significantly worse than that of patients remaining receptor-positive. ER or PR receptor conversion from positive in the primary BC to negative in distant metastases has negative prognostic value [4].
Similarly, the results of a recent study by Chen et al. [8] show that a positive ER status, not considering if in primary or metastatic BC, was associated with a prolonged metastases-free survival when compared with ER-negative primary tumors without conversion. Furthermore, a positive ER status in breast cancer metastatic tissue regardless of the primary tumor was associated with superior OS when compared with an ER-negative tumor without conversion.
Shin et al. [10] reported that patients with concordant ER or PR positivity or discordant ER or PR status had a significantly longer post-recurrence survival than those with respective concordant negativity between the primary lesion and recurrence site.
Also, survival analyses by Woo et al. [11] indicated that a positive-to-negative conversion of ER was an independent poor prognostic factor in patients with primary ER-positive breast cancer. Identically, Dieci et al. [9] reported that patients with ER loss in recurrence had poor OS, whereas those with PR did not.
Bachmann et al. [18] found that PR and HER2 discordance correlated to shortened interval to metastasis. Aurilio et al. [19] reported that the time interval did not statistically significantly affect the discordance rate for ER, PR, or HER2.
According to our results, the higher percentage of hormonal receptors positivity in metastatic tumor correlated with the longer time to progression. However, PFS after mastectomy was shorter in case of HER2 positivity of metastatic tissue, which is confirmed with the results of our previous study [20].
Loss of HR or MIB1 seemed to be associated with a poor prognosis, too [21]. High MIB1 levels in primary lesion are known to be associated with the growth and invasion of BC. The study by Ibrahim et al. [6] showed that patients with MIB1 ≥ 20% had a significantly poorer median PFS than those with MIB1 < 20%. According to our study, the higher the MIB1, the lower the expression of hormone receptors, however we did not observe significant effect of MIB1 on OS.
In summary, hormonal receptor status should always be investigated at the time of diagnosis of metastatic disease before deciding about its treatment. IHC evaluation of metastases for receptor status may change treatment decisions for patients with metastatic breast cancer. In cases of positive-to-negative conversion, hormone therapy should be discontinued to avoid unnecessary side effects of the treatment. While the probability of hormone receptor conversion in distant BC metastases is almost 60%, conversion of HER2 neu should remain stable.
This is the first study comparing receptor profiles between primary BC lesions and its metastases to the brain, lung and liver in Czech population. Moreover, this study includes exclusively tissue samples obtained by mastectomy or partial resection of the breast and samples obtained by metastasectomy. We consider this a big positive as mere biopsy is to be considered not objective due to the well-known heterogeneity of the tumor. Also, presenting a single-institution analysis, we were able to provide more detailed and specific data thanks to strictly uniform processing technique, which is usually not possible with a large pooled literature review.