IntroductionWhen breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor (receptor conversion), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections.MethodsA total of 233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ERα, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result.ResultsUsing a 10% threshold, receptor conversion by IHC for ERα, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from ER+ or PR+ to ER-/PR- and in 3.4% from ER-/PR- to ER+ or PR+ was found. Using a 1% threshold, ERα and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from ER+ or PR+ to ER-/PR-, and 8.2% from ER-/PR- to ER+ or PR+ occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ERα and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases.ConclusionsReceptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ERα and HER2, and is more frequent for PR, especially in brain, liver and gastro-intestinal metastases.
Summary The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin-embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0-3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5+6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P<0.001) and progesterone receptor positivity (P<0.001) and low tumour grade (P<0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P<0.001) and c-erb-B-2 positivity (P<0.001), high Ki-67 index (P<0.001), mitotic index (P<0.001) and large tumour size (P=0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3-6) had a significantly better disease-free (P=0.004) and overall (P=0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease-free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P=0.07) and negative (HR=0.55, 95% CI 0.27-1.12, P=0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node-negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series.
BACKGROUND: Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor a (ERa) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ERa and PR on survival in a large group of distant non-bone breast cancer metastases. METHODS: Receptor conversion was studied by immunohistochemistry in a group of 233 metastatic breast cancer patients. Kaplan-Meier overall survival curves were plotted, and differences between the curves were analyzed by log-rank analysis. The additional prognostic value of conversion to established prognosticators was studied by Cox regression. RESULTS: Overall survival of patients showing conversion from positive to negative ERa or PR, or from negative to positive ERa or PR, or remaining receptor negative was comparable, and significantly worse than patients remaining receptor positive. ERa or PR receptor conversion from positive in the primary breast tumor to negative in distant metastases has independent negative prognostic value. CONCLUSIONS: ERa or PR receptor conversion from positive in the primary breast cancer to negative in distant metastases has negative prognostic value. Cancer 2012;118:4929-35. V C 2012American Cancer Society.KEYWORDS: receptor conversion, breast cancer, metastases, prognostic value, estrogen receptor a, progesterone receptor. INTRODUCTIONTraditionally, metastatic tumors are rarely biopsied because of limited accessibility or because it is deemed unnecessary for further therapeutic decision making. When breast cancer patients develop distant metastases, the choice of systemic treatment with chemotherapy, hormonal therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, and/ or antiangiogenesis therapy is based on assessment of the primary tumor characteristics by routine histopathology, immunohistochemistry (IHC), and/or molecular analysis. However, we and several previous studies have indicated that distant breast cancer metastases may show receptor conversion from primary tumors to their distant metastases. This indicates that it may be clinically important to biopsy distant metastases to assess hormone receptor and HER2 status whenever possible. Several recent guidelines now include this recommendation, [32][33][34] and distant metastases are now much more often biopsied.Although estrogen receptor a (ERa) and progesterone receptor (PR) expression levels of the primary breast tumors correlate with prognosis in patients, 35,36 little information is yet available on whether survival is influenced by receptor conversion of ERa and PR in breast cancer metastases.Therefore, we evaluated the prognostic value of receptor conversion for ERa and PR in a large group of distant nonbone breast cancer metastases by restaining all primary tumors and metastases with current optimal immunohistochemical methods on full sections.
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