Breast cancer is one of the leading causes of cancer-related deaths in women, but over the past few decades there has been a sustained decline in mortality rates due to incremental application of increasingly effective adjuvant medical treatments and regular mammography screening programs. Mammography screening has led to detection of early-stage (<2 cm) node-negative breast cancer and has certainly contributed to improved outcomes, but there are still many challenges for clinicians regarding the choice of optimal adjuvant treatment, avoidance of overtreatment in patients who only receive a modest benefit, while suffering from toxic side effects. On the other hand, undertreatment or incorrect treatment also has to be avoided. It is therefore necessary to define specific characteristics, which provide possibilities for individual treatment optimization.
- ESTROGEN RECEPTOR (ER): ER is undoubtedly the most important biomarker in breast cancer, because it provides the index for sensitivity to endocrine treatment. Cancer cells that have estrogen receptors on them receive signals from estrogen to promote their growth such cancers are called estrogen-receptor-positive or ER+. ER is therefore the direct target of endocrine therapies. The Oxford overview confirms that patients with ER-negative disease have no benefit from 5-year adjuvant treatment with tamoxifen, but some benefit may be derived in the uncommon group of ER-negative and progesterone receptor (PgR)-expressing breast tumors. In contrast, such treatment reduces the annual breast cancer death rate by 31% in ER-positive disease.
While the absence or presence of the ER is used to make treatment decisions, their quantitative expression levels can also be used as a predictive indicator. Evidence from the 1970s suggests a direct correlation between ER expression levels and response to endocrine therapy. The Early Breast Cancer Trialists’ Collaborative Group reported that higher levels of ER were associated with a lower risk of recurrence when receiving adjuvant tamoxifen. Similar results were obtained in the NSABP-14 trial using the ligand-binding assay and mRNA expression of ER. More recent analyses from the large prospective adjuvant trials anastrozole, tamoxifen, alone or in combination (ATAC) and BIG 1-98 (letrozole versus tamoxifen) comparing aromatase inhibitors (AIs) with tamoxifen did not find a subgroup of ER-positive patients with different ER expression levels, which derives a greater benefit from AIs versus tamoxifen. The trials revealed, however, that higher ER levels were related to improved outcome of both the endocrine treatments.
ER status also predicts response to chemotherapy in the neoadjuvant setting. Multiple clinical studies have demonstrated that the ER-negative breast cancer patients are more likely to achieve a pathological complete response (pCR) with neoadjuvant chemotherapy than the ER-positive patients, with pCR rates of 7–8 vs 21–33% respectively being reported.
An initial report also indicated that ESR1 gene amplification in breast cancer could be detected in ∼20% of all invasive tumors, and that there was a correlation between the gene amplification and ER expression levels.
- PROGESTERONE RECEPTOR: Tumors expressing PgR but not the ER are uncommon and account to <1% of all breast cancer cases. For this reason, tumors with PgR expression lacking ER expression should undergo a retesting of their ER status to eliminate false ER negativity.In the rare cases of solely PgR-expressing patients, some limited benefit from tamoxifen is described, but endocrine therapy is still widely recommended.
In case of metastatic breast cancer, the response to anti-estrogen treatment is better among patients with tumors expressing both ER and PgR than those who only show ER positivity but lack the PgR expression.
The ATAC trialists published a hypothesis suggesting that patients with PgR-negative breast cancer obtain a substantially greater benefit from anastrozole than from tamoxifen compared with PgR-positive patients. However, this hypothesis was not confirmed in centrally analysed material from 1856 ER- and/or PgR-expressing patient. Moreover, the BIG 1-98 trial reported that the benefit from letrozole over tamoxifen did not vary according to the PgR status. Nevertheless, these adjuvant trials clearly supported the existence of a strong relationship between PgR expression levels and prognosis on endocrine therapy, which may be useful in estimating residual risk.
- HER2: The oncogene HER2 is an important indicator in patient’s prognosis. This gene is overexpressed and amplified in about 20% of breast cancers. When overexpressed, it provides the cell with potent proliferative and antiapoptosis signals resulting in tumor development and progression for this subset of breast cancer.
The monoclonal antibody trastuzumab and target HER2, but this drug benefits only patients with overexpression of this gene and does not benefit patients who don’t have an overexpression of this gene so assessment of this gene is a predictive marker.
HER2 testing approaches include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization.