Biomarkers and personalisation

Given the heterogeneity of breast cancer, personalisation of treatment is critical. Biomarkers can play an essential role in determining patient prognosis as well as aiding treatment decisions and assessing potential treatment response.

Recent guidelines from the European Group on Tumour Markers offer a series of recommendations around the use of biomarkers in breast cancer (Duffy et al., 2017).

Oestrogen receptor (ER) and progesterone receptor (PR) measurement

Treatment selection

The main application of HR measurement is to identify patients with invasive breast cancer who are likely to benefit from endocrine therapy. As such, they are used in the neoadjuvant, adjuvant and advanced disease setting.


Patients with HR+ tumours tend to have better outcomes than those with HR- tumours. However, for HR+ tumours, the favourable prognosis occurs largely during the first 5–7 years after diagnosis. Thereafter, the risk of recurrence seems to be greater in patients with HR+ tumours than those with HR- tumours. However, the effect of treatment on these prognostic outcomes cannot be excluded with some studies showing that the improved outcomes in HR+ patients was only seen in patients who received endocrine therapy.


  1. ER and PR should be measured in all newly diagnosed primary invasive breast cancers
  2. The European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) Consensus Conference for Advanced Breast Cancer (ABC) group and the National Comprehensive Cancer Network (NCCN) guidelines state that in mBC, endocrine therapy is recommended if any biopsy is receptor positive. However, the American Society of Clinical Oncology (ASCO) guidelines recommend using the metastatic biopsy status if discordance is seen between the primary and metastatic site
  3. ER and PR should be measured by IHC using an analytically and clinically validated assay

Human epithelial growth factor receptor 2 (HER2) measurement

Treatment selection

Once considered an indicator for poor prognosis, the development of multiple anti-HER2 therapies has greatly improved outcomes (Global Status of Advanced/Metastatic Breast Cancer 2005–2015 Decade Report, 2016). Measurement of HER2 should be principally used to predict response to anti-HER2 therapy in the neoadjuvant, adjuvant and advanced disease setting. However, HER2 gene amplification/overexpression appears to be necessary but not sufficient for response to available anti-HER2 treatments.


  1. HER2 gene amplification or overexpression should be determined for all patients with primary invasive breast cancer and, where feasible, any metastatic lesion
  2. As for the ER/PR status, the ESO-ESMO ABC group and NCCN both recommend that patients with any biopsy that is HER2+ should receive anti-HER2 therapy. However, ASCO again recommend that should there be discordance between the primary tumour site and metastatic lesions, the HER2 status of the metastatic site should be used to guide treatment
  3. HER2 positivity should be measured and defined according to the ASCO/College of American Pathologists (CAP) guidelines (Wolff et al., 2013) and should be performed using an approved IHC, brightfield in situ hybridisation (ISH) or a fluorescent ISH (FISH) assay

Ki67 measurement

Ki67 is a nuclear antigen that is expressed in proliferating cells and elevated levels have been shown to be independently associated with adverse outcomes in patients with breast cancer. Despite intra-tumour heterogeneity in staining and inter- and intra-observer variability in scoring, Ki67 has been shown to be a prognostic and predictive marker in breast cancer (Duffy et al., 2017; Koopman et al., 2018).

While high Ki67 levels have been consistently shown to be associated with poor patient outcomes, high Ki67 levels in the neoadjuvant setting have been frequently, although not always, linked to chemotherapy response. With endocrine therapy, treatment-induced reductions in Ki67 levels have been shown to be predictive of patient response and outcome. However, little data is available in the metastatic setting (Duffy et al., 2017).


  1. Ki67 may be used in combination with established prognostic factors for determining patient prognosis. Poor precision exists at intermediate levels, but low levels (<10% cell staining) and high levels (>25% cell staining) are of use. Indeed, the high levels threshold (>25% cell staining) has been associated with a greater risk of death compared with lower levels.
  2. Until a standardised Ki67 assay becomes available, measurement of Ki67 should follow the International Ki67 in Breast Cancer Working Group recommendations (Dowsett et al., 2011).

Multigene signature measurements

In recent years, several commercially available multianalyte tests have been developed to predict outcomes in patients with newly diagnosed invasive breast cancer. The majority have been validated in ER+, HER2-, lymph node-negative patients between 40 and 65 years of age. However, some (Oncotype DX, MammaPrint, Endo-Predict and Prosigna) have been found to be prognostic in lymph node-positive patients as well.

Current recommendations for the use of multianalyte tests include:

Table 3: Recommendations for the use of multianalyte tests in ER+, HER2- breast cancer patients by different expert groups. (Adapted from Duffy et al., 2017).

Recommendations for the use of multianalyte tests in ER+, HER2- breast cancer patients by different expert groups. (Adapted from Duffy et al., 2017).