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Published in final edited form as: Pathology. 2023 Dec 12;56(2):186–191. doi: 10.1016/j.pathol.2023.10.014

Predictive and prognostic biomarkers in breast tumours

MELISSA KRYSTEL-WHITTEMORE 1, PUAY HOON TAN 2, HANNAH WEN 3
PMCID: PMC10949537  NIHMSID: NIHMS1960019  PMID: 38212230

Summary

In the age of precision medicine, extensive research has investigated tumour biomarkers to predict the behaviour of cancer and/or response to treatment in order to better understand the prognosis and treatment of disease. In breast cancer, significant progress has been made to categorise a common disease into subtypes defined by intrinsic tumour biology, measured by tumour biomarkers. This review encompasses the established biomarkers within breast cancer with the most up-to-date information regarding their understanding and clinical use as predictive and/or prognostic markers of breast cancer.

Keywords: Breast pathology, molecular pathology, breast clinical oncology, breast cancer, breast biomarkers

INTRODUCTION

Breast cancer is the most common cancer in women in the US, with approximately 13% of women diagnosed with breast cancer during their lifetime and a median age at diagnosis of 63 years. There were 297,790 estimated new cases in 2023, which accounts for 15.2% of all new cancer cases.1 While there were 43,170 estimated deaths in 2023 (7.1% of all cancer deaths), breast cancer has a relatively high 5-year relative survival at 90.8%. The rate of new breast cancer cases diagnosed has held relatively steady in the past 20 years, while the death rate has been slowly decreasing from 31.6/100,000 in 1992 compared to 19.1/100,000 in 2020.

Breast cancer is a heterogeneous disease with prognosis and treatment options dependent on the intrinsic biological features of the tumour. Treatment advances over time have developed due to expansion of this knowledge. The standard predictive and prognostic breast cancer biomarkers include oestrogen-receptor expression, progesterone receptor expression, HER2 expression, and Ki-67 proliferative index. As techniques have advanced over time, we are now able to access gene-expression profiling, immune-tumour microenvironment, as well as molecular alterations which can impact treatment and prognosis. This review will focus on the most up-to-date information regarding predictive and prognostic biomarkers in breast tumours.

BIOMARKERS IN BREAST CANCER

Oestrogen receptor/ESR1 alterations

Oestrogen is a lipid-soluble steroid hormone. It is predominantly produced by the ovaries and performs various crucial physiological functions.2 Oestrogen acts on oestrogen receptors which function as transcription factors, enabling them to regulate gene transcription through oestrogen response elements (EREs). There are two subtypes of the oestrogen receptors (ER-α and ER-β).3 ER-α is encoded by ESR1, located on chromosome 6, whereas ESR2 (which encodes ER-β) is located on chromosome 14. The binding of oestrogens to ER-α leads to gene transcription. In females, ERα is present mainly in the breast tissue, uterus, and ovary (thecal cells).4 Disturbances in ER signalling can give rise to various disorders, including breast cancer and other types of cancer. The ER signalling pathway is involved in cell growth, proliferation, and differentiation. In breast cancer, ER serves as a critical tumour marker, indicating the sensitivity to endocrine therapy.5

The 2020 American Society of Clinical Oncology (ASCO)/College of American (CAP) Guidelines recommend using immunohistochemistry (IHC) as the standard method for ER testing in invasive breast cancers. This is used to predict patients who may benefit from endocrine therapy.6 Tumours with 1–100% of tumour nuclei exhibiting positive staining should be classified as ER positive. In the 2020 guidelines, the expert panel acknowledges there are limited data regarding the benefit of endocrine therapy for cancers with 1–10% of cells staining ER positive. In such instances, a new reporting category, termed ‘ER low positive,’ should be used, along with a comment. Samples with less than 1% or 0% of tumour cell nuclei showing ER staining are considered ER negative.

Additionally, ASCO/CAP recommends newly diagnosed ductal carcinoma in situ (DCIS) also be evaluated by ER testing to determine potential benefit of endocrine therapy, which can help to reduce risk of future breast cancer.6

Selective ER modulator or aromatase inhibitors and other anti-oestrogen agents are prescribed for first-line treatment of hormone receptor positive tumours. Unfortunately, resistance to these treatment modalities is common, and can be seen in over 20% of patients with early stage disease.7 Mutations in the ligand-binding domain of ESR1, which encodes ER-α, are the most frequently identified alteration (specifically D538G and Y537S), although amplifications, deletions, and gene rearrangements can be seen as well. ESR1 mutations are rarely identified in treatment naïve hormone receptor-positive breast cancer, so its presence indicates prior treatment (and resistance) to endocrine therapy. Treatment with selective ER degrader or CDK4/6 inhibitors are commonly used when resistance to first line endocrine therapy has occurred.

Progesterone receptor

PGR (located on chromosome 11) encodes the progesterone receptor (PR). There are two isoforms of PR: PR-A and PR-B. Additionally, PR-C inhibits the action of PR-B.8 The 2020 ASCO/CAP guidelines recommend PR testing in invasive breast cancer, and using a 1% positivity threshold. Additionally, reporting the percentage and intensity of cells staining is also advised. However, unlike ER reporting, the low positive reporting category and comment recommendation, which is applicable for samples with 1–10% ER expression, does not extend to PR. While some argue the clinical utility of PR testing, evidence indicates that PR-positive tumours treated in the neoadjuvant or metastatic setting show higher rates of clinical response to endocrine therapy. However, in randomised trials in the adjuvant setting, there has been no significant difference in the benefit from adjuvant endocrine treatment based on PR status.9 However, ER positive tumours with low or negative PR expression have shown a worse overall prognosis.10 When used in combination with ER expression levels, PR can be used to determine prognostic tools such as the Magee equation, Oncotype Dx, and AJCC prognostic staging groups.11

ERBB2/HER2

ERBB2 is the gene that encodes the protein HER2. ERBB2 is within the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Its activation mediates downstream signalling of MAPK and PI3K signalling pathways. HER2-positive tumours (tumours with HER2 overexpression or ERBB2 gene amplification) account for approximately 15% of all invasive breast carcinoma. While HER2 amplified tumours have an overall worse prognosis compared to hormone receptor-positive tumours, the outcome is significantly improved by targeted therapy using anti-HER2 agents such as trastuzumab and pertuzumab.

The 2018 ASCO/CAP guidelines for HER2 testing recommend performing HER2 IHC testing for primary, recurrent, and metastatic tumours. IHC score of 0 (no staining or incomplete faint membrane staining in <10% of tumour cells) or IHC score of 1+ (incomplete faint membranous staining in >10% of tumour cells) are considered negative. IHC score of 3+ (complete intense circumferential staining >10% of tumour cells) is considered positive (Fig. 1). IHC score of 2+ (weak to moderate complete membranous staining in >10% of tumour cells) is considered equivocal and reflex testing must be performed with in situ hybridisation (ISH) or IHC performed on a different specimen.12

Fig. 1.

Fig. 1

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Invasive breast carcinoma with HER2 IHC 1+ staining (A and B), 2+ staining (C and D), and 3+ staining (E and F).

In the past 5 years, an emerging subtype of ‘HER2-low’ breast cancer, defined as HER2 IHC 1+ or 2+ with negative ISH results, has gained interest. HER2-low breast cancers could account for over 45% of invasive breast carcinomas. Previously, these tumours did not show benefit with targeted HER2 therapy (trastuzumab), so they were classified as HER2 negative. Groundbreaking results were published in the 2022 DESTINY-BREAST04 trial, which showed that treatment with trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer resulted in significantly prolonged progression-free and overall survival compared to chemotherapy.13 Trastuzumab deruxtecan is an antibody-drug conjugate (ADC). ADCs work by combining cytotoxic therapeutics (payload) bound to monoclonal antibodies (vehicle) linked together by a synthetic linker.14 Trastuzumab deruxtecan is comprised of an anti-HER2 monoclonal antibody which is linked to a topoisomerase-I inhibitor by a cleavable linker. While HER2-low tumours do not benefit from direct anti-HER2 therapy, it is thought the ADC’s efficacy is attributed to the ability of the anti-HER2 monoclonal antibody to bring the cytotoxic agent directly to the tumour microenvironment.

The 2023 ASCO/CAP guideline update affirmed the 2018 guideline. The guideline recommends pathologists to make the distinction between HER2 0 and HER2 1+, as the eligibility for trastuzumab deruxtecan (HER2 IHC or 1+ or 2+/FISH negative) depends on this distinction.15 Additionally, the guidelines recommend a footnote to be included on HER2 testing reports regarding this distinction. At this time, the terminology of ‘HER2-low’ has not been adopted, and HER2 IHC 0 or 1+ remains within the category of HER2 negative.

In October 2022, the US Food and Drug Administration (FDA) approved the companion diagnostic assay (PATHWAY anti-HER2 4B5; Ventana, USA), which is used to identify patients that could benefit from fam-trastuzumab deruxtecan-nxki. The PATHWAY anti-HER2 (4B5) includes a scoring algorithm which would help pathologists assign HER2-low status to acceptable tumours. When compared to HercepTest (Dako, Denmark), the PATHWAY anti-HER2 4B5 significantly reduced the amount of equivocal results.16 Additionally, using HercepTest demonstrated overscoring of IHC 2+.17 However, the study by Ruschoff and colleagues also found HercepTest had higher sensitivity for HER2 expression in tumours with ERBB2 gene amplification, increased gene count, and HER2-low tumours.

The DESTINY-BREAST06 trial is an ongoing clinical trial examining the use of trastuzumab deruxtecan versus clinical choice chemotherapy in HER2-low, hormone-positive breast cancer in patients with progression on endocrine therapy in the metastatic setting. The eligible criteria include HER2-low or HER2-ultralow (HER2 IHC >0, <1 expression). The primary outcome measure is progression-free survival. The estimated primary completion date was December 2023 with estimated study completion in July 2026.18

The DAISY trial on HER2 examined the efficacy of trastuzumab deruxtecan in HER2-overexpressing, HER2-low, and HER2 non-expressing metastatic breast cancer.19 The trial showed trastuzumab deruxtecan had an increased anti-tumour activity with higher HER2 expression, however, there was anti-tumour activity observed in HER2 IHC 0 tumours, suggesting there are some HER2 IHC 0 tumours with some level of HER2 expression, which could represent a HER2-ultralow subgroup.

It is important to note pre-analytical factors can impact HER2 IHC staining, and therefore can impact the categorisation of HER2-low tumours, as differentiating between HER2 0 and HER2 1+ can be difficult. ASCO/CAP recommends the following to optimise standardisation of HER2 testing: cold ischaemia time should be less than 1 hour, samples should be fixed in 10% neutral buffered formalin for 6–72 hours, cytology specimens must be fixed in formalin, and samples should be sectioned at 5–10 mm intervals and placed in sufficient volume of neutral buffered formalin.15

Missense mutations of ERBB2 within exons 19–20, can be seen frequently in HER2-low tumours.14 These exons encode the tyrosine kinase domain, with the most common single nucleotide variants (SNVs) including L755S, V777L, and D769H/Y.20 Additionally, mutations within exon 8, which encode the extracellular domain, are also seen, with common SNVs including S310F/Y.21 Tumours with ERBB2 mutations (without concurrent HER2 amplification) have worse relapse-free survival compared to those without mutations.22 Studies have investigated the use of tyrosine kinase inhibitors, such as neratinib, in patients with ERBB2 SNVs. The results suggest the drug shows greatest efficacy in individuals who have ERBB2 tyrosine kinase mutations.23

Ki-67 proliferation index

Ki-67, a nuclear protein expressed in proliferating cells and detectable by IHC, has been proposed as a prognostic marker in hormone receptor-positive breast cancer. Currently, there are three main suggested clinical uses for Ki-67 in breast cancer: prognosis estimation in early stage disease and determining need for chemotherapy/treatment; monitoring during or after neoadjuvant therapy;24 and selecting patients for CDK4/6 inhibitors based on MonarchE trial results, although this recommendation has recently changed.25 The International Ki-67 in Breast Cancer Working Group (IKWG) recently provided guidelines for Ki-67 assessment.24 The IKWG recommended T1–2 N0–1 ER+/HER2– breast cancer with Ki-67 ≤5% or ≥30% can withhold or proceed with chemotherapy without the need for gene expression assay (such as Oncotype DX), as these patients would likely have a low or high recurrence score (RS), respectively. The clinical utility of this would be to replace gene expression assay for ER positive early-stage tumours, if the Ki-67 index is ≤5% or ≥30%. Additionally, studies from University of Pittsburgh Medical Center (UPMC) have shown tumours with Magee score (MS) of <18, 18–25 with low mitotic score, or >31 can safely forego gene expression assays.26,27 In contrast to the IKWG guidelines which only use the Ki-67 IHC proliferation index value, the Magee equations are multiple linear regression analyses performed to model the prediction of the Oncotype DX RS. Three models were built and these three equations are referred to as the ‘Magee equations’. The input for the Magee equations includes: Nottingham score (range 3–9), Ki-67 labelling index (0–100), tumour size, ER and PR, and HER2 status.26 Preliminary studies have shown Magee equations, but not IKWG guidelines may better predict Oncotype DX RS.28 Additionally, while low and high Magee scores may infer Oncotype DX testing results, intermediate results would benefit from Oncotype DX testing. In 2021, the St Gallen International Consensus Conference endorsed the IKWG recommendation, using Ki-67 proliferation index of 30% as a threshold for recommending adjuvant chemotherapy in ER-positive, HER2-negative, node-negative breast cancer.

In 2020, the results from the MonarchE trial were published which found abemaciclib combined with endocrine therapy showed a significant improvement in invasive disease-free survival in patients with hormone receptor-positive, HER2-negative, node-positive early breast cancer.25 Inclusion criteria for this trial included Ki-67 proliferation index greater than 20%. As such, in its initial approval of abemaciclib in 2021 as an adjuvant therapy, the FDA required a ≥20% Ki-67 proliferation index. Concurrently, the FDA also granted pre-market approval to Ki-67 IHC MIB-1 pharmDx (Dako Omnis, Agilent, USA) as a companion diagnostic for abemaciclib. However, follow-up studies found a combination of abemaciclib and endocrine therapy showed benefit in patients with high risk clinicopathological features regardless of Ki-67 index.29 As a result, the FDA has removed the requirement for Ki-67 ≥20% (and Ki-67 companion diagnostic test) for use of abemaciclib.

PD-L1/immunotherapy

Immune checkpoint inhibition has proven beneficial in the treatment of many cancer types. Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) expression have been suggested as prognostic markers in both early- and late-stage triple-negative breast cancer (TNBC).30 In the treatment of metastatic TNBC, the presence of PD-1/PD-L1 expression is associated with benefits from the addition of checkpoint inhibitors to chemotherapy. Additionally, PD-L1 testing serves as a predictive marker for determining the benefit of checkpoint inhibitors in advanced TNBC. Frequently, PD-L1-positive TNBC also has high tumour infiltrating lymphocytes (TILs). TILs appear to serve as a prognostic marker to assess the response to neoadjuvant chemotherapy; however, there is a lack of a standard cut-off for TILs to make treatment decisions.

In 2020, the FDA approved the PD-L1 IHC 22C3 pharmDx (Agilent) as the companion diagnostic test to determine eligibility for pembrolizumab in patients with advanced TNBC. The scoring method for 22C3 uses the combined positive score (CPS), which evaluates the number of PD-L1 staining cells (including tumour cells, lymphocytes, and macrophages) divided by the total number of viable tumour cells, multiplied by 100. A CPS score ≥10 is considered positive, which was determined by the KEYNOTE-355 clinical trial. This study found that among patients with metastatic TNBC and a CPS of ≥10, the combination of pembrolizumab and chemotherapy showed a clinically significant improved progression-free survival when compared to the placebo-chemotherapy group.31 Additionally, the KEYNOTE-522 trial demonstrated patients with high risk early stage TNBC had a significantly higher pathological complete response when treated with pembrolizumab in combination with neoadjuvant chemotherapy, followed by surgery, and then continued adjuvant treatment with pembrolizumab. These results were seen regardless of PD-L1 expression.32 As a result, in 2021 the FDA also approved pembrolizumab treatment for TNBC in combination with chemotherapy as neoadjuvant therapy, and then continued adjuvant treatment after surgery without the need for PD-L1 positivity.

Microsatellite instability in breast cancer

Microsatellite instability (MSI) is caused by the loss of DNA mismatch repair activity and results in a hypermutable phenotype. MSI-high tumours have been granted the first FDA agnostic drug approval of pembrolizumab independent of tumour type. MSI-high breast cancers are very rare, accounting for less than 1% of cases. While there is an association with MSI-high tumours and the efficacy of pembrolizumab in other tumours,33 the prognosis of MSI-high breast cancers treated with pembrolizumab is yet to be determined.

Oncotype Dx

Oncotype DX (ODX; Genomic Health, USA) is a 21-gene reverse transcriptase polymerase chain reactin (RT-PCR) gene expression assay used for early stage, hormone receptor-positive, HER2-negative breast cancer, with or without nodal metastases. ODX evaluates the gene expression of Ki67, STK15, BIRC5, CCNB1, MYBL2, GRB7, HER2, ER, PGR, BCL2, SCUBE2, GSTM1, BAG1, CD68, MMP11, CTSL2 and reference genes ACTB, GAPDH, GUS, RPLPO, TFRC. From this data, a recurrence score (RS) from 0–100 is generated. This score is used as a prognostic and predictive factor. In general, tumours with RS <25 have a low risk of recurrence, and patients can forgo treatment with chemotherapy and are treated with endocrine therapy alone. However, tumours with RS >25 have a high risk of recurrence and are treated with both chemotherapy and endocrine therapy.

In 2015, initial results from the TAILORx trial (examining women with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer) demonstrated tumours with RS 0–10 had low rate of recurrence at 5 years when treated with endocrine therapy alone without chemotherapy.34 In 2018, additional results showed endocrine therapy was non-inferior to chemotherapy and endocrine therapy in the analysis of invasive disease-free survival for patients (age >50 years) with RS of 11–25.35 Of note, the trial did observe some benefit of chemotherapy in women younger than 50 with a RS 16–25. In 2021, the results from RxPONDER trial were published, which evaluated hormone receptor-positive, HER2-negative breast cancer, with one to three positive axillary lymph nodes (nodal stage N1). This showed no benefit of chemotherapy with endocrine therapy among postmenopausal women with one to three positive lymph nodes and a recurrence score of ≤25.36 However, the benefit of chemotherapy was observed within premenopausal women with positive lymph nodes even with low risk recurrence score.

PIK3CA mutations

PIK3CA is a gene which encodes p110α, a protein involved in the PI3K/AKT/mTOR pathway, and is one of the most commonly mutated genes in hormone receptor positive breast cancer, seen in approximately 40% of hormone receptor-positive tumours.37 In 2019, the FDA approved alpelisib (a targeted PI3K inhibitor) for patients with PIK3CA-mutated hormone receptor-positive and HER2-negative tumours. The approval occurred as a result of the SOLAR-1 trial which demonstrated prolonged progression-free survival after treatment with alpelisib plus fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive and HER2-negative tumours who had failed on previous endocrine therapy as compared to placebo plus fulvestrant.37

The prognostic impact of PIK3CA mutations remains unclear. While some studies have identified PIK3CA mutations as a poor prognostic factor in hormone-positive, HER2-negative tumours,37 others have not shown a clear impact on recurrence-free interval and overall survival.38

AKT mutations/PTEN alterations

Mutations in AKT1 and deletions in PTEN can result in activation of the PI3K/AKT/mTOR pathway, similar to PIK3CA mutations. These alterations are less common than PIK3CA mutations, with AKT1 mutated in approximately 7% of hormone-positive breast cancer39 and PTEN mutated in approximately 5–10% of breast cancers.40 Most commonly, PTEN is altered by frameshift mutations which results in the loss of PTEN functionality.40

Currently, there are multiple active clinical trials investigating the use of AKT inhibitors in breast cancer. Capivasertib is one AKT inhibitor which has activity against the three AKT isoforms. Phase I and II studies have shown benefit of capivasertib when used in combination with paclitaxel and fulvestrant in hormone-positive, HER2-negative breast cancer. There are ongoing phase III trials examining its use with fulvestrant, palbociclib, and paclitaxel.41

Homologous repair deficiency/germline and somatic alterations of BRCA1/2

Inherited deleterious alterations are identified in approximately 10% of breast cancers, with half of these attributed to germline alterations in BRCA1/2.42 Germline BRCA1-associated breast cancers are more often triple-negative, and those with BRCA2 variants are more often hormone receptor-positive.43 BRCA1/2 proteins are involved in DNA repair by repairing double-stand DNA breaks through the homologous recombination repair pathway.44 While BRCA1/2 variants are commonly associated with inherited cancer predisposition, somatic (or tumour only) BRCA1/2 mutations can also occur. Genomically, BRCA associated tumours tend to have high numbers of point mutations, lower levels of CpG methylation, and increased tandem duplications and interchromosomal translocations.45

In 2022, the FDA approved olaparib (a polyadenosine diphosphate-ribose polymerase inhibitor, PARP inhibitor) for adjuvant treatment of patients with germline BRCA-mutated HER2-negative early breast cancer after treatment with neoadjuvant or adjuvant chemotherapy. PARP inhibitors function by inhibiting another DNA repair pathway which is triggered in cells with homologous recombination deficiency, resulting in cell death.46 The approval for olaparib came after results from the OlympiA trial, which demonstrated adjuvant olaparib was associated with significantly longer disease-free survival compared to placebo in patients with germline BRCA1/2 HER2-negative breast cancer.47

CONCLUSIONS

Understanding the predictive and prognostic biomarkers within breast cancer is necessary as we move forward in the age of precision medicine. It is clear that understanding the intrinsic tumour biology plays an important role in not only the prognosis of disease, but its ability to be targeted for treatment. Recent and current studies are further elucidating the best clinical practices to use our current knowledge for the best possible outcomes for patients.

Acknowledgements:

Research reported in this publication was supported in part by a Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute (Grant No. P30CA008748).

No special funding was received by the authors of this review.

Footnotes

Conflicts of interest

Melissa Krystel-Whittemore, scientific advisory board for AstraZeneca and professional services for Foundation Medicine Inc. Hannah Wen, speaking honoraria for Roche, and scientific advisory board for AstraZeneca and Daiichi Sankyo. Puay Hoon Tan, no conflicts of interest to disclose.

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