Cancer Dictionary · Breast

Breast Cancer

Hormone receptor and HER2 status split breast cancer into groups that behave differently and are managed differently. Within each group, genomic questions arise at different points: recurrence-risk scoring in early hormone receptor positive disease, resistance mutations in advanced disease, and DNA repair status across several groups. Germline testing is a prominent and separate question.

Also called Carcinoma of the breast.

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The governing idea

Breast cancer is divided first by receptor status, and that division decides which questions are even worth asking. Genomic profiling answers different questions in each of the resulting groups.

01Before any molecular question

How it usually presents

Usually established before any genomic discussion: oestrogen and progesterone receptor status, HER2 status, tumour grade, stage, and nodal involvement. These come from standard pathology and immunohistochemistry, not from sequencing. HER2-low has become a distinct reporting category alongside positive and negative.

Usually already established

ER, PR and HER2 status from immunohistochemistry and, where needed, in situ hybridisation
Grade, stage and nodal status
Whether disease is early, locally advanced or metastatic
In early hormone receptor positive disease, whether a recurrence-risk score has been done

Major disease categories

The divisions below are not labels. Each one changes what the treatment discussion is actually about.

Hormone receptor positive, HER2 negative

The largest group. In early disease the question is often how much benefit chemotherapy adds, which is where recurrence-risk genomic scores are discussed. In advanced disease the questions turn to endocrine resistance mechanisms.

HER2 positive

A well-defined group with a large targeted treatment class. Whether HER2 status has been confirmed by the appropriate testing sequence matters.

HER2 low

A newer reporting category, defined by immunohistochemistry and in situ hybridisation results that fall short of positive. It has become relevant to specific treatment classes.

Triple negative

Hormone receptor and HER2 negative. DNA repair status, immune markers and trial access are prominent in the discussion.

Male breast cancer

Uncommon, usually hormone receptor positive, and with a higher prior probability of a germline finding, which is why the germline question is raised routinely.

03What is discussed

Molecular considerations

In advanced disease the alterations most discussed include PIK3CA, AKT1 and PTEN in the PI3K pathway, ESR1 mutations as a mechanism of acquired endocrine resistance, ERBB2 (HER2) mutations as distinct from amplification, and BRCA1, BRCA2 and PALB2 in the DNA repair pathway. Mismatch repair status and tumour mutational burden are assessed in some settings. ESR1 is specifically an acquired alteration: it is usually absent at diagnosis and appears under endocrine treatment pressure, which is why the timing of the sample matters more here than almost anywhere else.

Biomarkers commonly discussed

ER and PR

Immunohistochemistry, not sequencing. The first division in the whole disease.

HER2 (ERBB2)

Amplification is the classic finding. Mutation is a separate and less common one. HER2-low is a third reporting category.

PIK3CA

A frequent alteration in hormone receptor positive advanced disease.

ESR1

Acquired under endocrine therapy. Best looked for at progression, not at diagnosis.

BRCA1 and BRCA2

Relevant both as tumour findings and as inherited risk. The two questions are different.

PALB2

Another DNA repair gene relevant to both tumour and germline discussions.

AKT1 and PTEN

Also in the PI3K pathway, and part of the same conversation as PIK3CA.

MMR / MSI

Uncommon in breast cancer, but assessed in some advanced-disease pathways.

This is not an exhaustive list, and which markers are relevant depends on the individual case. Not every marker listed is assessed in every patient.

04What is tested, and from what

Testing, inherited risk and blood-based monitoring

Genomic testing considerations

Two quite different kinds of testing carry the name genomic in breast cancer, and confusing them is common. Recurrence-risk assays in early hormone receptor positive disease measure gene expression to estimate benefit from chemotherapy. Comprehensive genomic profiling in advanced disease looks for DNA alterations that point to specific treatment classes. They answer different questions at different stages, and one does not substitute for the other. In advanced disease, plasma testing is well established, and is particularly suited to looking for ESR1, which may only be present in a subclone.

Germline considerations

Breast cancer is one of the diseases where the germline question is raised most often and most consequentially. Young age at diagnosis, triple negative disease, bilateral disease, male breast cancer, a personal or family history of ovarian, pancreatic or prostate cancer, and Ashkenazi Jewish ancestry are among the recognised prompts. A germline finding affects the patient’s own management, surgical decisions, and the testing pathway offered to relatives. It is a different test from tumour profiling, and a tumour panel reporting a BRCA alteration does not by itself establish that it is inherited.

Cancer genetics and hereditary risk

ctDNA and liquid biopsy considerations

Plasma ctDNA is well established in advanced breast cancer, particularly for PIK3CA and ESR1. Because ESR1 mutations emerge under treatment and may be present only in part of the disease, plasma sampled at progression can find what an archival tissue block from diagnosis cannot. Serial ctDNA for residual disease after curative-intent treatment is an active research area.

When molecular information matters

Testing that arrives after the decision it was meant to inform has already been made is a common and avoidable problem. This is the sequence in which molecular information tends to become relevant.

At diagnosis, early diseaseReceptor status, grade and stage lead. In hormone receptor positive node-negative disease, a recurrence-risk score is often the genomic question that actually arises.
At diagnosis, where germline risk is suggestedGermline testing may influence surgical decisions, so its timing relative to surgery is part of the discussion rather than an afterthought.
Before first-line treatment in advanced diseaseComprehensive profiling and DNA repair status inform the sequence of treatment classes.
At progression on endocrine therapyThe moment when ESR1 is worth looking for, and when a fresh sample is more informative than an archival one.
After curative-intent treatmentResidual disease monitoring is under study rather than routine, and the question of what would be done with an early positive result is worth asking before testing.

06Take these to your team

Questions worth raising

When a decision is being made

Questions worth raising with a treating team.

Has HER2 status been reported using the current three-category framework, including HER2-low?
In early hormone receptor positive disease, is the question recurrence risk or is it comprehensive profiling? They are different tests.
In advanced disease, has the sample used for profiling been taken recently, or is it archival tissue from the original diagnosis?
Has a germline assessment been discussed, and if so, will its result be available before surgical decisions are made?
If a BRCA alteration is reported on a tumour panel, has it been clarified whether it is germline or somatic?

At progression, recurrence or resistance

The molecular picture at diagnosis is not always the molecular picture later.

Has ESR1 been looked for specifically, on a sample taken at progression rather than at diagnosis?
Has HER2 status been reassessed, since it can differ between the primary and a metastatic site?
Has the molecular profile been reassessed rather than carried forward from the original report?

07What shapes eligibility

Clinical trial considerations

Trial eligibility in breast cancer is usually written in terms of receptor subtype, specific alterations such as PIK3CA or ESR1, DNA repair status, and the exact prior treatment sequence. Because the subtypes are so well defined, an inaccurate subtype designation is one of the more common reasons a match fails.

Ask about trial matching

Plain-language glossary for this entry (5 terms)

Term	What it means
Receptor status	Whether the cancer carries oestrogen, progesterone and HER2 receptors. Determined by staining tissue, not by sequencing.
HER2-low	A reporting category between positive and negative, relevant to specific newer treatment classes.
Recurrence-risk score	A gene expression test in early disease that estimates how much benefit chemotherapy would add. Not the same as genomic profiling.
Endocrine resistance	When a cancer stops responding to hormone-blocking treatment. ESR1 mutation is one recognised mechanism.
Somatic versus germline	Somatic changes arise in the tumour. Germline changes are inherited and present in every cell.

Where OnKommon fits

These are the services most often relevant to this cancer. Which of them applies is a clinical question, not an automatic one.

Signature STb O+The 523-gene comprehensive panel, with TMB and MSI.See how it works HeritageInherited-risk testing, and a tested pathway for relatives.See how it works SentinelSerial monitoring during active treatment.See how it works ClearMolecular residual disease surveillance after curative-intent treatment.See how it works

This entry is educational. It describes what is commonly discussed in this cancer, not what should happen for any individual. Which of it applies depends on the specific diagnosis, stage, prior treatment and the person themselves. Nothing here is a recommendation, and no list of biomarkers here is exhaustive. Decisions belong with a treating team who know the whole case.

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