A new lump or thickening in the breast or armpit; a change in the size, shape or feel of the breast; puckering, dimpling, a rash or redness of the skin; fluid from the nipple when not pregnant or breastfeeding; a nipple that turns in (Cancer Research UK). The symptoms are the same as for other breast cancers, but triple-negative tumours arrive younger, more often between screening rounds, and more often at a higher grade
Redness may look darker or reddish brown on brown or black skin (Cancer Research UK symptoms page)
Less often found by screening : 29 percent of triple-negative cancers against 48 percent of hormone receptor-positive, HER2-negative cancers presented through an abnormal screening mammogram in US cancer centres (Lin 2012)
Referral rules : an unexplained breast lump at 30 or over, or nipple discharge, retraction or other change in one nipple at 50 or over, goes on the suspected cancer pathway; skin changes or an unexplained axillary lump at 30 or over should prompt the same consideration (NICE NG12 1.4)
How it is confirmed
One-stop breast clinic and triple assessment : examination, mammogram, ultrasound and a needle core or vacuum-assisted biopsy, with ultrasound and needle biopsy of any abnormal axillary node (Cancer Research UK)
ER, PR and HER2 are tested together on the biopsy at diagnosis by quality-assured immunohistochemistry and reported quantitatively (NICE NG101 1.3.1 to 1.3.4); results take about 2 to 4 weeks (Cancer Research UK)
Triple-negative means ER under 1 percent, PR under 1 percent (1 to 10 percent is ER Low Positive and behaves the same way) and HER2 0, 1+ or 2+ without gene amplification (ASCO/CAP 2020 and 2018)
ER and PR by immunohistochemistry : negative under 1 percent of nuclei; 1 to 10 percent reported as ER Low Positive (ASCO/CAP 2020) and behaving like triple-negative disease
Grade (almost always 3) and Ki-67 (median about 60 percent; prognostic and predictive within triple-negative disease but without a clinical-utility threshold)
Intrinsic subtype (basal-like in about 79 percent) and the Lehmann or Burstein triple-negative subtype, research classifications with different chemotherapyresponse rates
Special histological type (adenoid cystic, secretory, low-grade adenosquamous, fibromatosis-like metaplastic), which can spare chemotherapy
TP53 mutation : 80% (80% of basal-like tumours in the TCGA breast study (Cancer GenomeAtlas 2012))
PIK3CA mutation (amplification in a further tenth): 10-18% (9% of basal-like tumours (Cancer GenomeAtlas 2012))
PTEN mutation or deletion (loss): 12-35% (PTEN mutation or loss in 35% of basal-like tumours, with INPP4B loss in 30% (Cancer GenomeAtlas 2012))
RB1 mutation or deletion (loss): 15-20% (RB1 mutation or loss in 20% of basal-like tumours (Cancer GenomeAtlas 2012))
Homologous recombination deficiency hrd (hrdetect-high, or hrd score 42 or more / tumour brca): 59-71% (HRDetect-high in 58.6% of 237 population-based TNBC whole genomes (35.9% low, 5.5% intermediate))
MYC amplification : 18-35% (cBioPortal: high-level amplification in 34 of 119 triple-negative samples, 28.6%, in brca_tcga_pub and 37 of 119, 31.1%, on the 2018 calls)
PIK3CA / AKT1 / PTEN pi3k-akt pathway alteration (any of the three): 20-27% (28 of 140 first-linemetastatic TNBC patients, 20%, in PAKT, where capivasertib gave a progression-free survivalhazard ratio of 0.30 in that subgroup (Schmid 2020))
EGFR amplification : 3-6% (EGFRamplified (gains included) in 23% of basal-like tumours, alongside PIK3CA 49%, KRAS 32% and BRAF 30% (Cancer GenomeAtlas 2012))
Androgen receptor (LAR subtype) ar expression and luminalandrogen receptor subtype: 12-16% (LAR was 16% of tumours by TNBCtype-4 and 9% by the original six-subtype call (Lehmann 2016))
Tumour mutational burden tmb 10 or more mutations per megabase : 4-5% (5% of 3,969 breast cancers of all subtypes were hypermutated, higher in HR-negative/HER2-negative and metastatic samples (8.4% metastatic versus 2.9% primary), with APOBEC (59.2%) and mismatch repair deficiency (36.4%) the dominant processes (Barroso-Sousa 2020, Ann Oncol))
CD274 (PD-L1), SP142 immune-cell score ic 1% or more (sp142): 41-51% (46.4% of 614 centrally scored IMpassion130 samples (Rugo 2021))
CD274 (PD-L1), 22C3combined positive score cps 10 or more (22c3): 27-38% (The CPS-10 subgroup of KEYNOTE-355 carried the overall survival benefit, 23.0 versus 16.1 months (Cortes 2022))
TROP2 (TACSTD2) proteinexpression (h-score) and amplification: 2-4% (Trop-2 expression was assessable in 290 of 468 ASCENT patients and sacituzumab govitecan benefit was seen at high and medium expression (progression-free survival 6.9 and 5.6 versus 2.5 and 2.2 months), with the low group too small to judge (Bardia 2021))
ERBB2 (HER2) her2-low (ihc 1+ or 2+/ish-negative): 24-37% (36.6% of triple-negative against 65.4% of hormone receptor-positive disease among 3,689 HER2-negative patients (Schettini 2021))
ERBB2 (HER2) her2-ultralow (ihc 0 with faint membrane staining in 10% or fewer cells): 38% (37.6% ultralow, 38.4% null and 24.0% low among 367 non-metastatic TNBCs)
Stromal tumour-infiltrating lymphocytes stils (immune infiltration): 21-30% (Mean sTILs 23% with 77% of patients at 1% or more among 2,148 early TNBC patients on anthracycline chemotherapy (Loi 2019))