The scienceTriple-negative breast cancer (TNBC)

ASCENT benefit was independent of TROP2 IHC level

80% of basal-like tumours in the TCGA breast study (Cancer Genome Atlas 2012); 81% of 447 sequenced TNBCs from METABRIC and TCGA, 92% in the BL1 subtype (Bareche 2018); cBioPortal: 67 of 84 exome-sequenced triple-negative samples, 79.8%, in brca_tcga_pub and 100 of 123, 81.3%, on the 2018 calls; 237 of 299, 79.3%, in brca_metabric; 159 of 176 samples, 90.3%, in breast_msk_2018. TP53, PIK3CA and PTEN mutations were the clonally dominant events in 104 primary TNBCs (Shah 2012).

46.4% of 614 centrally scored IMpassion130 samples (Rugo 2021); 50.9% of 232 population-based early TNBCs (Sigurjonsdottir 2023); the IMpassion130 PD-L1-positive subgroup was defined by this score (Schmid 2018).

37.6% ultralow, 38.4% null and 24.0% low among 367 non-metastatic TNBCs; ultralow tumours were smaller and lower grade and more often carried BRCA1 promoter methylation, and HER2 category did not affect relapse-free survival over 10.3 years (Boissiere-Michot 2026).

KEYNOTE-355 screening

The CPS-10 subgroup of KEYNOTE-355 carried the overall survival benefit, 23.0 versus 16.1 months (Cortes 2022); 27.2% of 232 early TNBCs, with CPS 1 or more in 53.9% (Sigurjonsdottir 2023); harmonised CPS 10 concordance with SP142 IC 1% was about 75% in IMpassion130 (Rugo 2021). cBioPortal: CD274 amplification in 8 of 119, 6.7%, in brca_tcga_pan_can_atlas_2018 and 20 of 320, 6.2%, in brca_metabric.

36.6% of triple-negative against 65.4% of hormone receptor-positive disease among 3,689 HER2-negative patients (Schettini 2021); 395 of 1,162 hormone receptor-negative tumours, 34.0%, in four German neoadjuvant trials (Denkert 2021); 24.0% of 367 chemotherapy-naive non-metastatic TNBCs (Boissiere-Michot 2026); 63 of 557 DESTINY-Breast04 patients, 11.3%, were hormone receptor-negative (Modi 2022). cBioPortal: IHC 1+ or 2+ recorded for 34 of 166 scored triple-negative samples, 20%, with a further 66 recorded as 0 to 1+ (breast_msk_2018); ERBB2 mutation in 10 of 299, 3.3%, in brca_metabric.

28 of 140 first-line metastatic TNBC patients, 20%, in PAKT, where capivasertib gave a progression-free survival hazard ratio of 0.30 in that subgroup (Schmid 2020); cBioPortal: PIK3CA, AKT1 or PTEN mutation or PTEN deep deletion in 47 of 176 samples, 26.7%, in breast_msk_2018. AKT1 mutation alone in 13% of LAR tumours (Bareche 2018), 10 of 299, 3.3%, in brca_metabric and 4 of 176, 2.3%, in breast_msk_2018. LOTUS randomised 124 patients with PTEN-low tumours as a co-primary population (Kim 2017).

PTEN mutation or loss in 35% of basal-like tumours, with INPP4B loss in 30% (Cancer Genome Atlas 2012); cBioPortal: deep deletion in 25 of 119, 21.0%, and mutation in 8 of 123, 6.5%, in brca_tcga_pan_can_atlas_2018; mutation in 18 of 299, 6.0%, and deep deletion in 16 of 320, 5.0%, in brca_metabric; mutation in 15 of 176, 8.5%, and deep deletion in 10 of 176, 5.7%, in breast_msk_2018. PTEN alterations (mutation or one- or two-copy deletion) in 29% of 62 metastatic TNBC patients treated with checkpoint inhibitors, where they went with a 6% versus 48% response rate (Barroso-Sousa 2020, Clin Cancer Res).

BRCA1 predominant

~40-50% HRD by scar

RB1 mutation or loss in 20% of basal-like tumours (Cancer Genome Atlas 2012); RB1 loss of heterozygosity in 72% of basal-like tumours among 88 carcinomas, with low RB1 mRNA (Herschkowitz 2008); cBioPortal: deep deletion in 13 of 119, 10.9%, and mutation in 6 of 123, 4.9%, in brca_tcga_pan_can_atlas_2018; mutation in 18 of 299, 6.0%, and deep deletion in 8 of 320, 2.5%, in brca_metabric; mutation in 17 of 176, 9.7%, and deep deletion in 11 of 176, 6.2%, in breast_msk_2018. Copy-number deletion of RB1 marked the BL1 subtype (Bareche 2018).

LAR was 16% of tumours by TNBCtype-4 and 9% by the original six-subtype call (Lehmann 2016); 77 of 485 classifiable TNBCs, 16%, with 92% of LAR patients aged 45 or over (Bareche 2018); AR nuclear staining above 10% in 12% of 424 ER/PR-negative patients screened for TBCRC 011 (Gucalp 2013); 78 of 118 enrolled enzalutamide patients had 10% or more nuclear AR (Traina 2018). AR mutation is rare: 2 of 123 in brca_tcga_pan_can_atlas_2018 (cBioPortal).

9% of basal-like tumours (Cancer Genome Atlas 2012); 20% of 447 sequenced TNBCs, 55% within the LAR subtype (Bareche 2018); cBioPortal: 9 of 84, 10.7%, in brca_tcga_pub and 14 of 123, 11.4%, on the 2018 calls; 53 of 299, 17.7%, in brca_metabric; 23 of 176, 13.1%, in breast_msk_2018. PIK3CA amplification in 10 of 119, 8.4%, (brca_tcga_pan_can_atlas_2018) and 34 of 320, 10.6%, (brca_metabric).

8.5% of 1,824 TNBC patients unselected for family history (Couch 2015); 11.1% of 207 registry patients (Sharma 2014); BRCA1 and BRCA2 together 17.2% (50 of 291) in GeparSixto (Hahnen 2017) and 11.2% (Couch 2015); pathogenic variants in the TNBC risk genes BARD1, BRCA1, BRCA2, PALB2 and RAD51D in 12.0% of 10,901 patients, 3.7% outside BRCA1/2 (Shimelis 2018). Biallelic loss of BRCA1 or BRCA2 in 29 of 237 whole genomes, 20 germline and 9 somatic (Staaf 2019).

NOTCH1 and NOTCH2 rearrangements causing constitutive activation in 6 of 66 TNBCs, 9%, and in no other solid tumour type (Stoeck 2014); PEST-domain mutations of NOTCH1, NOTCH2 and NOTCH3 and focal NOTCH2/NOTCH3 amplifications significantly enriched in the TNBC subset of TCGA (Wang 2015); cBioPortal: NOTCH1 mutation in 16 of 299, 5.4%, in brca_metabric and 9 of 176, 5.1%, in breast_msk_2018; NOTCH2 amplification in 21 of 119, 17.6%, in brca_tcga_pan_can_atlas_2018.

EGFR amplified (gains included) in 23% of basal-like tumours, alongside PIK3CA 49%, KRAS 32% and BRAF 30% (Cancer Genome Atlas 2012); cBioPortal high-level amplification: 5 of 119, 4.2%, in brca_tcga_pan_can_atlas_2018; 19 of 320, 5.9%, in brca_metabric; 5 of 176, 2.8%, in breast_msk_2018. Growth-factor signalling defines the BL2 subtype (Lehmann 2011).

2.7% of 1,824 unselected patients (Couch 2015); 4.3% of 207 (Sharma 2014); somatic calls in 5 of 123, 4.1%, in brca_tcga_pan_can_atlas_2018, 7 of 299, 2.3%, in brca_metabric and 8 of 176, 4.5%, in breast_msk_2018 (cBioPortal). Metastatic TNBCs carried somatic biallelic loss-of-function mutations in homologous recombination genes in 7% against 2% of early TNBCs (Bertucci 2019).

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); cBioPortal: TACSTD2 amplification in 3 of 119, 2.5%, in brca_tcga_pan_can_atlas_2018 and 14 of 320, 4.4%, in brca_metabric; no TACSTD2 mutation in either.

1.2% of 1,824 unselected patients (Couch 2015); 5 pathogenic germline variants among 237 whole genomes, 2.1%, two of them biallelic (Staaf 2019); 1.0% of 1,136 Nigerian breast cancer patients, eleven cases against no controls (Zheng 2018); cBioPortal: 2 of 176, 1.1%, in breast_msk_2018 and 1 of 123 in brca_tcga_pan_can_atlas_2018.

No MSI-high tumour among 195 by PCR and one mismatch-repair-deficient tumour (lost MSH2) among 440 by IHC in Chinese TNBC (Ren 2021); 2 of 228 Japanese TNBCs MSI-high, 0.9% (Kurata 2020); about 4.7% of HRDetect-low tumours, roughly 1.7% of all 237 whole genomes, mismatch-repair deficient (Staaf 2019); cBioPortal: MSIsensor score 10 or more in 3 of 122 triple-negative exomes in brca_tcga_pan_can_atlas_2018, an algorithmic call not confirmed by PCR.