# Triple-negative breast cancer

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## TL;DR

Triple-negative breast cancer lacks the three commonest treatment targets, so hormone therapy and HER2 drugs do not work against it and treatment rests on chemotherapy, immunotherapy and antibody-drug conjugates. It is more aggressive than most breast cancer and harder to treat once it has spread.

## Summary

Triple-negative breast cancer is defined by the absence of oestrogen receptor, progesterone receptor and HER2 expression on the tumour. IARC's GLOBOCAN programme estimated 2.3 million new breast cancer cases and 670,000 breast cancer deaths worldwide in 2022, making it the second most common cancer type after lung cancer, with 2.43 million new cases estimated for 2024; globally one in 20 women will be diagnosed with breast cancer in her lifetime and one in 70 will die of it. In the United States, SEER projects 321,910 new breast cancer cases and 42,140 deaths in 2026, with overall five-year relative survival of 91.9% for 2016 to 2022. Triple-negative disease makes up about 15% of all breast cancers by NCI's figures, with other reviews estimating a range of 10% to 15%, and it carries a markedly worse prognosis once it has spread than breast cancer overall.

Treatment is organised by stage and by a small number of biomarkers rather than by the hormone and HER2 pathways used elsewhere in breast cancer. High-risk early-stage disease is treated with neoadjuvant pembrolizumab plus chemotherapy continued as adjuvant pembrolizumab after surgery, approved by the FDA in 2021 on the strength of KEYNOTE-522, with long-term follow-up now showing a 34% reduction in the risk of death. Patients left with residual disease after neoadjuvant chemotherapy may receive adjuvant pembrolizumab, off-label capecitabine, or adjuvant olaparib for one year if they carry a germline BRCA mutation, the last approved in 2022 on the OlympiA trial. In the metastatic setting, pembrolizumab is added to chemotherapy only when PD-L1 combined positive score is 10 or more, and 2026 brought two further first-line approvals for Trop-2-directed antibody-drug conjugates: sacituzumab govitecan, as monotherapy for patients ineligible for immunotherapy or combined with pembrolizumab for PD-L1-high disease, and datopotamab deruxtecan for patients ineligible for PD-1/PD-L1 therapy.

Nuclear medicine has only a general, not a triple-negative-specific, role in this disease. FDG PET/CT is not indicated for routine staging of early breast cancer and is reserved for equivocal conventional imaging or systemic staging of stage IV or recurrent disease. Fluoroestradiol PET, approved in 2020 as an adjunct to biopsy for detecting oestrogen-receptor-positive lesions and later added to NCCN guidelines for ER-positive and lobular disease, is by definition unable to characterise triple-negative tumours, since it images the very receptor these tumours lack, and it cannot assess HER2 or progesterone receptor status either. No FDA-approved molecular imaging agent identifies triple-negative lesions specifically, predicts response to a TNBC-directed drug, or serves as a companion diagnostic for pembrolizumab, sacituzumab govitecan, datopotamab deruxtecan or olaparib in this disease; PD-L1 and BRCA status are established entirely by tissue-based testing.

## Fields

- Kind: Indication
- Last checked: 2026-09-23
- Also known as: TNBC
- Tags: breast; immunotherapy; trop2
- Group: breast
- Burden: IARC GLOBOCAN estimated 2.3 million new breast cancer cases and 670,000 breast cancer deaths worldwide in 2022, rising to an estimated 2.43 million new cases in 2024, and ranks it the second most common cancer type worldwide after lung cancer; globally one in 20 women will be diagnosed with breast cancer in her lifetime and one in 70 will die of it. In the United States, SEER projects 321,910 new cases and 42,140 deaths in 2026, with an age-adjusted incidence of 132.5 and mortality of 18.9 per 100,000 women per year, and overall five-year relative survival of 91.9% based on 2016-2022 data. Triple-negative breast cancer, defined by the absence of oestrogen receptor, progesterone receptor and HER2 expression, accounts for about 15% of all breast cancers per NCI, with other reviews estimating 10% to 15%.
- Subtypes: Early-stage, high-risk TNBC treated with neoadjuvant chemoimmunotherapy; Residual disease after neoadjuvant chemotherapy (non-pathological complete response); Germline BRCA1/2-mutated, HER2-negative, high-risk early disease; Metastatic or locally recurrent TNBC with PD-L1 combined positive score of 10 or more; Metastatic TNBC in patients ineligible for PD-1/PD-L1 inhibitor therapy
- Biomarkers: Oestrogen receptor (ER) by immunohistochemistry, required to be below 1% positivity for a triple-negative diagnosis; Progesterone receptor (PR) by immunohistochemistry, also required to be negative; HER2 by immunohistochemistry/in-situ hybridisation, required to be negative (IHC 0-2+ or ISH non-amplified); Germline BRCA1/2 mutation status, reported in roughly 9% to 35% of TNBC cohorts, which determines eligibility for adjuvant or metastatic olaparib; PD-L1 combined positive score by the 22C3 pharmDx assay, required to be 10 or more to add pembrolizumab in first-line metastatic disease

## Standard of care

- Early-stage, high-risk TNBC (neoadjuvant and adjuvant): Pembrolizumab combined with chemotherapy is given before surgery and continued as a single agent after surgery, approved by the FDA on 26 July 2021 based on KEYNOTE-522, which showed a pathological complete response of 63% versus 56% and an event-free survival hazard ratio of 0.63; long-term follow-up at a median of 75.1 months showed a 34% reduction in the risk of death.
- Residual disease after neoadjuvant chemotherapy (non-pCR): NCCN education materials list adjuvant pembrolizumab if a pembrolizumab-containing regimen was given preoperatively, adjuvant capecitabine for six to eight cycles based on the CREATE-X trial (used off-label, NCCN category 2A), or adjuvant olaparib for one year with a germline BRCA mutation, with no established evidence on sequencing or combining the three.
- Early-stage, germline BRCA-mutated, HER2-negative, high-risk disease: Adjuvant olaparib for one year received accelerated FDA approval on 11 March 2022 based on OlympiA, which showed three-year invasive disease-free survival of 85.9% versus 77.1% (hazard ratio 0.58) and an updated overall survival hazard ratio of 0.68, a 32% reduction in the risk of death.
- Metastatic or locally recurrent TNBC, first line, PD-L1 CPS 10 or more: Pembrolizumab plus chemotherapy received accelerated approval on 13 November 2020 based on KEYNOTE-355, which showed a progression-free survival hazard ratio of 0.65, and converted to full approval in July 2021 on final overall survival data of 23.0 versus 16.1 months (hazard ratio 0.73); the PD-L1 IHC 22C3 pharmDx assay was approved as the companion diagnostic.
- Metastatic TNBC, first line: Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, was approved on 24 June 2026 as first-line monotherapy for patients ineligible for PD-1/PD-L1 therapy (ASCENT-03) or combined with pembrolizumab for PD-L1 CPS 10 or more disease (ASCENT-04/KEYNOTE-D19); datopotamab deruxtecan, another Trop-2-directed antibody-drug conjugate, was approved on 22 May 2026 for patients ineligible for PD-1/PD-L1 therapy based on TROPION-Breast02, with median overall survival of 23.7 versus 18.7 months (hazard ratio 0.79) and a progression-free survival hazard ratio of 0.57.

## State of the art

- Metastatic first-line treatment for TNBC changed twice in 2026: sacituzumab govitecan was approved as monotherapy for patients ineligible for immunotherapy or combined with pembrolizumab for PD-L1 CPS 10 or more disease, and datopotamab deruxtecan was separately approved for patients ineligible for PD-1/PD-L1 therapy. Both are Trop-2-directed antibody-drug conjugates, marking a shift from cytotoxic chemotherapy backbones toward targeted ADCs even in a disease defined by the absence of a single dominant receptor target.
- Long-term follow-up of KEYNOTE-522 at a median of 75.1 months showed that neoadjuvant and adjuvant pembrolizumab reduces the risk of death by 34% compared with chemotherapy alone in high-risk early-stage TNBC, confirming that the early pathological complete response benefit translates into a durable survival advantage.
- Receptor status is not fixed over the course of disease: the French ESME cohort found a 27.0% total discordance rate for hormone receptor and/or HER2 status between the primary tumour and metastases, with ER status changing in 15.1% of cases and PR status in 31.1%, which is why ASCO/CAP guidance calls for retesting receptors at metastatic recurrence.

## Open problems

- TNBC lacks all three routinely druggable receptors, so chemotherapy, immunotherapy and antibody-drug conjugates remain the only broadly available systemic options, and no reliably hormone-receptor-directed adjuvant target exists outside germline BRCA carriers.
- The disease is molecularly and spatially heterogeneous, which undermines single-biomarker prognostic and predictive models; spatial profiling has shown sharp shifts in PAM50 subtype and immune infiltration within the same tumour.
- Resistance to immune checkpoint inhibition is common and appears tied to homologous-recombination status: BRCA-mutant, homologous-recombination-deficient tumours tend to have more tumour-infiltrating lymphocytes and respond better to immunotherapy, while homologous-recombination-proficient tumours are often refractory.
- Receptor status can change between the primary tumour and a metastasis at rates high enough to alter treatment eligibility, meaning a single primary-tumour biopsy can misclassify a patient's disease over time.
- No FDA-approved nuclear medicine agent identifies triple-negative lesions specifically or predicts response to TNBC-directed therapy; fluoroestradiol PET, the one approved receptor-imaging breast agent, explicitly cannot assess HER2 or progesterone receptor status and has no defined role in oestrogen-receptor-negative disease.

## Sources

- IARC press release: global cancer burden 2022: https://www.iarc.who.int/wp-content/uploads/2025/02/pr361_E.pdf
- NCI: What Is Triple-Negative Breast Cancer (TNBC)?: https://www.cancer.gov/types/breast/breast-cancer-types/triple-negative
- SEER Cancer Stat Facts: female breast cancer: https://seer.cancer.gov/statfacts/html/breast.html
- FDA: approval of sacituzumab govitecan-hziy monotherapy and with pembrolizumab, first line: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sacituzumab-govitecan-hziy-monotherapy-and-combination-pembrolizumab-first-line
- FDA: approval of datopotamab deruxtecan-dlnk for unresectable or metastatic TNBC: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-triple-negative-breast-cancer
- Merck: FDA approval of pembrolizumab for high-risk early-stage TNBC (KEYNOTE-522): https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/

## Connected records

- targets: [Sortilin (SORT1)](https://nuclide.cc/targets/sortilin/), [TROP2](https://nuclide.cc/targets/trop2/)
- technologies: [FDG PET](https://nuclide.cc/technologies/fdg-pet/), [TROP2 PET](https://nuclide.cc/technologies/trop2-pet/)
- drugs: [Fluoroestradiol F-18 (FES PET)](https://nuclide.cc/drugs/fluoroestradiol-f18/)
- opportunities: [TROP2 imaging where no tissue test is required](https://nuclide.cc/opportunities/opp-trop2-imaging-heterogeneity/)

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