Tumour heterogeneity and a long-standing paucity of effective therapies other than chemotherapy have contributed to triple-negative breast cancer (TNBC) being the subtype with the least favourable outcomes. In the past few years, advances in omics technologies have shed light on the relevance of the TNBC microenvironment heterogeneity, unveiling a close dynamic relationship with cancer cell features. An improved understanding of tumour-immune system co-evolution supports the need to adopt a more comprehensive view of TNBC as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody-drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease. The current therapeutic scenario is only the tip of the iceberg, as hundreds of new compounds and combinations are in development. The translation of these experimental therapies into clinical benefit is a welcome and ongoing challenge. In this Review, we describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can define different levels of risk and provide improved opportunities for tailoring treatment.

Treatment landscape of triple-negative breast cancer - expanded options, evolving needs

Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.

Triple negative breast cancer (TNBC) is characterized by the lack of estrogen and progesterone receptor expression and lacks HER2 overexpression or gene amplification. It accounts for 10-15% of incident breast cancers and carries the worst prognosis. TNBC is overrepresented among Black and pre-menopausal women and is associated with significant psychological and treatment-related burdens, including financial toxicity. Like other breast cancers, TNBC is biologically heterogeneous, leading to diverse clinical and epidemiological behaviors, however, unlike the other clinical subtypes, in TNBC we still lack tumor-specific targeted therapy. Early TNBC outcomes have improved due to the intensification of therapies, including improvements in polychemotherapy and the addition of immunotherapy. Future efforts are needed to identify targetable aberrations for specific drug therapy, prevent immune evasion, and increase social-economic support. Given that the name TNBC illustrates its lack of specifically targeted and effective therapy, we look forward to being able to retire the name in favor of a group of targetable entities within what is now called "TNBC". 

/pdf/triple-negative-breast-cancer-pitfalls-and-progress-hjblln2v.pdf

Triple negative breast cancer: Pitfalls and progress

Global estimates indicated 2.3 million new cases of breast cancer in 2020, contributing to nearly 12% of all new cancer cases, with 685 000 deaths in the same year.1 Breast cancer detection has increased due to improvements in screening techniques. The mortality rate has decreased in recent years in Western populations, especially in younger age groups,2,3 but breast cancer is still the leading cause of cancer-related deaths for women worldwide. Most early breast cancer (EBC) cases can be cured by multimodality treatment, although cure rates vary by clinical stage and subtype. 

Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up†.

Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition. Breast cancers are highly heterogeneous. Treatment strategies for breast cancer vary by molecular features, including activation of human epidermal growth factor receptor 2 (HER2), hormonal receptors (estrogen receptor [ER] and progesterone receptor [PR]), gene mutations (e.g., mutations of breast cancer 1/2 [BRCA1/2] and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha [PIK3CA]) and markers of the immune microenvironment (e.g., tumor‐infiltrating lymphocyte [TIL] and programmed death‐ligand 1 [PD‐L1]). Early‐stage breast cancer is considered curable, for which local‐regional therapies (surgery and radiotherapy) are the cornerstone, with systemic therapy given before or after surgery when necessary. Preoperative or neoadjuvant therapy, including targeted drugs or immune checkpoint inhibitors, has become the standard of care for most early‐stage HER2‐positive and triple‐negative breast cancer, followed by risk‐adapted post‐surgical strategies. For ER‐positive early breast cancer, endocrine therapy for 5‐10 years is essential. Advanced breast cancer with distant metastases is currently considered incurable. Systemic therapies in this setting include endocrine therapy with targeted agents, such as CDK4/6 inhibitors and phosphoinositide 3‐kinase (PI3K) inhibitors for hormone receptor‐positive disease, anti‐HER2 targeted therapy for HER2‐positive disease, poly(ADP‐ribose) polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple‐negative disease. Innovation technologies of precision medicine may guide individualized treatment escalation or de‐escalation in the future. In this review, we summarized the latest scientific information and discussed the future perspectives on breast cancer.

Breast cancer: an up‐to‐date review and future perspectives

Importance Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95];P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92];P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19];P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13];P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration ClinicalTrials.gov Identifier:NCT01112826

/pdf/effect-of-capecitabine-maintenance-therapy-using-lower-1ubntu5jle.pdf

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

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Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.