Targeting low-risk triple-negative breast cancer: a review on de-escalation strategies for a new era

Introduction

Triple-negative breast cancer (TNBC) is a distinct subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. TNBC accounts for approximately 15–20% of all breast cancer cases, with most cases being high-grade and associated with younger age, aggressive behavior, and poor prognosis (1). However, TNBC is a highly heterogeneous group that includes tumors of different histological types, each with distinct molecular drivers and consequently varying prognoses and treatment responses (2-4). Most TNBCs are no special type (NST) carcinomas, but they are enriched in special histologies, some with more favorable prognoses than NST (2).

Regarding molecular subtypes, Lehmann et al. identified two subtypes of basal-like tumors [basal-like 1 (BL1) and basal-like 2 (BL2)], a mesenchymal-like, and a luminal androgen receptor (LAR) (3,4). BL1 is enriched in DNA homologous recombination repair genes, while BL2 is enriched in growth factor signaling pathways. Mesenchymal-like presents genes acting in epithelial-mesenchymal transition and growth factors pathways. The LAR is enriched in hormonally regulated pathways driven by androgen receptor (AR). An immunomodulatory (IM) phenotype was identified among these subtypes, more expressive in BL1, reflecting the tumor-infiltrating lymphocytes (TILs) population (3,4). Burstein et al. incorporated the IM into the basal-like phenotype and reclassified them into basal-like immunoactivated (BLIA) and basal-like immunosuppressed (BLIS) (5).

Molecular classification shows that TNBC comprises a group of tumors with different drivers and biologies. Two decades ago, we had no treatment options for these tumors besides chemotherapy. However, as new biomarkers are being identified and validated, we now have the opportunity to personalize the management of TNBC (6).

The biggest challenge in therapeutic decision-making is early-stage disease. The omission of adjuvant therapy is barely considered for tumors pT1a and pN0. However, other TNBCs with a low risk of recurrence exist, and for these cases, we can discuss either omission or de-escalation of treatments (7).

To explore these possibilities, we conducted a literature review by searching the PubMed database for combinations of the terms “early-stage”, “TNBC”, and “low-risk”. We retrieved eight articles (7-14) and added some others that were presented as similar by PubMed. These articles were the base for discussing low-risk TNBC candidate to de-escalation of treatment.

Low-risk TNBC

Low-risk TNBC represents a subgroup of TNBC patients with favorable clinical course. This group includes small-sized/early-stage tumors (pT1a/b, pN0), certain special histological types, tumors with high TILs, and tumors with low Ki-67 (7). Importantly, low-risk TNBCs have a lower risk of recurrence than other TNBC subtypes, suggesting that these patients may be candidates for de-escalation strategies to reduce treatment intensity and toxicity without compromising outcomes.

Histological special types

Breast salivary gland-type tumors present frequently with a triple-negative phenotype and are associated with good prognosis. The histological types included in the 2019 World Health Organization (WHO) Classification of Tumors are adenoid cystic carcinoma (AdCC), acinic cell carcinoma (ACC), secretory carcinoma, mucoepidermoid carcinoma (MEC), polymorphous adenocarcinoma, and tall cell carcinoma with reversed polarity (TCCRP) (2).

Metaplastic carcinomas are a group of heterogeneous tumors, generally more aggressive than NST carcinomas, with two exceptions: low-grade adenosquamous carcinoma and fibromatosis-like metaplastic carcinoma, both considered low-risk tumors (2).

It is crucial to recognize these special histologies because, despite their triple-negative phenotype, they are of low malignant potential. Pathologists can struggle to identify these tumors because they are rare and mimic other histological types.

AdCC

AdCC is the most frequent special histological type in the breast after excluding lobular carcinoma, accounting for approximately 0.1% of all breast tumors (15). The mean age of patients is around 60 years. The histology is identical to the salivary counterpart, although the prognosis is much better. These tumors are characterized by a double cell population, epithelial and myoepithelial/basaloid cells, distributed in cribriform, solid, tubular, or trabecular architectural patterns (Figure 1). The immunohistochemical profile highlights the two cellular types, with epithelial cells expressing epithelial membrane antigen (EMA), low-molecular-weight cytokeratins (CK7, CK8/18), high-molecular-weight cytokeratins (CK5/6), and CD117. Myoepithelial cells express myoepithelial markers such as p63, calponin, p40, S100, smooth muscle myosin, and high molecular weight cytokeratins. Based on the architectural and cytological features, AdCC can be classified as classical, solid-basaloid, and with high-grade transformation (16). The classical pattern is the most frequent, has tubular and cribriform patterns, and has the best prognosis. The solid-basaloid variant presents large solid nests with atypical basaloid cells showing a high mitotic rate. A high-grade transformation is characterized by a distinct high-grade component that confers an aggressive behavior (16).

Figure 1 AdCC, classical pattern, showing infiltrative growth pattern (A) and frequent cribriform architecture (B) (hematoxylin-eosin stain). Immunohistochemistry stain with calponin highlights the myoepithelial component (C), while CD117 (KIT) stains the epithelial component (D). AdCC, adenoid cystic carcinoma.

AdCC classical and the solid-basaloid variant belong to the basal-like intrinsic molecular subtype, assigned to the basaloid/myoepithelial cells component. However, unlike other TNBC histologies, they have fewer gene copy aberrations and express higher levels of MYB and BRCA (17). Most AdCCs harbor MYB-NFIB fusion gene. Others may have MYBL1 rearrangements or MYB amplification.

Classical AdCCs have a good prognosis, are curable with surgery without the need for adjuvant therapy (18-20), and have 10-year survival rates of more than 90% (20,21).

ACC

ACC was described from 20 to 80 years old, and it is considered a tumor with intermediate aggressive potential (18). It is morphologically like the salivary gland counterpart, characterized by eosinophilic or amphophilic cells with granular cytoplasm arranged in microglandular or solid structures. The cells can contain zymogen or other enzymes such as amylase, lysozyme, and alpha-1-antichymotrypsin. The tumor cells are positive for EMA, S100, and lysozyme (18). Although lymph nodal involvement is described, ACC has a favorable prognosis (20). These tumors do not have a specific genomic profile, but among the described alterations, the most frequent is TP53 mutations. Other genomic alterations involve BRCA, PIK3CA, and MLH1, conditions that can offer opportunities for target therapy in the rare cases of advanced disease (22).

Secretory carcinoma

Secretory carcinoma presents cells with ample eosinophilic or vacuolated cytoplasm arranged in microcystic, solid, tubular, or papillary patterns. Intracytoplasmic or extracellular secretion can be seen (Figure 2). The immunohistochemical profile includes expression of S100, carcinoembryonic antigen (CEA) polyclonal, mammaglobin, SOX10, MUC4, CK5/6, and EGFR. They are characterized by the pathognomonic ETV6-NTRK3 fusion that can be demonstrated to confirm the diagnosis by reverse transcription-polymerase chain reaction (RT-PCR) (ETV6 and NTRK3 primers), fluorescent in situ hybridization, next-generation sequencing, or immunohistochemistry (less sensitive) (2).

Figure 2 Secretory carcinoma with solid nests of tumor cells with ample eosinophilic cytoplasm and extracellular secretion (hematoxylin-eosin stain).

These tumors can occur in children and very young women. However, they affect all ages, from 8 to 81 years, in the study of Hoda et al. (23). The prognosis is particularly favorable in children and adolescents, but in older patients and tumors larger than 2 cm, lymph node metastasis can occur. Overall, they have a favorable outcome. In the study of Horowitz et al. with 83 patients from the National Cancer Institute’s Survival, Epidemiology, and End Results (SEER), 10-year overall survival and 10-year cause-specific survival were 76.5% and 91.4% (24).

MEC

MEC is rarely seen in the breast. It is characterized by the presence of basaloid, epidermoid, and mucinous cells, which are arranged in solid or cystic patterns (2). These tumors are graded similarly to the salivary gland counterparts using the following parameters: intracystic component <20%, neural invasion, necrosis, mitosis, and anaplasia (25). The immunohistochemical profile highlights the different cellular types with the expression of low- (CK7) and high- (CK5/7, CK14) molecular weights cytokeratins, p-cadherin, p63, and EGFR. Basbug et al. described a case of breast MEC in the area of burn scars. They performed a comprehensive review of the literature, demonstrating that none of the patients with low- or intermediate-grade died of the disease, as well as those with high-grade tumors but without distant metastasis. Death occurred in all patients with distant metastasis (26).

Polymorphous adenocarcinoma

The very rare polymorphous adenocarcinoma is composed of uniform cells in variable architectural patterns, such as solid, linear, trabecular, cribriform, tubular, and papillary, similar to the salivary gland. The central area is generally solid. The tumor cells express strong BCL2, weak CK7, patchy e-cadherin, basal cytokeratins (CK5/6, CK14), CD117, S100, and focal GFAP (27,28). One patient of the three described in the first report of this histological type in breast died of the disease (27).

TCCRP

TCCRP resembles morphologically the tall cell variant papillary thyroid carcinoma. Foschini et al. described 13 cases under the classification of “solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms” and a review of the literature with 26 cases. The median age of patients was 61 years (range, 48–85 years) (29). This tumor is characterized by solid and/or papillary nests of tumor cells in dense fibrous stroma. Some tumors exhibit areas with follicular structures associated with colloid-like material. Tumor cells can be cuboidal or columnar, some with nuclei at the apical pole (Figure 3). Nuclear grooves, nuclear pseudoinclusions, and psammoma bodies can be observed (30).

Figure 3 TCCRP showing columnar cells with nuclei at the apical pole (A; hematoxylin-eosin stain). Nests of tumor cells are arranged in solid and papillary structures (B; hematoxylin-eosin stain), showing heterogeneous immunostain for CK5/6 (C). TCCRP, tall cell carcinoma with reversed polarity.

The TCCRP harbors IDH2p.Arg172 mutations in over 80% of cases. Immunohistochemical stains for IDH2 can help diagnose this histology (31). It also expresses calretinin and CK5/6, the last in a mosaic pattern, similar to usual ductal hyperplasia (Figure 3) (32).

The TCCRP has an indolent course with a favorable prognosis (18,29).

Low-grade adenosquamous carcinoma

Low-grade adenosquamous carcinoma is a rare variant of metaplastic carcinomas. It involves patients of a broad age range. Van Hoeven et al. reported 32 patients aged 33 to 88 years with a mean of 57 years, similar to a more recent cohort of Lewis et al., with 25 patients aged 35 to 85 years and a median of 66 years (33,34). It is characterized by an admixture of small nests of squamous cells and tubule-glandular structures with minimum atypia and low proliferative activity. These cellular neoplastic groups are haphazardly arranged in a spindle cell stroma surrounded by a lymphocytic infiltrate (2,34). Intraductal papilloma is associated in one-third of cases (34).

Immunohistochemical stains are variably positive for squamous markers (p63, p40) and luminal and basal cytokeratins (CK5/6, CK7, CK8, CK14, CK17) (18).

These tumors have an excellent prognosis, although they can locally recur in about 10% of cases (35). Treatment is locoregional achieving free margins, without the need for adjuvant therapy (34,35).

Fibromatosis-like metaplastic carcinoma

Fibromatosis-like carcinoma is a very rare variant of metaplastic carcinoma, described in patients aged 40 to 80 years (36). It is characterized by bland spindle epithelial cells resembling fibroblasts and myofibroblasts disposed in wavy interlacing fascicles (Figure 4). These cells can present areas of epithelial morphology and foci of squamous differentiation, generally in less than 5% of the tumor area (18). Immunohistochemical stains highlight the epithelial nature of tumor cells with positive cytokeratins and p63, besides vimentin expression (36).

Figure 4 Fibromatosis-like metaplastic carcinoma composed by bland spindle cells that infiltrate the adipose tissue (hematoxylin-eosin stain).

The tumors have a high rate of local recurrence in breast, although no metastatic potential (36).

The role of TILs

TILs are the players of the immune mechanisms involved in the behavior of many types of tumor influencing their prognosis and response to systemic therapies, including immunotherapies. The TILs population is heterogenous, composed of different types of mononuclear immune cells in the tumor stroma, mostly CD8⁺ lymphocytes with cytotoxic properties, but also other cellular types, including FOXP3⁺ cells, with regulatory function (37,38).

The International Immuno-Oncology Working Group standardized the evaluation of TILs (37,39-41). According to these recommendations, TILs can be evaluated either in biopsies (neoadjuvant setting) or in surgical specimens (upfront surgery or residual disease post-neoadjuvant therapy). One 4–5 µm thickness histological section per patient is sufficient. The tumoral area is outlined, excluding necrosis, fibrosis, normal tissue, and in situ carcinoma. Mononucleate cells can be evaluated in the stroma next to the tumor nests [stromal TILs (sTILs)] (Figure 4) or between the neoplastic cells [intratumoral TILs (iTILs)]. Although both iTILs and sTILs have similar values, sTILs are easier to evaluate and more reproducible among pathologists (42). Granulocytes, generally associated with necrosis, are excluded. The sTILs value is expressed as a percentage based on images the site provides (39). If the distribution is heterogeneous, the mean of different areas is used. Peritumoral immune cells and tertiary lymphoid follicles are not included in the TILs population, although they also reflect immune activation.

Besides the heterogeneity, other factors can complicate the TILs evaluation, such as desmoplastic stromal reactions and angiogenesis, conditions in which distinguishing immune cells from other cell types (fibroblasts, endothelial cells) is often challenging. In these cases, the use of immunohistochemistry can aid the identification of immune cells and improve reproducibility among pathologists, with CD8 and CD3 being particularly useful (43).

High levels of TILs are well established as predictive of pathological complete response (pCR) in neoadjuvant treatment. In a pooled analysis of 3,771 patients treated with neoadjuvant therapy from six randomized German Breast Cancer Group trials, TNBC corresponded to 906 patients (24% of the total) (44). A pCR was achieved in 80 (31%) of 260 patients with low TILs (0–10%), 117 (31%) of 373 with intermediate TILs (11–59%), and 136 (50%) of 273 with high TILs (60% or more) (P<0.0001) (44). Ruan et al. evaluated TILs in tumors from 166 patients with TNBC who underwent neoadjuvant therapy. They found a significant correlation between higher TILs and pCR rates, with a threshold of 20% of TILs as an independent predictive variable for pCR (45). With this same cut-off, Abuhadra et al. also found a higher rate of pCR (59% vs. 31%) (46). However, as we can see in Table 1, the threshold for sTILs as predictive for pCR is highly variable among the different studies.

In cases that did not achieve pCR, increasing TILs from the baseline is a favorable prognostic factor (54,55). The 4-year distant disease-free survival was 77.9% in the group with an increase of TILs in the residual disease compared to 41.7% in the cases without an increase (55).

Prognosis is also affected by TILs. The authors of the German Breast Cancer Group study cited above observed longer disease-free survival and overall survival for each 10% TILs increase. The hazard ratio (HR) for disease-free survival was 0.93 [95% confidence interval (CI): 0.87–0.98] (P=0.011), and for overall survival was 0.92 (95% CI: 0.86–0.99) (P=0.032) (44). Similar results were observed in early breast cancer submitted to adjuvant chemotherapy in a pooled analysis of 2,148 patients from nine studies conducted by Loi et al. TILs were associated with longer invasive disease-free survival and overall survival. Node-negative and TILs 30% or more were associated with invasive disease-free survival of 92% (95% CI: 89–98%), distant disease-free survival of 97% (95% CI: 95–99%), and 99% of overall survival (95% CI: 97–100%) (56).

Even in patients with early-stage disease without systemic treatment, TILs maintain their prognostic role. Leon-Ferre et al., in a retrospective pooled analysis, included data of 1,966 patients from 13 centers in North America with early-stage TNBC who were treated by surgery with or without radiotherapy, but without chemotherapy. The median follow-up was 18 years. Patients with stage I tumors and TILs levels of 50% or more, compared to TILs less than 30%, presented longer 5-year distant recurrence-free survival (94%, 95% CI: 91–96% vs. 78%, 95% CI: 75–78%) and longer overall survival (95%, 95% CI: 92–97% vs. 82%, 95% CI: 79–84%). After adjusting for age, tumor size, lymph node status, histological grade, and radiotherapy, each 10% higher TILs increment was associated independently with longer invasive disease-free survival interval (HR, 0.92; 95% CI: 0.89–0.94), recurrence-free survival (HR, 0.90; 95% CI: 0.87–0.92), distant recurrence-free survival (HR, 0.87; 95% CI: 0.84–0.90), and overall survival (HR, 0.88; 95% CI: 0.85–0.91) (P<10e⁻⁶) (57). Similar results were observed by de Jong et al. and Park et al. (58,59). de Jong et al. reported 441 TNBC in patients age <40 years, negative lymph nodes. In this cohort, patients with tumors with high sTILs, defined as 75% or more, presented an excellent prognosis. In this group, the 15-year cumulative incidence of distant metastasis or death was 2.1% (95% CI: 0–5%), very low compared to patients with tumors with sTILs <30% (38.4%, 95% CI: 32.1–44.6%). Additionally, each 10% of increment of TILs were associated with a decreased risk of death (58). This young age population without chemotherapy was also explored in the study of Wang et al. to compare outcomes according BRCA1 status (60). The study included 399 patients with known BRCA1 status: 26.3% with germline mutation, 5.3% with somatic mutation, 36.6% with promoter methylation, and 31.8% with no BRCA1 alteration. They confirmed the prognostic value of sTILs, although the impact was higher in the group of BRCA1 methylation. Patients with tumor BRCA1 methylated and ≥50% of sTILs presented a 97% 15-year overall survival (95% CI: 92.9–100%). On the other hand, patients with germline BRCA1 mutation presented 50.8% of 10-year overall survival (95% CI: 39.7–65%) (60). Park et al. analyzed data from 476 patients from four centers with a broader age range (median age of 64 years) and median tumor size of 1.6 cm, 83% were node-negative and did not receive chemotherapy. TILs were associated with improved prognosis for each 10% increment. In patients with stage I disease and sTILs ≥30%, 5-year invasive disease-free survival was 91% (95% CI: 84–96%), distant disease-free survival was 97% (95% CI: 93–100%), and overall survival 98% (95% CI: 95–100%) (59).

The favorable prognosis associated with TILs could be confirmed by various authors in the literature, either in the neoadjuvant or in the adjuvant settings (61-63). The two metanalysis conducted by Gao et al. (64) and Li et al. (65) reinforced the predictive and prognostic roles of TILs in the TNBC. Based on this evidence (level 1b evidence), the WHO Classification of Tumors, in their 5^th edition (2), recommended the inclusion of this information in pathological reports following the International Immuno-Oncology Working Group scoring standardizing (39-41).

In the 5^th edition of WHO Classification of Breast Tumors, the carcinomas that were previously classified as medullary, atypical medullary, or carcinoma with medullary features, characterized by high tumor grade, pushing margins, syncytial architecture with extensive necrosis, and high TILs population, are now described as NST with medullary pattern (2). The better prognosis associated with this pattern is attributed to the high TILs, suggesting that the medullary pattern in breast carcinomas of NST corresponds to one end of the spectrum of tumors rich in TILs.

The predictive and prognostic role of TILs in TNBC is well established, but there are some concerns about their clinical use. The first is the subjectivity of pathologists’ interpretation (66-69). The International Immuno-Oncology Working Group scoring standardizing provided well-defined criteria for pathologists, and the impact could be observed in some studies (39,70,71). To improve the agreement between pathologists, a partnership between experts from the U.S. Food and Drug Administration and the international pathologist’s community created a freely available online medical education course (72). This course is interactive and provides expert commentaries about each case. Besides, it identified the common difficulties in the interpretation.

Most difficulties in evaluating the TILs are related to spatial density heterogeneity (38). It results from the intricate mechanisms involved in immune activation and can impact the predictive and prognostic role of TILs. The same value of TILs in different tumors, according to the fraction of stroma and the distance between immune cells and tumor cells, can have different biological meanings. The complexity of the variables involved in the heterogeneity of TILs density needs quantification through computer-assisted pathology tools. For now, the scoring of TILs is based on pathologist visual assessment. It is fundamental to have well-established criteria to develop artificial intelligence (AI)-assisted methods (73). The AI-assisted analysis of TILs has great potential. However, there are many challenges, such as the influence of preanalytical conditions, quality of the histological sections, selection of the correct areas, spatial heterogeneity, and validation (74,75).

Most of the TILs’ mononucleate cells are T cells (CD3⁺) and CD8⁺ (cytotoxic lymphocytes), although their composition includes other T-cells, B-cells, and macrophages (CD4⁺, FOXP3, CD68) (38,43,51,76,77). In cases where the differentiation of TILs from other stroma cells is doubtful, immunohistochemical testing can help score and improve the concordance between pathologists, mainly using CD3 and CD8 immunostains (43).

The different types of immune cells in the composition of TILs do not impact its predictive and prognostic value, but the expression of programmed death-ligand 1 (PD-L1) can offer additional information. PD-L1 is expressed by different types of cells, and it is the ligand of programmed death 1 (PD-1), expressed by CD8-positive lymphocytes. PD-L1 is a powerful inhibitor of the cytotoxic activity of TILs that occurs when it binds to PD-1, corresponding to one of the immune evasion mechanisms. The rationale of immunotherapy with PD-1 or PD-L1 inhibitors is blocking this evasion mechanism. Although PD-L1 can be expressed by tumor cells and immune cells, in TNBC, it is present mainly in immune cells (78,79). PD-L1 immunohistochemical expression is a biomarker for immunotherapies in advanced/recurrent TNBC using different companion assays (79-81). It is interesting to observe that the expression of PD-L1 in early disease is not necessary to predict the benefit of immunotherapy, probably because it reflects an evasion mechanism that will appear later in the disease course.

TILs correspond to a continuous variable deeply involved in the prognosis of TNBC. Different thresholds, from 10% to 60%, were utilized for predicting chemotherapy response and prognosis, so it is hard to define which subgroup could be safely spared from more aggressive systemic treatments. There is a tendency to consider 30%. However, observing the pCR rates according to TILs, it is not evident that only TILs could define a subset of tumors to de-escalate treatment. Other characteristics are likely involved, such as Ki-67 and histologic grade.

In summary, TILs play a critical role in the immune response to tumors and are a key prognostic and predictive factor in TNBC. Despite the obstacles in their evaluation, such as subjectivity, heterogeneous immune cell composition, and spatial density heterogeneity, high levels of TILs have consistently been associated with better response to neoadjuvant therapy and improved survival outcomes in both early and advanced settings. The need for standardization in the use of TILs is urgent, particularly in determining thresholds for de-escalating therapy in TNBC.

The role of Ki-67

Ki-67 antigen, product of the gene MKI67, can be assessed by immunohistochemistry by the monoclonal antibody Ki-67. It is expressed in nuclei of all cell cycle phases except for quiescent status G0 (82).

High Ki-67 in TNBC was associated with chemotherapy response but poor prognosis. Keam et al., more than a decade ago, presented 105 TNBC treated with neoadjuvant docetaxel/doxorubicin chemotherapy. Higher pCR was observed in patients with tumors with Ki-67 ≥10% (18.2% vs. 0%). However, despite more pCR, they presented lower disease-free (P=0.0053) and overall survival (P=0.0187) (83).

Abuhadra et al. prospectively studied 408 patients with early-stage TNBC submitted to neoadjuvant therapy to construct a model to predict pCR. They observed a pCR rate of 41% in the entire cohort. In the final model, a high Ki-67, defined as >35%, associated with high sTILs, defined as 20% or higher, were associated with a pCR rate of 65% (46).

Zhu et al. explored the prognostic role of Ki-67 through analysis of 1,800 patients with early TNBC submitted to surgery, followed by chemotherapy (85.22%) and radiotherapy (39.22%). They found a cut-off of 30% as an independent factor for overall and disease-free survival prognosis (84). TNBCs with Ki-67 ≤30% correspond to 5–10% of all TNBCs, and almost half have Ki-67 less than 10% (85). Srivastava et al. reported 70 cases of TNBC with low Ki-67 (≤30%) that presented a low pCR (11%), 90% were grade 1 or 2, and 80% had apocrine pattern (85). The apocrine pattern was explored by Wang et al. together with histiocytoid features (86). The authors presented clinicopathological and molecular features of 18 non-high-grade TNBC with apocrine and/or histiocytoid features, all with Ki-67 ≤20%. AR was positive in 17 (94.4%), and the average age was 67.2 years (range, 38–91 years), suggesting that they were of LAR molecular subtype. Four patients received neoadjuvant therapy, but none achieved pCR. One patient refused adjuvant therapy. All the others received adjuvant chemotherapy. None of the patients died from the disease.

Despite the lack of uniformity of the Ki-67 immunohistochemical analysis among the different studies, we cannot deny that it is a powerful predictor of chemotherapy response and indicates aggressive biology. Jang et al. compared two methods of evaluation of Ki-67 in 493 luminal carcinomas: average and hot spot. They found more reproducibility with the average method: counting the positive tumor cells in images from three different tumor areas and calculating the average percentage of positive cells. However, the predictive value for recurrence was the same for both methods (87). These authors illustrate the message we can retrieve from Ki-67 expression: a precise marker of cellular proliferation and prognosis, regardless of the method utilized, although not standardized and validated in clinical trials. TNBCs present Ki-67 >30% in about 90% of cases. The results of the studies mentioned earlier in this topic suggest that the benefit of chemotherapy in early-stage TNBC with ≤30% is doubtful.

Concluding, high Ki-67 levels have been linked to increased chemotherapy response but poor prognosis. Low levels are seen in TNBC with a more indolent clinical course, such as those with apocrine or histiocytoid features, where the benefit of chemotherapy is questionable. However, the lack of standardized cut-offs for Ki-67 expression highlights the need for further validation to optimize clinical use.

De-escalation strategies

The standard treatment for TNBC measuring >5.0 mm includes chemotherapy, although we can consider subsets of early-stage low-risk disease for omitting it and/or using other drugs. The candidates for this more conservative approach include favorable histologies, high-TILs tumors, low-Ki-67 tumors, and early-stage tumors that achieved pCR (Figure 5). However, the data supporting new standards are very limited.

Figure 5 Potential early TNBC candidates to de-escalation strategies. TIL, tumor-infiltrating lymphocyte; TNBC, triple-negative breast cancer.

The special histological types with more favorable prognoses comprise distinct tumors, each very rare and with a peculiar genomic profile, summarized in Table 2. As we have discussed previously, all these tumors have more favorable prognoses compared to carcinomas of NST. However, data are limited for most of them because of their rarity (18-20).

High levels of TILs can identify a subset of early-stage TNBC for whom we can consider omitting systemic treatment. Although an exact cut-off that fits all cases is not well established, based on the data from some publications, we consider sTILs above 30% as potential candidates (57-59,84).

The benefit of chemotherapy is unclear in tumors with low Ki-67 (84-86), mainly in patients with a tumor size ≤2 cm, lymph node-negative, and with stage I disease (84).

Patients with early-stage disease achieving pCR have excellent prognosis, with or without post-neoadjuvant chemotherapy. In the Spring et al. (88) meta-analysis, the authors analyzed 52 publications with 27,895 patients of all tumor types. Among TNBC, n=2,039 patients, pCR was associated with better event-free survival [HR, 0.18; 95% probability interval (PI): 0.10–0.31] and improved survival in 778 patients (HR, 0.20; 95% PI: 0.07–0.35). TNBC with pCR was associated with a 5-year event-free survival of 90% (95% PI: 81–95%), while those without pCR had a 5-year event-free survival of 57% (95% PI: 41–70%). Five-year survival among patients with pCR was 84% (95% PI: 60–97%), while those without pCR had a 5-year overall survival of 47% (95% PI: 13–77%). The additional adjuvant chemotherapy did not impact the results.

The prospective phase II neoadjuvant West German Study Group (WSG)-ADAPT TN Trial, part of the ADAPT umbrella protocol, a randomized study 1:1 to nab-paclitaxel plus gemcitabine or carboplatin. The primary endpoint was pCR. The omission of additional anthracycline-containing chemotherapy was allowed only in patients who achieved pCR, but it was not associated with a better invasive disease-free survival (HR, 1.29; 95% CI: 0.41–4.02). In the multivariable analysis, besides pCR rate, nodal status and high sTILs were independently associated with better prognosis (89).

De-escalation strategies omitting adjuvant or post-neoadjuvant cytotoxic chemotherapy have been discussed more and more for TNBC. However, we need to reinforce the knowledge about biomarkers already in use and explore new ones to have robust and safe criteria for de-escalation and escalation treatments. Numerous biomarkers have been explored in TNBC, such as TILs, PD-L1, tumor mutational burden (TMB), Ki-67, HER2, HER3, PI3K/AKT/mTOR pathway molecules, AR, DNA homologous recombination deficiency, microsatellite instability, EGFR, forkhead box C1 (FOXC1), among others (9,90-95). Recently, less aggressive systemic treatments, either omitting anthracyclines or the adjuvant pembrolizumab after neoadjuvant pembrolizumab plus chemotherapy, have been proposed according to the TNBC-DX genomic test, a clinical tool based on the HER2-DX assay, developed for HER2-positive breast cancer. It is composed of a 10-gene core immune gene module, 4-gene tumor cell proliferation, tumor size, and nodal staging (14). TNBC-DX offers two scores: one for predicting pCR and the other for risk (distant disease-free survival, event-free survival, and overall survival).

Some of the ongoing trials in de-escalation treatment in TNBC are summarized in Table 3.

Strengths and limitations

The strength of this review is a comprehensive literature search, including English literature, without any restrictions. It covers special clinical conditions without standard management but requires less aggressive approaches. We present literature-based evidence for identifying tumors that can be spared from the current treatment indicated for TNBC. This review’s potential limitations begin with the selection bias from the pathologist’s perspective. Despite the careful search of the literature, some studies may be missed. Besides, the rarity of conditions here analyzed, with little robust literature available, contributes to including heterogeneous literature.

Conclusions

Low-risk TNBC represents a distinct subgroup of TNBC patients with favorable prognosis and may benefit from de-escalation strategies aimed at reducing treatment intensity and toxicity. However, careful patient selection and personalized treatment approaches are essential to ensure that de-escalation strategies do not compromise oncological outcomes. Ongoing research efforts are focused on identifying reliable biomarkers and developing targeted therapies to further optimize the management of low-risk TNBC and improve patient outcomes.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-28/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-28/coif). F.M.C. received honorary for lectures and speaker from GlaxoSmithKline Ser U/Ltd, Merck Sharp Dohme Farmaceutica, AstraZeneca, Daiichi Sankyo Brasil, Produtos Roche Químicos e Farmaceuticos S.A., Pfizer. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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