Editor's Note: In recent years, significant advancements have been made in the treatment of triple-negative breast cancer (TNBC), particularly in the field of biomarker research. To delve deeper into this, Cancer Outlook invited Dr. Qiang Liu from Sun Yat-sen Memorial Hospital, Sun Yat-sen University to provide an in-depth analysis of two recent landmark studies. These studies explore the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage TNBC patients who have not undergone chemotherapy. The findings from these studies reveal a correlation between TIL levels and patient survival, offering a new perspective for identifying patients with a good prognosis who may not require chemotherapy. Additionally, Professor Liu shares insights from his own research on circulating tumor DNA (ctDNA) in breast cancer treatment, underscoring the importance of precision medicine in managing TNBC.Dr. Qiang Liu:
In recent years, the field of TNBC treatment has seen continuous progress. Today, I would like to share insights from two relevant articles.
The first article, titled “Tumor-Infiltrating Lymphocytes (TILs) in Triple-Negative Breast Cancer (TNBC),” was published in April this year in the renowned JAMA (Journal of the American Medical Association). The study aimed to explore the relationship between TIL abundance in breast cancer tissues and survival rates in early-stage TNBC patients who had not received chemotherapy. The data for this study was collected from 13 centers across North America, Europe, and Asia, involving 1,966 patients diagnosed with TNBC between 1979 and 2017. These patients underwent surgery and/or radiation therapy but did not receive adjuvant or neoadjuvant chemotherapy.
Previously, it was widely believed that TNBC was highly aggressive and that chemotherapy was almost mandatory (this belief is prevalent in China as well). However, the patients included in this study had not undergone chemotherapy. In my view, this is one of the standout features of the study and a key reason why it was published in JAMA.
The primary endpoint of the study was invasive disease-free survival (iDFS). Secondary endpoints included recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS). Associations were evaluated using a multivariable Cox model stratified by participating center. The study included 1,966 TNBC patients (median age 56 years [IQR, 39-71]; most tumors were T1 (60%) or T2 (36%), lymph node-negative (87%), and stage I (55%)). Among stage I TNBC patients, 65% were T1cN0. The median TIL level was 15% (IQR, 5%-40%). A total of 417 patients (21%) had TIL levels of 50% or higher (median age 41 years [IQR, 36-63]), and 1,300 patients (66%) had TIL levels below 30% (median age 59 years [IQR, 41-72]). Among patients aged 50 years and older, 4% had TIL levels of 75% or higher.
The study results showed that higher TIL levels were associated with improved iDFS, RFS, DRFS, and OS in a multivariable Cox model that included age, tumor size, lymph node status, histological grade, and receipt of radiotherapy (all likelihood ratio P-values <10^-6). For every 10% increase in TIL levels, the risk of iDFS events decreased by 8% (HR, 0.92 [95% CI, 0.89-0.94]), the risk of RFS events decreased by 10% (HR, 0.90 [95% CI, 0.87-0.92]), the risk of DRFS events decreased by 13% (HR, 0.87 [95% CI, 0.85-0.90]), and the risk of death decreased by 12% (HR, 0.88 [95% CI, 0.85-0.91]).
TIL Levels and Outcomes in Stage I and II Node-Negative TNBC
The 1,966 patients included 1,080 stage I TNBC patients, whose 5-year iDFS rate was 73% (95% CI, 70%-75%), RFS rate was 77% (95% CI, 75%-79%), DRFS rate was 82% (95% CI, 80%-83%), and overall survival rate was 85% (95% CI, 83%-87%). For patients with TIL levels ≥50%, the 5-year iDFS rate was 84% (95% CI, 80%-88%), RFS rate was 89% (95% CI, 86%-93%), DRFS rate was 94% (95% CI, 91%-96%), and overall survival rate was 95% (95% CI, 92%-97%). Meanwhile, for patients with TIL levels <30%, the 5-year iDFS rate was 69% (95% CI, 66%-72%), 5-year RFS rate was 73% (95% CI, 70%-76%), DRFS rate was 78% (95% CI, 75%-80%), and overall survival rate was 82% (95% CI, 79%-84%).
The study also included 779 stage II TNBC patients, whose 5-year iDFS rate was 62% (95% CI, 59%-64%), RFS rate was 65% (95% CI, 62%-68%), DRFS rate was 69% (95% CI, 66%-72%), and overall survival rate was 73% (95% CI, 70%-76%). Notably, among the 56 patients with TIL levels ≥75%, the 5-year iDFS rate was 85% (95% CI, 78%-93%), RFS rate was 91% (95% CI, 83%-96%), DRFS rate was 96% (95% CI, 92%-100%), and overall survival rate was 98% (95% CI, 95%-100%).
TILs are lymphocytes that infiltrate tumor tissues, with a significant portion being T cells specific to tumor-associated antigens. These cells are considered a specific immune response against tumor cells. Previous studies have shown that the stronger the immune response, the higher the TIL levels, leading to better responses to chemotherapy, higher rates of pathological complete response (pCR), and overall better patient outcomes. The study also found that younger patients tended to have higher TIL levels. For example, among the 417 patients with TIL levels ≥50%, the median age was 41 years [IQR, 36-63], while among the 1,300 patients with TIL levels <30%, the median age was 59 years [IQR, 41-72].
The study’s data indicate that some early-stage TNBC patients who did not receive adjuvant or neoadjuvant chemotherapy still had favorable survival outcomes, with high TIL levels in breast cancer tissues associated with significantly better survival rates. These results suggest that the abundance of TILs in breast tissue is an important prognostic factor for early-stage TNBC patients, independent of chemotherapy.
For stage I TNBC patients with small tumors and no lymph node metastasis, the absolute benefit of chemotherapy is currently unclear. No biomarker is available to identify those who might derive little benefit from neoadjuvant or adjuvant chemotherapy but have an excellent prognosis. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data specifically for stage I TNBC is lacking. Following the April JAMA article, another study titled “Tumor-Infiltrating Lymphocyte Assessment in Patients with Stage I Triple-Negative Breast Cancer Not Receiving Chemotherapy” was published in JAMA Oncology in June of this year. This cohort study used data from the Netherlands Cancer Registry, including patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who had not received neoadjuvant or adjuvant chemotherapy. Data analysis was conducted from February to October 2023.
The primary endpoint was breast cancer-specific survival (BCSS) at 5, 10, and 15 years, with predefined sTIL cutoffs of 30%, 50%, and 75%. Histological subtype, grade, and lymphovascular invasion were centrally reviewed using hematoxylin and eosin-stained slides, and sTIL levels were scored according to the guidelines of the International Immuno-Oncology Biomarker Working Group.
From 2005 to 2015, the study enrolled 4,511 stage I TNBC female patients (mean [SD] age at diagnosis, 64.4 [11.1] years; median follow-up time, 11.4 [95% CI, 10.9-11.9] years), of whom 2,109 did not receive neoadjuvant or adjuvant chemotherapy. After screening, sTIL data were obtained for 1,041 stage I patients. The majority of tumors (952 cases [91.5%]) were invasive cancers of no special type. Most patients (548 cases [52.6%]) had pT1cN0 tumors, and the median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels <30%, 266 (25.6%) had sTIL levels ≥30%, 203 (19.5%) had sTIL levels ≥50%, and 141 (13.5%) had sTIL levels ≥75%.
Patients with pT1abN0 tumors had better prognoses than those with pT1cN0 tumors, with 10-year BCSS rates of 92% (95% CI, 89%-94%) and 86% (95% CI, 82%-89%), respectively.
Overall, higher sTIL levels (≥30%) were associated with better BCSS compared to lower levels (<30%) (96% vs. 87%; HR, 0.45; 95% CI, 0.26-0.77).
For patients with pT1c tumors, sTIL levels ≥50% were associated with better outcomes compared to sTIL levels <50% (HR, 0.27; 95% CI, 0.10-0.74), with a 10-year BCSS of 95%. Patients with sTIL levels ≥75% had even better outcomes, with a 10-year BCSS of 98%.
Overall, with a median follow-up of 11.4 years, patients in the study cohort had favorable survival outcomes. Those with high sTIL levels who did not receive neoadjuvant or adjuvant chemotherapy had better 10-year BCSS. For TNBC patients, 10-year survival is almost equivalent to a cure. These findings further support the role of sTILs as a key biomarker for treatment optimization in prospective clinical trials for this patient group.
Regarding whether stage I TNBC patients should undergo chemotherapy, recommendations from major guidelines and consensus statements vary. The 2024 ESMO Clinical Practice Guidelines: Diagnosis, Treatment, and Follow-Up of Early Breast Cancer—Applicable to Pan-Asian Populations recommend neoadjuvant chemotherapy for T1c TNBC patients. The 2023 St. Gallen International Expert Consensus on Early Breast Cancer also supports chemotherapy for T1c patients but suggests that chemotherapy for T1a patients should be based on other risk factors. The 2024 NCCN Clinical Practice Guidelines in Oncology for Breast Cancer, Version 3 recommend no chemotherapy for T1a patients, while chemotherapy may be considered for high-risk T1b patients (but is not mandatory), and T1c patients are strongly recommended to undergo chemotherapy. In summary, guidelines and consensus statements generally recommend chemotherapy for T1c patients, with the main controversy surrounding the treatment strategy for T1a and T1b patients.
Comparing the patient cohorts in these two studies, the Dutch study involved 4,511 patients diagnosed with stage I TNBC from 33 pathology centers, of whom 2,109 did not receive neoadjuvant or adjuvant chemotherapy, with sTIL levels determined in 1,041 cases. In this study, TNBC was defined as ER and PR expression <10%, with no ERBB2 overexpression and/or gene amplification. Meanwhile, the study involving TNBC patients from 13 centers across North America, Europe, and Asia primarily used ER and PR expression <1% as a criterion, although three centers applied the 10% threshold. Although the inclusion criteria differed, both studies fall within the reasonable scope of TNBC definitions.
Additionally, the Dutch study data was sourced from the Netherlands Cancer Registry, so it only includes OS and BCSS data, without DRFS and RFS data, which is another distinction from the study involving centers in North America, Europe, and Asia.
Overall, these studies provide the following key insights:
- TNBC is not as daunting as it once seemed—many patients can be completely cured.
- In the era of chemotherapy-dominated treatment, some TNBC patients may only need surgery and radiotherapy. However, identifying these patients is a clinical challenge. These two articles suggest that TILs could serve as a biomarker for TNBC patients, not only predicting their response to chemotherapy and overall prognosis but also identifying early-stage patients who may not require systemic chemotherapy and could do well with only localized treatment. However, both studies are retrospective and may have selection biases, and prospective clinical studies are needed to validate these findings.
As clinicians, we do not want to see patients suffer disease recurrence due to delayed treatment, nor do we want to subject them to unnecessary treatments that could cause harm. In recent years, the concept of breast cancer as a systemic disease has been challenged, as a significant portion of breast cancer patients may only need localized treatment (surgery, radiotherapy) without the need for chemotherapy, immunotherapy, or other systemic treatments. The key lies in reliably identifying patients with primarily localized tumors. Both studies suggest that TILs could be a factor in prognostic stratification. If TILs are to be used as an indicator for determining whether to administer chemotherapy, further prospective studies are needed to confirm their validity. Another similar biomarker is circulating tumor DNA (ctDNA). High ctDNA levels indicate that tumor cells have entered the bloodstream, posing a high risk of systemic metastasis, which necessitates sufficient and effective systemic treatment. Conversely, if ctDNA levels are low or nearly absent, it may suggest that the patient has primarily localized tumors, potentially sparing them from unnecessary or overly aggressive systemic therapy.
Our center (Breast Cancer Center at Sun Yat-sen Memorial Hospital, Sun Yat-sen University) has also explored the clinical application of ctDNA in early-stage breast cancer patients, accumulating significant experience over nearly a decade. We have demonstrated the value of ctDNA in monitoring neoadjuvant treatment efficacy and stratifying recurrence risk, adding a new method for clinical assessment in the perioperative period of breast cancer. An article on this topic was published in JCO Precision Oncology in 2020. After its publication, the article was recognized by the American Society of Clinical Oncology (ASCO) as one of the “Top 5 Most Popular articles for ASCO’s journals in 2020.” Currently, another article from our center on ctDNA in early-stage TNBC is under review, which shows that 21.7% of early-stage TNBC patients (including some stage IIIc patients) had completely negative ctDNA throughout their treatment, and none of these patients experienced recurrence or metastasis during follow-up. This finding suggests that ctDNA levels are independent of and superior to traditional TNM staging in reflecting a patient’s systemic tumor burden, and we look forward to the publication of this data to provide more evidence-based medicine for ctDNA research. Based on these findings, we are also designing clinical studies to explore the possibility of sparing or de-escalating chemotherapy based on ctDNA levels.
In addition to the two biomarkers I mentioned, there are many others related to TNBC prognosis prediction (such as PD-L1). In my opinion, with the emergence of more related biomarkers, the field of TNBC treatment will undergo significant changes in the next five years, with TNBC treatment becoming increasingly precise.
Dr. Qiang Liu
- Professor, Chief Physician, Researcher, PhD Supervisor
- Director of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Sun Yat-sen University
- Executive Vice President of the Yixian Breast Cancer Hospital, Director of the Breast Cancer Center, and Chief of Breast Surgery
- Member of the ESO-ESMO International Consensus Group on Young Breast Cancer
- Executive Member and Deputy Secretary-General of the Breast Cancer Committee of the Chinese Society of Clinical Oncology
- Executive Member of the Breast Cancer Committee and the Molecular Medicine Committee of the Chinese Anti-Cancer Association
- Chairman of the Breast Disease Committee of the Guangdong Medical Association
- Deputy Editor-in-Chief of the Chinese Journal of General Surgery and the Chinese Journal of Endocrine Surgery
- PhD in Surgery from the National University of Singapore, former Lecturer at Dana-Farber Cancer Institute, Harvard University
- Leader of multiple national key projects, including several key projects funded by the National Natural Science Foundation of China and key international cooperative projects. He pioneered the application of liquid biopsy and immunotherapy in breast cancer and initiated and developed the first expert consensus on the diagnosis and treatment of young breast cancer in China. In 2020, he was honored with the “Exemplary Model of National Physicians” by People’s Daily. He specializes in the diagnosis, surgery, and comprehensive treatment of breast cancer, particularly in challenging breast-conserving surgeries, individualized precision treatment of young breast cancer, and triple-negative breast cancer.
