Liquid Biopsy in Triple-Negative Breast Cancer: A Simple Blood Test That Could Revolutionize Treatment

Table of Contents

• Key Points
• Background: Understanding Triple-Negative Breast Cancer
• What Is a Liquid Biopsy?
• Circulating Tumor Cells in Early TNBC
• Measuring Treatment Response Before and After Surgery
• Circulating Tumor Cells in Metastatic TNBC
• Detecting Targetable Genetic Alterations
• Detecting Tumor Heterogeneity
• ctDNA in Early TNBC: Detecting Minimal Residual Disease
• Using Liquid Biopsy to Measure Neoadjuvant Therapy Effectiveness
• Ongoing Clinical Trials in Liquid Biopsy for TNBC
• Clinical Implications: What This Means for Patients
• Limitations of Current Liquid Biopsy Technology
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Liquid biopsy uses blood tests to detect ctDNA or circulating tumor cells, giving a real-time view of TNBC. It is noninvasive.
• In early TNBC, ctDNA detection after surgery can identify minimal residual disease and higher relapse risk, as shown before.
• In the I-SPY 2 trial, patients who cleared ctDNA by surgery were more likely to achieve pCR, while persistent ctDNA raised recurrence risk.
• Liquid biopsy can detect targetable mutations like PIK3CA in metastatic disease, potentially guiding therapy without tissue biopsy.
• Limitations exist: not all tumors shed detectable ctDNA, and trial results vary, so it is not yet a replacement for tissue biopsy.

Background: Understanding Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a particularly challenging form of breast cancer. It is defined by what it lacks: TNBC tumors test negative for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). Because these three common targets for breast cancer treatment are absent, TNBC does not respond to hormone therapy or HER2-targeted drugs like many other breast cancers do.

TNBC represents approximately 10%-15% of all breast cancers. It is more common in women younger than 40 years and is considered the most aggressive and highly heterogeneous of all breast cancer subtypes. Its aggressive nature means that finding reliable ways to detect the disease early, predict treatment response, and monitor for relapse is absolutely critical.

Currently, treatment decisions for TNBC rely on several prognostic and predictive factors, including immunohistochemical biomarkers such as programmed death-ligand 1 (PD-L1) and germline BRCA1/2 mutations (inherited mutations in the BRCA1 or BRCA2 genes) which are present in about 10%-20% of TNBC cases and lead to a condition called homologous recombination deficiency—a defect in the cell's ability to repair DNA damage. Among metastatic TNBC cases, approximately 20%-38% of patients express PD-L1, a protein that helps tumors evade the immune system and is a target for immunotherapy drugs.

Another important biomarker is the presence of tumor-infiltrating lymphocytes (TILs)—immune cells that have invaded the tumor tissue. Elevated TIL counts are well established as a favorable prognostic factor, associated with better prognosis, improved response to immunotherapy, and higher rates of pathologic complete response (pCR), meaning no cancer cells remain at the time of surgery. The location of these lymphocytes also matters: the best outcomes occur when TILs infiltrate both the tumor epithelium (the layer of cells lining the tumor) and the surrounding stroma (supportive tissue). Conversely, TILs restricted to the tumor margins or completely absent are associated with the worst prognosis. The International Immuno-Oncology Biomarker Working Group recently confirmed the favorable prognostic role of TIL abundance in breast cancer tissue among patients with early-stage TNBC who did not receive adjuvant (post-surgery) or neoadjuvant (pre-surgery) chemotherapy.

Given the limitations of existing biomarkers, researchers are increasingly turning to liquid biopsy—a noninvasive blood test that can provide real-time information about the tumor's genetic makeup and behavior. This approach could help doctors determine treatment efficacy in both the neoadjuvant and adjuvant settings, detect early relapse, and monitor how the tumor evolves (clonal evolution) during treatment.

What Is a Liquid Biopsy?

Liquid biopsy involves analyzing components released by tumors into bodily fluids. These include cell-free DNA (cfDNA)—fragments of DNA circulating in the blood—as well as circulating tumor cells (CTCs) (intact cancer cells that have broken away from the tumor), extracellular vesicles (tiny sacs released by cells), and RNA. These components can be detected in blood, urine, cerebrospinal fluid, or bone marrow, offering a minimally invasive window into the disease.

When mutations are found in cfDNA that match the tumor's genetic profile, this is referred to as circulating tumor DNA (ctDNA). These mutations serve as highly specific markers for cancer. One fascinating characteristic of ctDNA is that its half-life in circulation ranges from just 16 minutes to 2.5 hours. This means ctDNA analysis provides a real-time snapshot of the disease at any given moment—unlike traditional tissue biopsies, which capture only a single point in time and a single location within the tumor.

CTC levels also carry important prognostic information. In metastatic breast cancer, the number of CTCs can stratify patients into two prognostic groups: stage IV indolent (slower-growing disease) or stage IV aggressive, based on a threshold of 5 or more CTCs per 7.5 ml of blood. Patients in the stage IV indolent group exhibit a longer median overall survival (the time from diagnosis or treatment start until death from any cause).

Circulating Tumor Cells in Early TNBC

Several landmark studies have investigated the prognostic value of CTCs in early-stage TNBC. In the adjuvant SUCCESS A trial, researchers evaluated the presence of CTCs before chemotherapy and again two years after chemotherapy in 1,087 patients with high-risk breast cancer. Two years after completing chemotherapy, 198 patients (about 18%) were CTC positive. This CTC positivity was found to be an independent, statistically significant prognostic factor for poor overall survival (OS) and disease-free survival (DFS—the time after treatment during which no cancer is detected). Importantly, the CTC status at the 2-year follow-up was independent of baseline CTC status. Patients who were CTC positive both at baseline and at the 2-year follow-up had the worst OS and DFS outcomes of all.

These findings matter because they suggest that a simple blood test performed years after initial treatment could identify patients at higher risk of relapse who might benefit from additional or different treatment strategies.

Measuring Treatment Response Before and After Surgery

In the neoadjuvant setting (chemotherapy given before surgery to shrink tumors), CTCs have shown significant clinical value. In patients with nonmetastatic TNBC, the presence of one or more CTCs after completing neoadjuvant chemotherapy (NAC) was associated with significantly decreased overall survival and relapse-free survival.

A major meta-analysis conducted by Bidard et al. pooled data from 21 studies that detected CTCs using the FDA-cleared CELLSEARCH methodology in 2,030 patients with early breast cancer, of whom 25.8% had TNBC. The authors demonstrated that CTCs have a prognostic role in patients with early breast cancer treated with NAC, independent of tumor subtype. This means that CTC status adds valuable prognostic information on top of what doctors already know from tumor characteristics, helping to refine current prognostic models.

CTC detection after surgery or during adjuvant (post-surgery) therapy has also been associated with poor prognosis. In one study of 286 women with early TNBC, researchers evaluated CTC levels after surgery. Patients with more than 5 CTCs per 7.5 ml of blood experienced worse outcomes compared to those with fewer than 5 CTCs. Specifically, patients with higher CTC counts had a recurrence rate of 22.4% at seven days post-surgery—a striking figure that highlights how quickly residual disease can manifest.

Circulating Tumor Cells in Metastatic TNBC

The prognostic value of CTC enumeration has been demonstrated in metastatic breast cancer using several studies with the FDA-cleared CELLSEARCH methodology, though multiple other detection technologies are now available. In metastatic TNBC, higher CTC counts are consistently linked to poorer outcomes.

Patients with CTC counts at or above the threshold of 5 per 7.5 ml of blood before treatment, and those who fail to clear these cells during treatment, have significantly worse outcomes compared with patients who maintain a CTC count of less than 5 after starting systemic therapy. Another study showed that patients with CTCs of 5 or more per 7.5 ml, and/or those who experienced an increase in CTC counts at 3-5 weeks and/or 6-8 weeks after the start of treatment, had decreased progression-free survival (PFS—the time during and after treatment during which the disease does not worsen) and overall survival.

However, not all results have been positive. The SWOG S0500 trial did not demonstrate improved clinical outcomes in any metastatic breast cancer subtype, including TNBC, when using early CTC-guided treatment changes. This suggests that merely detecting and responding to rising CTC counts does not automatically translate into better survival—therapies must still be effective against the specific cancer biology.

In a retrospective analysis, investigators classified patients into three prognostic subgroups based on baseline CTC enumeration, confirming that patients with higher CTC counts per 7.5 ml of blood had worse outcomes. Additionally, in the TBCRC 001 trial, a head-to-head comparison of two CTC enumeration methods—CELLSEARCH and IE/FC (immunofluorescence/flow cytometry)—showed high concordance between the techniques. CTC enumeration performed 7-14 days after treatment initiation was correlated with time-to-progression, suggesting that CTCs may serve as an early marker of response to targeted therapy and may be a more reliable indicator of progression risk than baseline counts.

One particularly concerning feature of CTCs in TNBC is the formation of multicellular CTC clusters. These cell clusters are associated with worse outcomes compared to single CTCs. In fact, CTC clusters can promote the development of metastatic disease 20 to 100 times more frequently than a single CTC. This finding underscores the aggressive biology of TNBC and the importance of detecting and monitoring these clusters.

Detecting Targetable Genetic Alterations

Beyond simply counting CTCs, analyzing their molecular characteristics can reveal actionable genetic information. Abreu et al. immunoisolated CTCs from a cohort of 32 patients with stage III and IV TNBC using CELLSEARCH technology. The samples were characterized using a panel of genes related to cancer aggressiveness and plasticity. The expression signature identified in these CTCs was associated with a hybrid epithelial-mesenchymal transition (EMT) status—a state in which cancer cells acquire properties that help them invade and spread—and a stem-like phenotype (cells with the ability to self-renew and seed new tumors). These aggressive cells were detected in 42% of patients, and 3 of these patients also had CTC clusters. All CTC-positive patients were metastatic at the time of sample collection, and 26% of these patients had more than 5 CTCs. No correlation was found between the number of CTCs and other clinicopathologic features, suggesting CTC enumeration captures independent biological information. Patients with more than 5 CTCs had worse progression-free survival and overall survival. The cellular plasticity indicated by hybrid EMT and stem cell marker expression in CTCs was associated with poor prognosis and increased tumor aggressiveness.

Another targetable alteration is the PIK3CA gene, an actionable cancer gene already demonstrated to be important in hormone receptor-positive metastatic breast cancer. Pestrin et al. analyzed PIK3CA mutational status within single CTCs isolated from 39 patients with metastatic breast cancer, 20 of whom had samples enriched with 5 or more CTCs. PIK3CA mutations were identified in six patients, and discordance between the PIK3CA status of the primary tumor (wild type, or normal) and the matched CTC (exon 20 mutation) was observed in only one patient. While this is a small study, it provides proof of concept that liquid biopsy can potentially guide targeted therapy selection without the need for invasive tissue biopsies.

Detecting Tumor Heterogeneity

One of the greatest challenges in treating TNBC is its heterogeneity—the fact that different parts of a tumor, and different tumor cells within the same patient, can have different genetic profiles. CTCs change their characteristics during tumor cell spreading, mainly through the epithelial-mesenchymal transition (EMT) process, which together with the expression of stemness markers can facilitate chemotherapy resistance and promote the capacity to metastasize.

Rothé et al. investigated metastatic breast cancer heterogeneity by analyzing CTCs matched with synchronous tumor biopsies from three patients with metastatic breast cancer. Considering tumor mutational burden (TMB) in tumor biopsies from the patient with TNBC, 38% of all single-nucleotide variants (SNVs) found in the CTC samples were also present in tumor biopsies. This partial overlap reveals that CTCs capture some, but not all, of the genetic diversity present in the tumor—highlighting both the potential and the limits of liquid biopsy for understanding tumor heterogeneity. Importantly, it also suggests that CTCs may reflect subclones (distinct cell populations within a tumor) that are not easily captured by a single tissue biopsy, making liquid biopsy a complementary tool.

ctDNA in Early TNBC: Detecting Minimal Residual Disease

Perhaps one of the most exciting applications of liquid biopsy is the detection of minimal residual disease (MRD)—the tiny amounts of cancer cells that remain after treatment and are too small to be detected by imaging or standard tests. The International Expert Consensus Conference in 2017 concluded that ctDNA and CTCs are potentially useful biomarkers to guide treatment de-escalation—meaning doctors could safely reduce the intensity of therapy in patients at lower risk of relapse.

Notably, ctDNA may be detectable in early breast cancer using high-sensitivity MRD assays. The detection of ctDNA after surgical resection reflects the persistence of micrometastatic residual disease—microscopic clusters of cancer cells that have spread beyond the original tumor but are not yet clinically detectable. Therefore, ctDNA could potentially serve as a marker of residual disease in patients with TNBC to guide therapeutic decisions after neoadjuvant therapy.

Based on this potential, the Q-CROC-03 trial examined patients with TNBC undergoing neoadjuvant chemotherapy, with tumor biopsies carried out before and after chemotherapy as well as blood samples collected before, during, and after NAC to determine molecular factors of response or resistance to standard treatment. The results were striking: a slight increase in ctDNA levels was predictive of incomplete pathologic response, and the absence of ctDNA at the presurgical specimen was associated with long-term relapse-free survival and overall survival, with a prognostic value similar to pCR status itself. In other words, a simple blood test before surgery could give patients and doctors a preview of whether the chemotherapy is working as effectively as hoped.

Using Liquid Biopsy to Measure Neoadjuvant Therapy Effectiveness

Further information can be obtained from liquid biopsy to anticipate how well a patient will respond to neoadjuvant chemotherapy. Magbanua et al. provided robust evidence regarding the role of ctDNA as a predictive biomarker for response and outcome in the I-SPY 2 trial. This groundbreaking study collected blood samples at four time points: before treatment (T0), 3 weeks after starting paclitaxel chemotherapy (T1), between paclitaxel and anthracycline regimens (T2), and right before surgery (T3).

The results were dramatic. At T0 (before treatment), 73% of patients had detectable ctDNA. This percentage decreased steadily over time: 35% at T1, 14% at T2, and just 9% at T3 (right before surgery). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after neoadjuvant chemotherapy (83% non-pCR rate) compared with those who cleared their ctDNA (52% non-pCR rate).

Encouragingly, all patients who achieved pCR after neoadjuvant chemotherapy were ctDNA negative by the time of surgery. In the group that did not achieve pCR, ctDNA-positive patients had a significantly increased risk of metastatic recurrence. By contrast, ctDNA-negative patients in the non-pCR group had excellent outcomes, similar to those who achieved pCR. This suggests that rising ctDNA before surgery may be an early indicator of increased relapse risk, and could help identify patients who might benefit from treatment intensification before surgery to achieve pCR and prevent distant recurrence.

Ongoing Clinical Trials in Liquid Biopsy for TNBC

A substantial number of clinical trials are currently exploring liquid biopsy applications in TNBC. Here are the key studies that are actively enrolling patients:

Early-Stage TNBC Trials

• Serial ctDNA Monitoring During Adjuvant Capecitabine (NCT04768426): A phase II trial monitoring ctDNA during adjuvant capecitabine chemotherapy in TNBC patients with residual disease after standard neoadjuvant chemotherapy. The goal is to characterize the ctDNA profile and correlate ctDNA levels with genomic features and survival. Started February 2021, estimated duration 5 years.
• Apollo (NCT04501523): A prospective phase II trial using ctDNA to initiate post-operative boost radiation therapy after neoadjuvant chemotherapy in TNBC. ctDNA-positive patients are randomized to receive boost therapy or standard therapy. Started August 2020, estimated 7-year duration.
• PERSEVERE (NCT04849364): A phase II ctDNA-enriched, genomically directed post-neoadjuvant trial. Patients with residual TNBC after preoperative therapy are assigned to one of three arms based on plasma ctDNA positivity and genomic markers. Started August 2021, estimated 13-year duration.
• ZEST (NCT04915755): A randomized phase III double-blinded study comparing the efficacy and safety of niraparib (a PARP inhibitor) with placebo in participants with either HER2-negative BRCA-mutated breast cancer or TNBC with molecular disease (detectable ctDNA) following surgery or completion of adjuvant therapy. Started June 2021, estimated 8-year duration.
• Safe-De (NCT05058183): A trial evaluating safe de-escalation of chemotherapy for stage 1 HER2-positive or TNBC, assessing ctDNA rates in patients treated with surgery alone. Started June 2023, estimated 6-year duration.
• ASPRIA (NCT04434040): A single-arm phase II trial of atezolizumab (immunotherapy) combined with sacituzumab govitecan (an antibody-drug conjugate) to prevent recurrence in TNBC patients with residual cancer in the breast or lymph nodes and detectable ctDNA. Started July 2020, estimated 5-year duration.
• TARMAC (NCT04771871): A phase II study evaluating treatment response and microRNA profiles in Nigerian women with TNBC receiving standard chemotherapy, examining the potential of circulating microRNA and CTCs as surrogate markers of chemotherapy resistance. Started November 2021, estimated 2-year duration.
• Artemis (NCT04803539): A prospective phase II trial using ctDNA to identify TNBC patients at high relapse risk and initiate post-operative boost therapy. Started April 2021, estimated 7-year duration.
• BreastImmune03 (NCT03818685): A multicenter randomized phase II study comparing post-operative radiotherapy plus nivolumab and ipilimumab (both immunotherapies) versus radiotherapy plus capecitabine for TNBC patients with residual disease after NAC. ctDNA detection and molecular subtyping are secondary outcomes. Started July 2019, estimated 5-year duration.
• OXEL (NCT03487666): A pilot study of immune checkpoint inhibitor therapy, capecitabine, or combination therapy as adjuvant treatment for TNBC with residual disease following NAC, with ctDNA quantified at multiple time points. Started July 2018, estimated 4-year duration.
• RESPONSE (NCT05020860): A phase II trial correlating early clinical response to pathologic outcome in early breast cancer, determining whether a decrease in ctDNA levels from baseline to surgery correlates with clinical or pathologic response. Started April 2023, estimated 6-year duration.
• Atorvastatin Trial (NCT03872388): A study evaluating atorvastatin (a cholesterol-lowering medication) in patients with stage IIB-III TNBC who did not achieve pCR after neoadjuvant chemotherapy. The primary objective is to determine the proportion of patients with undetectable CTCs at 6 months. Started January 2019, estimated 4-year duration.
• Eliminating Surgery or Radiotherapy (NCT02945579): A trial evaluating whether surgery or radiotherapy can be safely eliminated after systemic therapy in HER2-positive or TNBC patients, with changes in blood and plasma biomarkers as outcome measures. Started January 2017, estimated 9-year duration.

Metastatic TNBC Trials

• GIM25CAPT (NCT05266937): A phase II trial of atezolizumab plus carboplatin plus paclitaxel as first-line therapy in metastatic PD-L1-positive TNBC. Measures ctDNA variation from baseline to first evaluation and from first evaluation to progression, using the FoundationOne Liquid NGS panel, and analyzes gene expression changes. Started July 2020, estimated 4-year duration.
• Talazoparib Trial (NCT03990896): A phase II trial evaluating the effectiveness of talazoparib (a PARP inhibitor) in 30 patients with metastatic breast cancer who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Started November 2021, estimated 3-year duration.
• EPIK-B3 (NCT04251533): A phase III, multicenter, randomized, double-blind, placebo-controlled study assessing alpelisib in combination with nab-paclitaxel in patients with advanced TNBC who carry either a PIK3CA mutation (study part A), have PTEN loss without PIK3CA mutation (part B1), or PTEN loss regardless of PIK3CA status (part B2). PIK3CA mutation is determined by ctDNA. Started June 2020, estimated 7-year duration.
• Eribulin + Copanlisib Trial (NCT04345913): A phase I/II trial evaluating the safety and efficacy of eribulin combined with copanlisib in metastatic breast cancer, determining ctDNA mutation profiles at baseline, on cycle 2 day 1, and at disease progression to correlate with treatment response. Started March 2021, estimated 3-year duration.
• NADiR (NCT04837209): A phase II study of niraparib, dostarlimab, and radiotherapy in metastatic PD-L1-negative or immunotherapy-refractory TNBC, evaluating changes in ctDNA using a patient-specific NGS assay. Started July 2021, estimated 8-year duration.
• 4CAST (NCT04947189): A phase Ib dose exploration and expansion trial evaluating INO-464 (a novel agent) in combination with chemotherapy in metastatic breast cancer, with gene expression analysis (RNA-seq or single-cell RNA-seq) on tumor biopsies and ctDNA analysis in blood. Started November 2021, estimated 4-year duration.
• PAveMenT (NCT04360941): A phase Ib study of palbociclib and avelumab in metastatic androgen receptor-positive TNBC, exploring ctDNA suppression as a potential biomarker of response. Started August 2020, estimated 4-year duration.
• Pembrolizumab + GTX-024 (NCT02971761): A phase II trial combining pembrolizumab (immunotherapy) with the selective androgen receptor modulator GTX-024 in metastatic androgen receptor-positive TNBC, evaluating the effect on peripheral blood CTCs, ctDNA, tumor-derived exosomes (TEX), and TEX-associated immune biomarkers. Started June 2017, estimated 5-year duration.
• CFI-400945 + Durvalumab (NCT04176848): A phase II study of CFI-400945 (a PLK4 inhibitor) combined with durvalumab (immunotherapy) in advanced or metastatic TNBC, measuring immune effects in cfDNA. Started December 2019, estimated 3-year duration.
• RADIOLA (NCT05340413): A trial predicting olaparib sensitivity in patients with unresectable locally advanced or metastatic HER2-negative breast cancer with BRCA1, BRCA2, PALB2, RAD51C, or RAD51D mutations or low RAD51 foci. A secondary outcome evaluates the capacity of ctDNA drop after 4 weeks of treatment to predict olaparib efficacy. Started March 2022, estimated 2-year duration.

Clinical Implications: What This Means for Patients

For patients with TNBC, the potential implications of liquid biopsy are far-reaching. This technology could eventually transform cancer care in several key ways:

• Earlier relapse detection: Liquid biopsy could detect cancer recurrence months before it becomes visible on imaging scans, potentially allowing earlier intervention when the disease burden is smaller and more treatable.
• Smarter treatment de-escalation: Patients who clear their ctDNA and achieve undetectable levels may be candidates for reduced treatment intensity, sparing them from unnecessary side effects. The 2017 International Expert Consensus Conference already recognized ctDNA and CTCs as potentially useful biomarkers to guide treatment de-escalation.
• Better treatment intensification: Conversely, patients who remain ctDNA positive during neoadjuvant therapy may be identified early as non-responders and could be switched to alternative regimens before surgery—potentially improving their chances of achieving pCR.
• Targeted therapy matching: The ability to detect actionable mutations like PIK3CA from a blood sample instead of a tissue biopsy could expand access to targeted therapies, especially in metastatic disease where repeat tissue biopsies are often difficult or risky.
• Real-time monitoring of clonal evolution: Because ctDNA has a half-life of only minutes to hours, it reflects the tumor's current state. As tumors evolve and develop resistance to therapy, ctDNA can capture these changes, potentially allowing doctors to switch treatments at the moment resistance emerges.

Limitations of Current Liquid Biopsy Technology

Despite its enormous promise, liquid biopsy is not yet ready to replace traditional tissue biopsies in all settings. Several limitations must be acknowledged:

• Not all tumors shed detectable DNA or cells: Some TNBC tumors may not release enough ctDNA or CTCs into the bloodstream to be detected. In the I-SPY 2 trial, for example, 27% of patients had no detectable ctDNA even before treatment started.
• Mixed trial results: The SWOG S0500 trial failed to show that early CTC-guided treatment changes improved outcomes, reminding us that detection alone is not enough—we also need effective therapies to act on the information.
• Heterogeneity gap: As shown by Rothé et al., only 38% of the genetic variants found in CTCs matched those in tumor biopsies. Liquid biopsy captures only part of the tumor's full genetic picture.
• Technology standardization: Multiple different platforms exist for detecting and analyzing CTCs and ctDNA (CELLSEARCH, IE/FC, various NGS panels, patient-specific assays). While some show high concordance, there is no universally accepted standard yet.
• Cost and accessibility: High-sensitivity MRD assays and comprehensive genomic panels remain expensive and are not yet universally available in all clinical settings.

Recommendations for Patients

For patients currently navigating a TNBC diagnosis, here is practical advice based on this review:

1. Ask about clinical trials: Many of the trials listed above are actively enrolling patients. Ask your oncologist whether you might be eligible for a trial involving liquid biopsy, especially if you have residual disease after neoadjuvant chemotherapy or metastatic TNBC.
2. Understand your biomarkers: If you have TNBC, ask about your PD-L1 status and germline BRCA mutation status. These are currently the most relevant biomarkers for treatment decisions, including immunotherapy and PARP inhibitors.
3. Discuss ctDNA testing options: While not yet standard of care for all TNBC patients, ctDNA monitoring is being increasingly offered in academic medical centers. Ask your doctor whether ctDNA testing could add useful information to your treatment plan.
4. Consider TIL evaluation: Tumor-infiltrating lymphocyte counts in your biopsy tissue can provide important prognostic information. Ask your pathologist whether TIL status has been assessed in your biopsy.
5. Stay informed: Liquid biopsy is one of the most rapidly evolving areas in oncology. What is experimental today may become standard of care within just a few years. Keep the conversation open with your care team about new developments.

While liquid biopsy is not yet a replacement for standard tissue-based testing, the evidence compiled in this review makes a compelling case that it will soon play a central role in TNBC management. The goal is more precise, personalized care: the right treatment, for the right patient, at the right time.

Frequently Asked Questions

What is a liquid biopsy and how is it different from a regular tumor biopsy?

A liquid biopsy is a blood test that detects cancer-related material, such as circulating tumor DNA or circulating tumor cells, released into the bloodstream. Unlike a tissue biopsy, which samples one spot at one time, a liquid biopsy gives a real-time snapshot of the whole disease and can be repeated easily.

Can liquid biopsy detect if my triple-negative breast cancer will come back after treatment?

Yes, in early TNBC, detecting ctDNA after surgery or during follow-up can indicate minimal residual disease and a higher risk of relapse. In the SUCCESS A trial, patients who were CTC-positive two years after chemotherapy had worse survival. However, this is not yet standard of care for all patients.

How is liquid biopsy used to measure how well chemotherapy is working before surgery?

In patients receiving neoadjuvant chemotherapy, blood samples can track ctDNA levels over time. In the I-SPY 2 trial, patients who remained ctDNA-positive early were more likely to have residual disease at surgery. All patients who achieved pCR were ctDNA-negative before surgery, suggesting it predicts response.

Can liquid biopsy help doctors choose targeted therapy for triple-negative breast cancer?

Analyzing circulating tumor cells or ctDNA can reveal genetic alterations like PIK3CA mutations. A small study found PIK3CA mutations in CTCs matched the primary tumor in most cases. This could guide targeted therapy in metastatic disease without needing a tissue biopsy, though more research is needed.

What are the limitations of liquid biopsy for triple-negative breast cancer?

Not all tumors shed enough DNA or cells to be detected; in I-SPY 2, 27% had no ctDNA before treatment. Also, liquid biopsy captures only part of a tumor's genetic diversity, different test platforms lack standardization, and some trials failed to show survival benefit from changes guided by liquid biopsy.

What should I ask my doctor about liquid biopsy and biomarkers for my triple-negative breast cancer?

Ask about your PD-L1 status, germline BRCA mutations, tumor-infiltrating lymphocytes, and whether ctDNA or CTC testing might be useful. Inquire about clinical trials, especially if you have residual disease after neoadjuvant chemotherapy or metastatic TNBC. Consider TIL assessment in your biopsy tissue.

Source Information

Original Article: "Liquid biopsy in triple-negative breast cancer: unlocking the potential of precision oncology" by R. Mazzeo, J. Sears, L. Palmero, S. Bolzonello, A. A. Davis, L. Gerratana, and F. Puglisi.

Publication: ESMO Open, Volume 9, Issue 10, 2024. Published by Elsevier Ltd on behalf of the European Society for Medical Oncology. DOI: https://doi.org/10.1016/j.esmoop.2024.103700

This patient-friendly article is based on peer-reviewed research. It was adapted from the original scientific review to make the information accessible to patients and caregivers. All clinical decisions should be made in consultation with a qualified healthcare provider.