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From Evidence to Practice: Neoadjuvant Therapy and Immunotherapy in Triple-Negative Breast Cancer

Abstract

Neoadjuvant systemic therapy has become a key part of managing early-stage triple-negative breast cancer (TNBC). Administering treatment before surgery allows clinicians to observe tumor responses in real time, improves the chances of breast conservation, and provides early indicators that help shape adjuvant decisions. Pathologic complete response and the residual cancer burden index are well-validated measures that help identify patients at lower or higher risk of relapse. The addition of pembrolizumab to standard chemotherapy has further improved pathologic response and event-free survival, setting a new benchmark for high-risk disease. Post neoadjuvant therapy options have also expanded. Capecitabine benefits patients with residual human epidermal growth factor receptor 2 (HER2)-negative disease, trastuzumab emtansine improves outcomes in those with HER2-positive residual disease, and olaparib offers a clear advantage for germline breast cancer gene-‍mutated patients. However, adapting these advances in India is challenging, complicated by uneven access to pathology and imaging services, limited biomarker testing, and variation in multidisciplinary care. Effective implementation will require definitive criteria for selecting candidates for neoadjuvant therapy, wider use of germline testing, and consistent pathology reporting that includes Residual Cancer Burden and tumor-infiltrating lymphocytes. Building capacity to recognize and manage immune-related toxicities is also crucial as immunotherapy becomes more extensively used. Establishing a coordinated national TNBC registry and targeted training through the National Cancer Grid would help generate local evidence, support pragmatic clinical trials, and promote more equitable access to concurrent treatments. This position paper brings together current evidence and India-specific considerations to offer practical guidance for delivering response-informed, multidisciplinary neoadjuvant care in triple-‍negative breast cancer.

Background

Female breast cancer (BC) is the second most diagnosed malignancy globally, affecting 2.3 million women. It remains among the top five causes of cancer-related mortality as observed by the Global Cancer Observatory. The global incidence of BC is projected to rise by approximately 38% by 2050, with annual deaths expected to surpass 1.1 million.1 In India, BC is the leading cancer among women, as reported in the National Cancer Registry Programme Report 2020.2 With an age-adjusted prevalence rate of 25.8 per 100,000 women and a mortality rate of 12.7 per 100,000 women in 2020, the rising burden of disease underscores the need for a deeper understanding of its biology and the development of more effective therapeutic strategies.3

BC is clinically classified according to the expression of three key molecular markers: the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). Based on the presence or absence of these markers, tumors are broadly grouped into hormone receptor (HR)-positive, HER2-positive, and triple-negative breast cancer (TNBC). TNBC is defined by the absence of all three markers. Determining these markers requires accurate pathology diagnostic testing. Immunohistochemistry (IHC) is the standard initial method used to assess ER, PR, and HER2 expression, while fluorescence in situ hybridization is usually performed when HER2 status is uncertain.1

TNBC represents a biologically distinct and aggressive entity that accounts for roughly 10%–‍20% of newly diagnosed BC cases worldwide.1,4,5 In India, reported incidence is higher, ranging from 11.8% to 31.9%, and survival outcomes appear broadly similar to global figures.6,7 The distinct molecular profile, with the absence of three markers, underlies its aggressive nature and lack of targeted therapeutic options. Molecular and genomic profiling are increasingly used to subclassify TNBC further and identify potential therapeutic targets. Clinical management remains challenging due to its aggressive behavior, higher recurrence rate, and absence of hormone receptors or HER2 amplification.8 For many years, treatment relied almost exclusively on cytotoxic chemotherapy and radiotherapy, and outcomes remained inferior compared with those for non-TNBC disease. Among patients with stage I to III tumors, 5-year overall survival is approximately 64% for TNBC compared with 81% for other subtypes, and progression-free survival is 61% vs. 70%.5 Recurrence occurs in about one quarter to one half of patients, and among those who experience recurrence, most develop distant metastases with poor long-term survival ranging from 11% to 27%.1,4

Neoadjuvant systemic therapy (NST) refers to the administration of systemic treatments, such as chemotherapy, targeted therapy, or immunotherapy, before surgical intervention in cancer management. The role of NST has expanded considerably over the last several decades. Initially used to downstage locally advanced tumors and improve operability, NST serves both broader therapeutic and biological functions. Administering systemic therapy before surgery allows clinicians to evaluate in vivo tumor response, offers insight into chemosensitivity, and helps identify patients who may require post neoadjuvant escalation. Pathologic complete response (pCR) has emerged as a strong prognostic indicator of recurrence and survival, and the absence of pCR indicates the need for additional adjuvant therapy.9 Molecular profiling has further revealed substantial heterogeneity within TNBC, identifying subgroups such as basal-‍like, immunomodulatory, mesenchymal, and luminal androgen receptor (LAR). These patterns correspond to distinct biological behaviors and treatment sensitivities. Basal-like tumors often respond better to DNA-damaging agents, while LAR tumors show androgen-‍driven pathways with relative chemoresistance. Immunomodulatory tumors exhibit immune activation signatures that may predict response to checkpoint blockade. Although clinical implementation of molecular subtyping is still limited, these findings support personalized NST strategies integrating platinum agents, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, and immunotherapy.10

NST is now a central component of managing biologically aggressive and locally advanced BC. It offers early control of micrometastatic disease and improves surgical options through tumor and nodal downstaging. Evidence from major trials, including National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and NSABP B-27, showed similar survival whether chemotherapy was given before or after surgery, but patients who achieved pCR had significantly better outcomes. These trials laid the foundation for establishing NST as both a therapeutic and prognostic tool.11 More recently, the addition of immune checkpoint inhibitors (ICIs) to standard NST regimens has reshaped treatment algorithms for TNBC. Programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy improve outcomes in both early-stage and metastatic TNBC and are now incorporated into major guidelines. Although the benefits are clear, questions remain about optimal patient selection, chemotherapy combinations, predictive biomarkers, and approaches to managing immune toxicities. Addressing these issues is essential to ensure that the advantages of immunotherapy translate into real-world practice.12 NST serves several goals at both the surgical and oncologic levels. It improves resectability in patients with locally advanced and inflammatory BC (stages IIIA to IIIC), enhances the feasibility of breast-‍conserving surgery (BCS) by reducing tumor size, and decreases axillary morbidity by enabling less extensive nodal procedures when nodes are downstaged. For any patient who would otherwise require adjuvant systemic therapy, NST provides early systemic control while increasing opportunities for breast preservation and precision-based decision-making.13

Guidelines from major professional bodies affirm NST’s central role. The American Society of Breast Surgeons (ASBrS) outlines clear indications for neoadjuvant chemotherapy and endocrine therapy, and organizations such as the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) recommend NST as the preferred initial approach for stage II to III TNBC and HER2-positive BC, as well as selected high-risk HR-positive cases. These guidelines emphasize the need for coordinated multidisciplinary care, accurate baseline staging, and standardized response assessment using pCR and residual cancer burden (RCB).14–17 Implementing these recommendations in India requires adaptation to local constraints, including diagnostic capability, drug availability, and health system capacity. Aligning global guidance with national constraints is important for the equitable delivery of NST. Such an effort would extend the foundation laid by the National Cancer Grid (NCG) Breast Cancer Management Guidelines, which provide India’s only resource-stratified, nationally harmonized approach to BC care.18

The novelty of this paper is its focused integration of the latest global evidence on TNBC with the specific clinical, economic, and social parameters of the Indian healthcare setting. Thus, this position paper aims to offer a practical synthesis of contemporary evidence on NST in BC with a particular focus on TNBC. It brings together key guideline recommendations, recent clinical advances, and Indian contextual needs. The overarching goal is to support clinicians in delivering consistent, evidence-based, and accessible NST care across diverse practice settings.

Methodology

The development of this position paper followed a structured, evidence-based approach. A comprehensive search of the PubMed database was performed for publications from January 2000 to November 2025, supplemented with hand searching and citation tracking. PubMed was selected considering its strong indexing of peer-reviewed clinical trials, guidelines, and systematic reviews that inform modern oncology practice.19

The search terms included “triple-negative breast cancer,” “TNBC,” “neoadjuvant systemic therapy,” “neoadjuvant chemotherapy,” “pathologic complete response,” “pCR,” “Residual Cancer Burden,” “RCB,” “immune checkpoint inhibitor,” “ICI,” “pembrolizumab,” “platinum-based chemotherapy,” “post-neoadjuvant therapy,” “PARP inhibitor,” “breast cancer guidelines,” “India,” and “real-world practice.” The complete search strategy is provided in Annexure 1.

Randomized trials, cohort studies, real-world analyses, systematic reviews, meta-analyses, and national or international BC guidelines, published in the English language, that focused on early-stage or locally advanced TNBC were considered in this position paper. It included studies evaluating efficacy, safety, sequencing, biomarker-driven decisions, and surgical outcomes. Preclinical research was reviewed only when it provided mechanistic insights relevant to clinical decision-making.

These studies elucidate the underlying biological rationale, evolving strategies, role of immunotherapy, practice recommendations, India-specific issues, and future directions.

NST in TNBC

Tumor downstaging and breast Conservation

NST increases the feasibility of BCS for patients initially considered candidates for mastectomy, particularly in aggressive subtypes such as TNBC. Neoadjuvant endocrine therapy is another option for postmenopausal women with HR-positive and HER2-negative tumors when chemotherapy is not clearly indicated, but breast conservation is an important goal.20 In a secondary analysis of the BrighTNess trial, 53.2% of women with stage II to III TNBC who were not eligible for BCS at diagnosis became eligible after NST, raising the overall eligibility rate from 76.5% to 83.8%.21 A prospective cohort study of 600 patients found that 75% of women deemed ineligible for BCS because of an unfavorable breast-to-tumor ratio became eligible after NST, and nearly half ultimately avoided mastectomy. TNBC had the highest conversion rate at 84%.22 Earlier meta-analyses reported that NST reduces mastectomy rates without compromising overall survival, although a small increase in local recurrence has been noted.23,24 A large registry-based analysis also found that patients undergoing BCS after NST had significantly better 10-year BC-specific survival compared with patients treated with mastectomy without radiation therapy, with a hazard ratio of 0.46 and a 95% confidence interval (CI) of 0.27-0.78.25 These findings collectively support the role of NST in achieving breast preservation and favorable long-term outcomes in appropriate patients.

Axillary downstaging and surgical de-escalation

NST can downstage axillary disease and allow transition from axillary lymph node dissection (ALND) to less invasive procedures such as sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD), thereby reducing morbidity while maintaining accurate staging.26 In a prospective registry that assessed 3-year outcomes of TAD without completion ALND in 199 node-positive patients, no significant increase in recurrence (Hazard Ratio: 0.83; 95% CI: 0.34–2.05; p=0.69) or death (Hazard Ratio: 1.07; 95% CI: 0.31–3.70; p=0.91) was observed in the 119 patients treated with TAD alone when compared with the 80 patients who also underwent ALND.27 Another prospective study evaluating radar-localized reflector targeted dissection after NST in 86 patients showed a false-negative rate of 5.1%, demonstrating the technical feasibility of axillary de-escalation.28 A retrospective analysis of 235 patients with cT1 to 3 N1 to 2 BC reported comparable 10-year survival and regional control between TAD and ALND.29 A registry analysis also confirmed that SLNB after NST is safe when at least three sentinel nodes are retrieved, with recurrence rates similar to those historically seen with ALND. As axillary and regional nodal treatment becomes more conservative for patients who convert from node-‍positive to node-negative status, vigilant clinical and imaging follow-up remains critical to detect potential recurrences and to clarify their long-term impact.30

Early systemic intervention and survival benefit

Initiating systemic therapy before surgery addresses micrometastatic disease at an earlier stage and may lower the risk of distant relapse. This advantage is particularly relevant in aggressive biology, such as TNBC.31 A pooled analysis of 12 neoadjuvant trials demonstrated that pCR strongly correlates with improved survival (EFS) and overall survival (OS), with the association being most pronounced in TNBC (EFS Hazard Ratio: 0.24, 95% CI: 0.18–0.33; OS Hazard Ratio: 0.16, 95% CI: 0.11–‍0.25).32 A meta-analysis of more than 5000 patients reported that ICIs combined with chemotherapy improved pCR and event-free survival in early-stage TNBC and in programmed death-ligand 1 (PD-L1)-positive, HR-positive, and HER2-negative disease compared with chemotherapy alone (Hazard Ratio : 0.65, 95% CI: 0.42–1.00).33 In the phase III KEYNOTE 522 trial, adding pembrolizumab to platinum-based chemotherapy significantly improved pCR and event-free survival in early-stage TNBC.34 Together, these results reinforce the importance of early systemic intervention in high-risk BC.

Biologic insight to guide adjuvant care

Tumor response to NST provides practical and biologically meaningful information that guides adjuvant treatment. The CREATE-X trial demonstrated that adjuvant capecitabine improved invasive disease-free survival for patients with residual HER2-negative disease after NST.35 In HER2-positive BC, the KATHERINE trial showed that switching to trastuzumab emtansine (T-DM1) in patients with residual invasive disease significantly reduced the risk of invasive recurrence compared with continuing trastuzumab.36 A multicenter pooled analysis further confirmed the prognostic power of post-treatment pathology and provided quantitative stratification for decision-making.37 These findings show that using treatment response to inform adjuvant decisions allows more individualized care and improved outcomes.

RCB-based modulation of adjuvant therapy

The RCB index categorizes post-treatment pathology into RCB 0 to III by evaluating residual tumor volume, cellularity, and nodal involvement. Lower RCB categories (0 and I) correspond to excellent outcomes, while higher categories (II and III) indicate substantially higher relapse risk. In a large validation cohort, increasing RCB correlated with higher recurrence risk and earlier time to relapse, particularly in TNBC.38 High RCB, therefore, serves as a guidance for treatment escalation, consistent with evidence from CREATE-X—where adjuvant capecitabine improved disease-free and overall survival in patients with residual HER2-negative BC35—and KATHERINE—where T-DM1 was superior to trastuzumab in HER2-positive patients with residual cancer.36 In the immunotherapy setting, patients treated with pembrolizumab-based regimens continue pembrolizumab postoperatively according to KEYNOTE 522, with the greatest benefit expected among those with high RCB.34 RCB therefore translates pathology into actionable strategy, supporting escalation for high-risk patients and avoiding unnecessary treatment for low-risk responders.

Multidisciplinary team integration

Effective delivery of NST in TNBC requires close coordination across surgery, pathology, and radiology. Pretreatment imaging and biopsy provide a consistent baseline for staging, while mid-treatment assessments help confirm whether the tumor is responding or whether the regimen requires modification. Communication between surgeons and radiologists supports precise localization of the primary tumor and axillary nodes after therapy, especially when radiologic visibility is reduced. Pathologists play a key role by providing standardized assessments of pCR and RCB, which directly influence postoperative therapy. Real-world evidence suggests that structured multidisciplinary tumor boards improve adherence to evidence-based regimens, facilitate sound surgical decisions, and support better outcomes. Implementation of standardized clinical pathways for each newly diagnosed patient receiving neoadjuvant therapy has also been shown to deliver high standards of care across diverse populations.39,40

Role of Immunotherapy in Neoadjuvant TNBC

Early endpoints and their clinical relevance

pCR remains the most informative early endpoint for evaluating neoadjuvant strategies in early-stage TNBC. Its significance stems from a consistent association with reduced recurrence risk and improved long-term survival. An observational cohort examining outcomes in women who received NST showed that lack of pCR correlated with a higher likelihood of disease progression and mortality, reinforcing its utility as a prognostic marker.41 In TNBC, pCR is widely accepted as a reflection of systemic therapy sensitivity and is strongly linked to gains in event-free survival and overall survival.42 Evidence from a comprehensive meta-analysis further confirmed that pCR following neoadjuvant treatment corresponds to significantly better EFS and OS, particularly in TNBC and HER2-positive subtypes, where early eradication of tumor burden may represent effective control of micrometastatic cancer.43 The analysis also noted that similar survival outcomes in patients achieving pCR with or without adjuvant chemotherapy likely reflect favorable intrinsic tumor biology. Although pCR is a key early measure, it cannot fully substitute for longer-term endpoints. Interpretation of pCR should therefore be integrated with EFS and OS when evaluating the clinical value of neoadjuvant immunotherapy combinations.

Pembrolizumab as the foundational immunotherapy agent

Pembrolizumab has become the central immunotherapy backbone in high-risk, early-stage TNBC. The KEYNOTE-522 trial demonstrated that adding pembrolizumab to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, significantly improved pCR and event-‍free survival compared with chemotherapy alone.44 Updated analyses with extended follow-up reaffirmed the durability of the EFS benefit, establishing pembrolizumab as the preferred immunotherapy option in this setting.45 Beyond this established regimen, emerging studies are investigating pembrolizumab in combination with HER2-directed therapies, including trastuzumab with or without pertuzumab, alongside paclitaxel in the neoadjuvant phase. Such combinations aim to enhance pCR while permitting selective reduction of cytotoxic intensity, representing a potential pathway toward refined, biologically informed de-‍escalation.46 Collectively, evolving evidence reflects pembrolizumab’s shift from a single pivotal agent to an anchor for next-generation immunotherapy combinations.

Optimizing treatment timing and duration

Effective incorporation of immunotherapy into neoadjuvant and adjuvant pathways requires aligning systemic therapy cycles, surgical interventions, and imaging assessments. Concurrent administration of immunotherapy with neoadjuvant chemotherapy may enhance immunogenic cell death and augment immune-mediated elimination of micrometastases. Early trials of neoadjuvant immunotherapy have demonstrated superior pathologic responses and emerging long-term benefit in this setting.47 Postoperative continuation of immunotherapy provides an opportunity to consolidate the initial response. However, treatment timing influences outcomes. Data from a brief systematic review indicate that delaying surgery beyond approximately 2–8 weeks after completing systemic therapy may adversely affect survival.48 A recent perspective highlights that treatment-to-treatment intervals may have nonlinear associations with outcomes, where both excessively short and excessively prolonged gaps can compromise efficacy.49 Clinical trials seldom evaluate the full spectrum of timing variables, and real-world delays may arise from medical, logistical, or social circumstances. In TNBC, where relapse risk peaks within the first 2 years, minimizing delays from diagnosis to therapy initiation, maintaining an uninterrupted systemic-surgery-immunotherapy sequence, and adhering to evidence-supported immunotherapy duration are especially important.50 Future trials should identify optimal adjuvant immunotherapy duration and timing to ensure maximal benefit.

Patient selection for neoadjuvant immunotherapy

Selecting the appropriate candidates for NST remains central to improving outcomes in early-‍stage TNBC. While clinically node-positive disease and larger tumors remain established indications, recent evidence supports the use of NST in selected node-negative patients who have high-risk biological features. According to a contemporary multidisciplinary review, even small, node-negative tumors may benefit from neoadjuvant therapy when the risk of systemic spread is significant or when downstaging could allow breast-conserving approaches.40 Meta-‍analyses of modern neoadjuvant trials show that early-stage TNBC achieves meaningful pCR rates regardless of nodal status, supporting NST in settings where response-guided adjuvant decisions or risk-based escalation might follow.43 Practical considerations include tumor size, nodal involvement, potential to expand breast conservation, and patient priorities. In India, selection flexibility is further influenced by heterogeneous imaging access, variable multidisciplinary workflows, and differences in surgical planning. Adopting context-sensitive criteria can help ensure the equitable and appropriate use of NST across diverse practice settings.

Anthracycline de-escalation strategies

Anthracyclines such as doxorubicin and epirubicin have long served as central components of NST for early BC, including TNBC. Their effectiveness is well documented, yet concerns regarding cumulative toxicity continue to shape contemporary discussion on de-escalation. Long-term risks include cardiotoxicity and the development of secondary hematologic malignancies such as acute myeloid leukemia and myelodysplastic syndrome.51 Evidence from a multicenter retrospective study demonstrates wide variation in cardiotoxicity incidence depending on cumulative dose, age, and coexisting conditions, supporting the need for careful cardiovascular monitoring and management of comorbidities such as hypertension.52 Cardio-‍oncology data further reinforce the dose-dependent nature of anthracycline toxicity and the potential for late cardiac sequelae extending years beyond treatment completion.53 In response to these safety considerations, several recent trials and meta-analyses have explored anthracycline-sparing or anthracycline-reduced regimens. Many of these studies report encouraging results, suggesting that carefully selected patients with TNBC might achieve comparable pathologic responses using anthracycline-free regimens.54 In practice, decisions regarding anthracycline omission should be individualized, incorporating the biological risk profile, predicted chemosensitivity based on genomic and biomarker data, and the institution’s ability to provide cardiac surveillance. Such tailored approaches balance the need to reduce cumulative toxicity while preserving oncologic effectiveness.

Platinum agents in neoadjuvant TNBC

Platinum agents, particularly carboplatin, have been incorporated into neoadjuvant chemotherapy for TNBC because of their activity in tumors with DNA repair deficiencies. A systematic review and meta-analysis demonstrated significantly higher pCR rates with platinum-‍based regimens compared with standard neoadjuvant chemotherapy, although at the cost of increased hematologic toxicity.55 A subsequent meta-analysis confirmed this pCR advantage. It highlighted the need to balance improved response rates against heightened risk of myelosuppression, which may be magnified when immunotherapy is also administered.56 More recent evidence examining anthracycline-free combinations of taxanes and platinum agents indicates that such regimens may reduce hematologic toxicity while maintaining response efficacy.54 Other than carboplatin, cisplatin has demonstrated activity in TNBC in a neoadjuvant trial, especially in patients with germline breast cancer gene (BRCA) mutations.57 Oxaliplatin, a third-‍generation platinum agent, showed promise in managing advanced or metastatic TNBC.58 Integration of platinum should be guided by clinical priorities, including the need to maximize pCR in high-risk TNBC, patient comorbidities, and anticipated sequencing with immunotherapy or post neoadjuvant treatments.

Response-guided post neoadjuvant therapy

Tailoring post-neoadjuvant therapy in TNBC relies heavily on the pathologic response achieved after neoadjuvant chemotherapy. Patients who attain a pCR generally proceed with completing the planned adjuvant protocol, as their residual relapse risk is low. In contrast, patients with residual invasive disease on surgical pathology are considered for treatment escalation or regimen switching based on risk category and RCB. A contemporary review of post neoadjuvant strategies highlights that patients with residual TNBC benefit from additional systemic therapy, such as capecitabine, ICIs, or PARP inhibitors, depending on the molecular profile and prior treatments.59 It is emphasized that early-stage TNBC is highly heterogeneous and aggressive and that patients failing to achieve pCR after neoadjuvant chemotherapy should be evaluated for additional systemic therapy to reduce recurrence risk. It is important to note that while immunotherapy has become an integral part of neoadjuvant and adjuvant treatment pathways, clinicians must remain vigilant for immune-related adverse events (irAEs), which are rare but potentially life-threatening and require early recognition and management.42,60 Collectively, these data support a response-adapted framework in which pCR identifies low-‍risk patients suitable for standard adjuvant completion, while residual disease appropriately triggers individualized, evidence-based intensification strategies.

PARP inhibitors in early-stage TNBC

PARP inhibitors have become essential for treating germline BRCA1/2-‍mutated, high-risk early-stage TNBC, particularly in patients with residual disease after neoadjuvant chemotherapy. The phase III OlympiA trial demonstrated that adjuvant olaparib significantly improved invasive disease-free survival and OS compared with placebo, establishing PARP inhibition as a targeted and effective post neoadjuvant option. However, the trial noted minimal impact on patient-reported quality of life.61 These findings support the integration of olaparib either sequentially after chemotherapy and immunotherapy or as part of a coordinated adjuvant strategy according to guideline recommendations. Talazoparib demonstrated activity as a neoadjuvant monotherapy in germline BRCA1/2-mutated early-‍stage TNBC with promising pCR rates in a phase II trial.62 Niraparib has been evaluated in combination with immunotherapy in metastatic and advanced TNBC with or without BRCA mutations, showing promising antitumor activity and tolerable safety profiles.63 A Cochrane systematic review confirms that PARP inhibitors are particularly effective in BRCA-mutated TNBC due to synthetic lethality, providing a targeted approach that reduces recurrence risk with manageable toxicity profiles.64 Given these benefits, early germline testing for BRCA1/2 is essential. Embedding germline testing into the diagnostic workflow enables timely identification of eligible patients and guides optimal sequencing with chemotherapy and immunotherapy, ensuring that PARP inhibitors are integrated into comprehensive, biologically informed care plans. A summary of pivotal trials informing neoadjuvant and post neoadjuvant management of TNBC is provided in Table 1.

Table 1: Key trials informing neoadjuvant and post neoadjuvant management of triple-negative breast cancer

TrialStudy populationIntervention/ comparatorPrimary endpoint(s)Key findingsClinical implications
KEYNOTE-52244Stage II–III TNBCNeoadjuvant pembrolizumab plus platinum–taxane chemotherapy followed by adjuvant pembrolizumab vs. identical chemotherapy without pembrolizumabpCR and event-free survivalAddition of pembrolizumab increased pCR rates and significantly improved event-free survival, with sustained benefit on extended follow-upEstablishes pembrolizumab-based neoadjuvant plus adjuvant therapy as the preferred standard of care for high-risk early-stage TNBC
BrighTNess65Stage II–III TNBCPaclitaxel with or without carboplatin and with or without veliparib, all followed by anthracycline-based chemotherapypCRCarboplatin significantly improved pCR; veliparib provided no added clinical advantageSupports the use of platinum agents in neoadjuvant regimens for selected patients with TNBC, where maximizing pCR is a priority
CALGB-4060366Stage II–III TNBCStandard neoadjuvant anthracycline–taxane chemotherapy ± carboplatin± bevacizumabpCRCarboplatin improved pCR across multiple subgroups; bevacizumab increased pCR, but without a clear survival benefitReinforces pCR improvement with platinum addition, informing regimen intensity decisions
GeparSixto; GBG-6667Stage II–III TNBCPaclitaxel and nonpegylated liposomal doxorubicin± carboplatinpCRCarboplatin significantly increased pCR, especially in patients with homologous recombination deficiencyProvides a biological rationale for platinum use in DNA-repair-deficient TNBC
CREATE-X UMIN35HER2-negative patients with residual disease after standard neoadjuvant chemotherapyAdjuvant capecitabine vs. observationDisease-free survival and overall survivalSignificant improvement in DFS and OS, with the largest effect observed in the TNBC subgroupEstablishes adjuvant capecitabine for patients with residual TNBC, following neoadjuvant chemotherapy
KATHERINE36HER2-positive patients with invasive residual disease after neoadjuvant therapyAdjuvant T-DM1 vs. trastuzumabInvasive disease-free survivalT-DM1 reduced the risk of recurrence by approximately 50% compared with trastuzumabDefines escalation strategy when residual HER2-‍positive disease is present; indirectly supports response-guided therapy models
OlympiA61Germline BRCA1/2-mutated, high-risk early-stage HER2-negative breast cancer1 year of adjuvant olaparib vs. placeboInvasive disease-free survival and overall survivalSignificant improvements in IDFS and OS, with consistent benefits in the TNBC populationEstablishes PARP inhibition as a key component of post neoadjuvant therapy for germline BRCA-‍mutated TNBC

BRCA1/2: Breast cancer gene 1 and 2; DFS: Disease-free survival; HER2: Human epidermal growth factor receptor 2; IDFS: Invasive disease-free survival; OS: Overall survival; PARP: Poly (ADP-ribose) polymerase; pCR: Pathologic complete response; T-DM1: Trastuzumab emtansine; TNBC: Triple-negative breast cancer.

Management of irAEs

Safe and effective delivery of immunotherapy in the neoadjuvant and adjuvant settings requires a structured approach to identifying and managing irAEs. Real-world studies show variability in irAE incidence and clinical outcomes compared with controlled environments, with a recent multicenter cohort study reporting a lower pCR rate than that of the KEYNOTE-522 trial, reflecting differences in comorbidity profiles, monitoring capacity, and treatment adherence.68 The ASCO clinical practice guideline outlines a detailed framework for baseline evaluation, symptom-triggered investigation, and graded escalation of management strategies, including timely immunosuppression where needed.69 A review underscores the importance of pretreatment counseling, early symptom reporting, and multidisciplinary coordination to minimize morbidity. It also highlights practical “clinical pearls” for managing common irAEs across dermatologic, endocrine, gastrointestinal, pulmonary, and hepatic systems, which can enable safe delivery of immunotherapy in both neoadjuvant and adjuvant phases.70 Real-world pharmacovigilance reports show substantial variability in irAE incidence, reinforcing the necessity of coordinated, multidisciplinary monitoring to detect atypical or delayed events.71 ESMO recommendations emphasize standardized assessment and consistent follow-up to guide decisions regarding continuation, modification, or discontinuation of treatment.72 These frameworks collectively support safe immunotherapy delivery across the neoadjuvant–‍adjuvant continuum.

Predictive and prognostic biomarkers for immunotherapy

As immunotherapy is increasingly integrated into early-stage TNBC management, biomarkers play an increasingly important role in predicting treatment response and guiding therapeutic stratification. Evidence supports complementary roles for PD-L1 expression, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and microsatellite instability (MSI). PD-‍L1 remains a validated predictive biomarker in metastatic TNBC for pembrolizumab selection. For early-stage TNBC, current guidelines and approvals do not require PD-L1 testing before initiating neoadjuvant or adjuvant pembrolizumab, as benefits have been demonstrated irrespective of PD-L1 status. Its expression nonetheless correlates with higher pCR rates and increased immune cell infiltration.44 NCCN and ASCO endorse PD-L1 (combined positive score ≥10) testing in metastatic disease to guide immunotherapy decisions.15,17 ILs represent a strong prognostic biomarker in early-stage TNBC, with high stromal TILs associated with improved pCR and survival. Although not yet used routinely in clinical practice, TIL quantification is recognized by both ESMO and the Society for Immunotherapy of Cancer and may support future de-escalation trials.72,73 TMB contributes to neoantigen generation, supporting enhanced sensitivity to ICIs. While TMB-high tumors are uncommon in TNBC, high TMB is recognized by NCCN as a tumor-agnostic biomarker for pembrolizumab in advanced solid tumors.15,74 MSI-high and mismatch repair deficiency tumors are extremely rare (<1%) in TNBC but remain a validated predictor of PD-1 inhibitor response across solid tumors. NCCN advises MSI testing when clinically indicated, especially in patients with suspected hereditary cancer syndromes.15 Integrative analyses suggest that combining biomarkers may capture multiple aspects of tumor-immune interactions, supporting treatment intensification or de-escalation; however, neoadjuvant pembrolizumab currently remains a biomarker-unrestricted indication.75 Guidelines emphasize that while biomarkers enhance response prediction, neoadjuvant pembrolizumab in early-stage TNBC remains a biomarker-unrestricted indication, highlighting the need for future biomarker-driven stratification to optimize de-escalation and escalation strategies.

Indian Real-World Considerations

Selection variability and pathway standardization

Patterns of NST use in India reveal considerable variation across institutions, particularly in decisions involving node-negative TNBC. Although TNBC is an aggressive subtype that benefits from early systemic therapy, real-world reports show that many small, node-negative tumors continue to be treated with upfront surgery.76 This tendency limits opportunities for response-guided treatment escalation, especially for patients who might benefit from early identification of residual disease. Multiple factors drive this inconsistency. Differences in clinician preferences, the availability and quality of baseline imaging, and institution-specific protocols all influence decision-making. In resource-diverse health systems, variation is often more pronounced in tier-two and tier-three centers, where access to breast magnetic resonance imaging (MRI), core biopsy, or specialized pathology reporting may be restricted. To address this fragmentation of care, establishing a set of minimal but practical selection criteria is essential. Offering NST for tumors measuring T2 or larger, high-grade lesions, or biologically high-risk node-negative disease can help standardize decisions while still accommodating Indian practice realities. Developing shared diagnostic workflows and embedding guideline-aligned treatment algorithms within multidisciplinary tumor boards may further reduce variations. As coordination improves, patients who stand to benefit from response-adaptive management are more likely to receive appropriate treatment. Table 2 compares major guideline recommendations for neoadjuvant and post neoadjuvant management of TNBC along with contextual considerations for India.

Table 2: Comparison of major guideline recommendations for neoadjuvant and post neoadjuvant management of triple-negative breast cancer

Guideline bodyNeoadjuvant therapy recommendationsImmunotherapy recommendationsPost-neoadjuvant therapyBiomarker/testing guidanceApplicability in Indian settings
NCCN (United States)15Recommends NST for stage II–III TNBC, node-positive disease, and high-risk node-negative tumors; supports the use of anthracycline–taxane regimens ± carboplatinPembrolizumab with neoadjuvant chemotherapy followed by adjuvant completion is standard for high-risk early TNBCCapecitabine for residual TNBC; olaparib for germline BRCA1/2-mutated high-risk diseaseAdvises germline BRCA1/2 testing for high-risk TNBC; PD-L1 testing required only in the metastatic settingWidely followed in major Indian cancer centers; however, some regimens are limited by cost
ASCO17Encourages NST for clinically node-positive and T2 or larger TNBC; supports consideration for tumors 1–2 cm based on biologyStrong recommendation for pembrolizumab in early-stage high-risk TNBCCapecitabine and olaparib are recommended for residual or BRCA-mutated diseaseSupports BRCA testing; PD-L1 not required for early-stage immunotherapyProvides pragmatic, resource-flexible recommendations suitable for adaptation in LMICs
ESMO72NST is recommended for most stage II–III TNBC; highlights the role of early downstaging and prognostic insightICIs are recommended in combination with chemotherapy for early TNBC; emphasizes the need for toxicity monitoringCapecitabine and olaparib endorsed; escalation guided by RCBSupports BRCA testing, TILs reporting in pathology, and PD-L1 testing in the metastatic settingAligns with European practice; TIL reporting may be feasible as a low-cost biomarker
NCG (India)18Recommends NST for stage II–III TNBC with anthracycline–taxane backbone; encourages use of carboplatin when feasibleImmunotherapy is recommended where available and affordable; acknowledges access variabilityCapecitabine is recommended for residual TNBC; olaparib is recommended for germline BRCA mutation (availability-dependent)Recommends BRCA testing for high-risk patients; endorses standard IHC-based subtypingResource-stratified guidance; recognizes gaps in pathology, radiology, and access to immunotherapy
ASBrS14Strong recommendation for NST in stage II–III TNBC and in cases where downstaging improves surgical optionsSupports pembrolizumab use aligned with NCCN/ASCOEmphasizes response-adapted adjuvant therapy frameworksAdvises standardized pathology reporting, including pCR and RCBHelpful for institutions modernizing MDT workflows

ASBrS: American Society of Breast Surgeons; ASCO: American Society of Clinical Oncology; BRCA1/2: Breast cancer gene 1 and 2; ESMO: European Society for Medical Oncology; ICI: Immune checkpoint inhibitor; IHC: Immunohistochemistry; LMICs: Low- and middle-income countries; MDT: Multidisciplinary team; NCCN: National Comprehensive Cancer Network; NCG: National Cancer Grid; NST: Neoadjuvant systemic therapy; pCR: Pathologic complete response; PD-L1: Programmed death-ligand 1; RCB: Residual Cancer Burden; TNBC: Triple-negative breast cancer; TIL: Tumor-infiltrating lymphocyte.

Special population considerations

TNBC in India disproportionately affects certain population groups, adding layers of complexity to treatment planning. Premenopausal women represent a large proportion of cases in India, often presenting with biologically aggressive cancer. Many of these patients require fertility preservation counseling, menstrual suppression strategies, and psychosocial support—‍components that are not uniformly available across centers—while elderly patients face different challenges. Poor nutritional status, limited caregiver support, inadequate transportation, and social vulnerabilities can influence treatment choices. Completion rates of neoadjuvant chemotherapy are lower among elderly individuals due to toxicity concerns and comorbid conditions, as real-world studies have shown.77 These limitations often result in dose attenuation or avoidance of neoadjuvant therapy even when clinical benefit is expected. Comorbidities such as cardiac disease, diabetes, or chronic kidney disease further restrict regimen selection, especially when anthracyclines or immunotherapy are considered. The absence of structured cardio-oncology evaluation in many regions, along with limited availability of regular echocardiographic surveillance, can lead clinicians to favor less intensive approaches even in otherwise fit patients. Collectively, these factors highlight the need for resource-adapted, individualized strategies that weigh oncologic benefit against feasibility and safety in the Indian context.

Infrastructure and capacity constraints

Delivery of timely and effective NST and immunotherapy in India is deeply influenced by institutional infrastructure, which varies widely across geographic locations. High-quality pathology services are essential for receptor testing, Ki-67 (a nuclear protein associated with cellular proliferation) evaluation, and reporting of RCB; however, significant shortages in IHC capacity, trained personnel, and standardized reporting lead to delays or inconsistencies. In some centers, turnaround times for pathology results directly impact the initiation of neoadjuvant therapy. Radiology capacity is similarly heterogeneous. While major cancer centers may have access to advanced imaging, including breast MRI and targeted axillary ultrasound, many district hospitals rely on limited modalities. Variability in image-guided biopsy capability also affects baseline staging. Such gaps hinder appropriate selection and response monitoring. Surgical services differ in their ability to perform oncoplastic procedures, SLNB, TAD, and accurate tumor localization after NST. Limited availability of localization tools, such as radioactive seeds or radar reflectors, may restrict the downstaging benefits that NST offers. Multidisciplinary tumor boards, which are considered standard in high-quality oncology care, are not universally established in smaller or remote centers. Evidence from African oncology systems demonstrates that even in low-‍resource settings, strengthening multidisciplinary processes benefits cancer care, leading to more coherent and higher-quality care.78 Similar principles apply in India, where better integration of pathology, radiology, surgery, and medical oncology is central to improving outcomes. Practice guidance from ASBrS reinforces the importance of coordination as a foundational element of neoadjuvant pathways.14 Strengthening these pillars will support equitable access to modern treatments across diverse healthcare environments.

Clinician judgment vs. guideline-based pathways

Clinical decision-making in TNBC management in India often relies heavily on clinician discretion, which contributes to variability in NST use. International guidelines, including the ASBrS recommendations, endorse clear criteria for offering NST based on tumor biology, extent of disease, and opportunities for downstaging.14 However, real-world use of these pathways in India is uneven. In resource-limited settings, clinicians may prefer upfront surgery when there are concerns regarding adherence, follow-up, or system capacity to monitor treatment-related adverse events. Limited imaging, delays in pathology, or concerns about treatment interruptions further push decisions toward surgery. In contrast, tertiary centers with well-established tumor boards and standardized care pathways demonstrate much higher adherence to international standards. The challenge lies in balancing guideline-driven care with individualized judgment that accounts for infrastructural and patient-specific constraints. Establishing minimum decision thresholds and integrating structured case reviews into multidisciplinary settings can help reduce unwarranted variation. Such an approach maintains flexibility while fostering greater alignment with evidence-based practices.

Limitations

This position paper draws strength from its comprehensive synthesis of the latest clinical trial evidence and international guidelines. The recommendations are robust, current, and anchored in sound best practices. By integrating advances such as the evolution of neoadjuvant immunotherapy, the use of precision biomarkers, and adaptive post neoadjuvant strategies, the document aims to equip clinicians with effective, evidence-based tools for managing TNBC across a range of clinical settings. Equally important is the manuscript’s recognition of the complexity and diversity of real-world TNBC care in India and other low- and middle-income countries. This approach addresses not only biological and treatment-related aspects but also strives to reflect the practical realities faced by patients. Disparities in access, financial challenges, and the need for supportive care are acknowledged throughout this paper. This patient-centered perspective seeks to honor each person’s unique experience and recognizes the critical role of multidisciplinary teams in providing compassionate care. However, there are inherent limitations. The recommendations rely primarily on studies and guidelines from higher-resource countries, since large-scale, indigenous clinical trials and a unified Indian consensus for TNBC management are still absent. Although the paper discusses barriers such as cost and access, there are limited data on local implementation and patient-reported outcomes in Indian populations. These gaps highlight an opportunity for future collaboration, including the development of multicenter registries and the development of guidelines tailored to regional needs. The goal remains to ensure that all patients, regardless of where they live or their socioeconomic circumstances, can benefit from ongoing progress in TNBC.

Future Directions

Progress in managing TNBC in India will depend on a coordinated research agenda that reflects local needs. Prospective multicenter studies evaluating NST patterns, real-world pCR and RCB distributions, treatment-related adverse events, and determinants of treatment adherence are essential. Pragmatic trials comparing anthracycline-sparing regimens, immunotherapy combinations, and escalation strategies for residual disease would generate evidence directly applicable to Indian practice. Integrating patient-reported outcomes and cost-effectiveness analyses will help in designing treatment strategies that are both clinically robust and economically feasible.

A national TNBC registry, ideally linked through the NCG, would greatly enhance real-world evidence generation. Such a platform could harmonize documentation of staging, tumor biology, surgical outcomes, treatment sequencing, and survival across different institutions. The adoption of synoptic pathology and radiology templates and systematic documentation of multidisciplinary decisions would support consistent data capture and facilitate benchmarking. Establishing an Indian expert consensus through collaborative networks, evidence synthesis, and regular updates is pivotal to optimizing care for TNBC and overcoming disparities.

Investing in human resource development across the cancer care continuum is equally important. Training programs through the NCG could strengthen competencies in neoadjuvant decision-making, response assessment, immune-related toxicity management, and standardized reporting. Expanding access to germline BRCA testing and building laboratory capacity for biomarkers, such as TILs, PD-L1, TMB, and circulating tumor DNA, will support the transition toward precision oncology. These measures can form a cohesive framework that links evidence generation, capacity building, and equitable delivery of TNBC care across India.

Position statements

Conclusion

The integration of NST and immunotherapy has reshaped the treatment landscape for TNBC, shifting practice toward more individualized, response-guided care. pCR continues to serve as a reliable indicator of a favorable prognosis, while tools such as the RCB index and early germline BRCA testing enable more precise decisions regarding when to escalate or de-escalate adjuvant therapy. The benefits demonstrated with pembrolizumab and adjuvant olaparib illustrate how targeted approaches can translate biological understanding into meaningful clinical improvement. For these advances to be fully realized within the Indian healthcare system, coordinated efforts are needed to strengthen diagnostic capacity, streamline care pathways, and expand clinician training. Establishing a national TNBC registry, reinforcing multidisciplinary workflows, and improving laboratory access for germline and biomarker testing represent practical steps that can elevate care quality across diverse settings. Equal attention must be given to patient-centered implementation, including reliable access to immunotherapy and structured systems for recognizing and managing immune-related toxicities. With sustained investment in research, infrastructure, and clinical capacity, precision-focused neoadjuvant care can become widely accessible in India. Such progress has the potential to improve survival outcomes and enhance the day-to-day experience of patients with TNBC, ensuring that scientific advances translate into equitable and meaningful gains.

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Annexure 1:

PubMed search strategy (13-11-2025)

StepConceptSearch Query
#1Population “Triple Negative Breast Neoplasms”[MeSH Terms] OR “triple-negative breast cancer”[All Fields] OR “TNBC”[All Fields] OR (“breast cancer”[All Fields] AND (((“triple”[All Fields] OR “triples”[All Fields]) AND (“negative”[All Fields] OR “negatively”[All Fields] OR “negatives”[All Fields] OR “negativities”[All Fields] OR “negativity”[All Fields])) OR “basal-like”[All Fields]))
#2Neoadjuvant Therapy“neoadjuvant systemic therapy”[All Fields] OR “NST”[All Fields] OR “preoperative chemotherapy”[All Fields] OR “pathologic complete response”[All Fields] OR “pCR”[All Fields] OR “Residual Cancer Burden”[All Fields] OR “rcb”[All Fields]
#3Immunotherapy “immune checkpoint inhibitor”[All Fields] OR “pembrolizumab”[All Fields] OR “PD-1 inhibitor”[All Fields] OR “PD-L1 inhibitor”[All Fields] OR “nivolumab”[All Fields] OR “durvalumab”[All Fields] OR “immunotherapy”[All Fields]
#4Outcomes “event-free survival”[All Fields] OR “EFS”[All Fields] OR “overall survival”[All Fields] OR “OS”[All Fields] OR “breast conserving surgery”[All Fields] OR “axillary downstaging”[All Fields] OR “tumor downstaging”[All Fields]
#5 Final combined search  (#1) AND (#2 OR #3) AND (#4)(“Triple Negative Breast Neoplasms”[MeSH Terms] OR “triple-negative breast cancer”[All Fields] OR “TNBC”[All Fields] OR (“breast cancer”[All Fields] AND (((“triple”[All Fields] OR “triples”[All Fields]) AND (“negative”[All Fields] OR “negatively”[All Fields] OR “negatives”[All Fields] OR “negativities”[All Fields] OR “negativity”[All Fields])) OR “basal-like”[All Fields]))) AND (“neoadjuvant systemic therapy”[All Fields] OR “NST”[All Fields] OR “preoperative chemotherapy”[All Fields] OR “pathologic complete response”[All Fields] OR “pCR”[All Fields] OR “Residual Cancer Burden”[All Fields] OR (“can j bioeth”[Journal] OR “rcb”[All Fields]) OR (“immune checkpoint inhibitor”[All Fields] OR “pembrolizumab”[All Fields] OR “PD-1 inhibitor”[All Fields] OR “PD-L1 inhibitor”[All Fields] OR “nivolumab”[All Fields] OR “durvalumab”[All Fields] OR “immunotherapy”[All Fields])) AND (“event-free survival”[All Fields] OR “EFS”[All Fields] OR “overall survival”[All Fields] OR “OS”[All Fields] OR “breast conserving surgery”[All Fields] OR “axillary downstaging”[All Fields] OR “tumor downstaging”[All Fields])