Cancer Research, Statistics, and Treatment

REVIEW ARTICLE
Year
: 2021  |  Volume : 4  |  Issue : 4  |  Page : 668--676

Management of triple-negative breast cancer in the era of novel therapies: A narrative review


Rakesh Kumar Sharma, Ajay Gogia 
 Department of Medical Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Ajay Gogia
357, Gautam Nagar, New Delhi - 110 049
India

Abstract

The evolution of therapeutics for triple-negative-breast cancer (TNBC) has been lagging behind in comparison to that of other breast cancer subtypes. This review focuses on the recent developments with the potential to change future clinical practice. We searched the PubMed database for randomized trials on TNBC published in the past 2 years using the key term, “Triple-negative breast cancer.” Abstracts and outcomes of various studies presented at major oncology meetings were also assessed. A total of 54 studies were included in this review. Recent advances in molecular studies have delineated several cellular alterations revealing various targetable biomarkers. In addition, immunotherapeutic agents are being explored in the neoadjuvant setting and have shown major improvements in pathological complete response. Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have transformed the management of TNBC, especially breast cancer gene-1/2 (BRCA1/2)-mutant and homologous recombination repair-deficient tumors. PARPi are now being utilized in the neoadjuvant setting, for maintenance following definitive treatment, and in metastatic disease. Sacituzumab govitecan has demonstrated improved outcomes in relapsed/refractory metastatic TNBC and has been approved for this indication. Capivasertib and ipatasertib have demonstrated promising results in patients harboring alterations in the phosphatidylinositol-3-kinase (PI3K)/protein kinase B pathway.



How to cite this article:
Sharma RK, Gogia A. Management of triple-negative breast cancer in the era of novel therapies: A narrative review.Cancer Res Stat Treat 2021;4:668-676


How to cite this URL:
Sharma RK, Gogia A. Management of triple-negative breast cancer in the era of novel therapies: A narrative review. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Aug 11 ];4:668-676
Available from: https://www.crstonline.com/text.asp?2021/4/4/668/334183


Full Text



 Introduction



Triple-negative breast cancer (TNBC) constitutes 15% of all breast cancers diagnosed worldwide.[1],[2],[3] The prevalence in India is higher than that in the Western countries; in India, TNBCs constitute 27% of all diagnosed breast cancers.[4] As there are no established targetable biomarkers, chemotherapy remains the major therapeutic arsenal for TNBC. However, advances in molecular studies have led to the classification of TNBCs into particular molecular subtypes; the various TNBC subtypes have defects in several cellular pathways, making them potentially targetable biomarkers.[5],[6],[7] Marra et al., highlighted the importance of biomarker-driven management of TNBC and suggested a practical classification of TNBCs into four subtypes, based on the altered pathways: Immune-enriched, luminal androgen receptor (LAR), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) activated, and DNA repair-deficient TNBCs.[8] Targeted therapies have been approved in various settings e.g., olaparib, or are in the pipeline for approval like AKT inhibitors.[9] With better understanding of the disease biology, chemotherapeutic agents like platinum compounds are being explored in various settings, especially in germline breast cancer gene-1/2 (BRCA1 or BRCA2)-mutant TNBC.[2] The advent of immunotherapy has been a major breakthrough and holds the potential to change the management of TNBC in future.[2]

In this review, we aim to describe the recent updates in the management of TNBC that have the potential to change future clinical practice.

 Methods



We comprehensively searched the PubMed database for randomized clinical trials published on TNBC treatment between July 1, 2019, and August 31, 2021, using the key term “Triple-negative breast cancer.” Abstracts and presentations on TNBC discussed in the San Antonio Breast Cancer Symposium (SABCS), European Society for Medical Oncology, and American Society of Clinical Oncology annual meetings for the years 2020 and 2021 were also screened. A total of 155 studies and abstracts published in the English language were screened and 101 were excluded. The authors independently reviewed the literature to identify trials with novel therapeutic interventions that could potentially change future clinical practice, including trials with negative results. A total of 54 studies were finally included in the review based on the consensus of all authors. The method used for the selection of articles is shown in [Figure 1].{Figure 1}

 Early-Stage and Locally Advanced Triple-Negative-Breast-Cancer



Despite major breakthroughs in other breast cancer subtypes, chemotherapy has remained the therapeutic backbone in the management of TNBC. Patients with tumor size ≥ 0.5 cm or lymph node involvement merit chemotherapy.[10],[11] Management principles of TNBC are similar to those of other subtypes of breast cancer. Early-stage TNBCs are usually managed with surgical resection followed by adjuvant chemotherapy, while in locally advanced disease, neoadjuvant chemotherapy (NACT) is the preferred modality.[10],[11] TNBCs are chemosensitive, as indicated by the higher pathological complete response (pCR) rates ranging from 30% to 40% with anthracycline-and taxane-based chemotherapy. Higher pCR rates translate into longer disease-free survival (DFS).[12],[13],[14] Although these tumors demonstrate higher clinical response rates to chemotherapy than other subtypes, their recurrence risk is greater along with poor outcomes.[11] Some of the important trials on TNBC conducted in the curative and metastatic settings are highlighted in [Table 1].{Table 1}

Systemic chemotherapy

Neoadjuvant and adjuvant chemotherapy consisting of anthracyclines and taxanes is the current standard for early and locally advanced TNBC.[10] Increasing the intensity and altering the sequence of administration of chemotherapy has been shown to have beneficial effects in breast cancer.[2] Gray et al. highlighted in their meta-analysis that dose-dense chemotherapy in comparison to conventional chemotherapy lowered the 10-year recurrence and mortality rates by 10% and 15%, respectively.[15] The maximal benefit was observed in estrogen receptor (ER)-negative tumors, with an absolute benefit of 3.7% in the 10-year recurrence risk compared to 3.1% in ER-positive tumors.[15]

There has been a paradigm shift favoring the use of NACT in TNBC, as it allows for the evaluation of pathological response. Achievement of pCR is an established surrogate marker for long-term survival outcomes.[16] The beneficial effect of dose-dense chemotherapy has been extrapolated to the neoadjuvant setting with fair improvements in pCR rates.[17],[18] However, patients not achieving pCR had higher relapse rates and dismal outcomes.[16],[19],[20] Masuda et al. demonstrated that patients not achieving pCR derived considerable benefit from adjuvant capecitabine, with a 5-year DFS of 69.8% in the capecitabine arm versus 56.1% in the observation arm (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.39–0.87) and a 5-year overall survival (OS) rate of 78.8% in the capecitabine arm versus 70.3% in the observation arm (HR, 0.52; 95% CI, 0.30–0.90).[21]

Novel strategies

TNBCs have high mutational burden, resulting in the production of neo-antigens, which ultimately activate the immunogenic pathway and lead to antitumor response.[22] Moreover, it is hypothesized that there is increased infiltration of tumor-infiltrating lymphocytes in TNBC.[23] Based on this hypothesis, various immunotherapeutic agents have been explored in the management of TNBC.

KEYNOTE-173, a phase-Ib trial, assessed the addition of pembrolizumab to NACT, with or without carboplatin, and reported a pCR rate of 60% (range, 49%–71%) with an acceptable safety profile in locally advanced TNBC.[24] Similarly in I-SPY2, a phase II trial, a higher pCR rate of 60% was demonstrated with the addition of pembrolizumab in the TNBC cohort; the pCR rate was 22% in the chemotherapy only arm.[25] Based on the promising results of the above trial, pembrolizumab was evaluated in a phase III trial, KEYNOTE-522. A total of 1174 patients with early-stage TNBC were randomized to receive NACT with carboplatin and paclitaxel (TP) followed by anthracycline and cyclophosphamide with or without pembrolizumab.[26] Additionally, patients in the pembrolizumab arm received nine cycles of maintenance pembrolizumab.[26] The pembrolizumab arm had a significantly higher pCR rate than the chemotherapy arm (64.8% vs. 51.2%; P < 0.001).[26] pCR benefit was greater in the patients with programmed-death-ligand-1 (PD-L1) positive tumors (combined positive score [CPS] >1%) (68.9% vs. 54.9%) as compared to PD-L1 negative tumors (45.3% vs. 30.3%).[26] Treatment-related grade 3/4 toxicities were higher in the pembrolizumab combination arm compared to the chemotherapy arm, but this did not interfere with the administration of the pre-planned combination schedule.[26] Interim analysis demonstrated an event-free survival benefit with the pembrolizumab combination (HR, 0.63, 95% CI, 0.43–0.93).[26] As this trial was designed before the results of the CREATE-X trial came out, adjuvant capecitabine was not allowed in patients not achieving pCR.[26]

Similarly, IMpassion031, a placebo-controlled phase III trial, studied the addition of atezolizumab to dose-dense NACT with nab-paclitaxel (weekly) followed by doxorubicin plus cyclophosphamide. The rationale behind nab-paclitaxel use was to minimize steroid use and achieve higher tumor cytotoxicity along with the release of neo-antigens, which would result in a potent immune response leading to favorable pCR rates. Adjuvant capecitabine was allowed in patients who failed to achieve pCR. The addition of atezolizumab resulted in an improvement in the pCR from 41% to 58% (P = 0.0044), irrespective of the PD-L1 status. pCR benefit was higher in PD-L1-positive (CPS >1%) tumors (68.8% vs. 49.3%) than in PD-L1 negative tumors (47.7% vs. 34.4%).

Patients with TNBC have impaired DNA damage repair pathways, higher prevalence of BRCA1/2 mutations, and BRCAness, which make these tumors sensitive to platinum compounds, as unfolded in various preclinical studies.[10],[11] Based on the concept of synthetic lethality, poly-adenosine di-phosphate ribose polymerase inhibitors (PARPi) have been introduced for BRCA-mutant or homologous recombination repair (HRR)-deficient tumors.[27]

In PARTNER, a phase II/III trial, the addition of olaparib to paclitaxel/carboplatin followed by anthracycline-based NACT was evaluated in basal type and germline BRCA-mutated TNBC. Safety analysis of this regimen was reported at the SABCS 2019, and it showed that that the combination of olaparib with NACT had a manageable toxicity profile.[28]

Talazoparib was evaluated as single-agent NACT in a single-arm, phase II study, in germline BRCA-mutated breast cancer. In this pilot study on 20 patients with breast cancer, of which 15 had TNBC, neoadjuvant talazoparib was given for 6 months followed by definitive surgery and adjuvant chemotherapy. A pCR rate of 57% was observed in the TNBC cohort, establishing the efficacy of single-agent PARPi, especially in germline-mutated TNBC.[29]

A novel NACT regimen containing eribulin was studied in a parallel-group, phase II trial, JBCRG-22. Patients were stratified by age, germline BRCA mutation status, and homologous recombination deficiency (HRD) score. Patients aged less than 65 years with high HRD scores and germline BRCA mutations were treated with either weekly paclitaxel and carboplatin or eribulin and carboplatin followed by an anthracycline combination regimen. The pCR rate was 65% (46%–81%) in the paclitaxel arm and 45% (27%–65%) in the eribulin arm. A pCR rate of 19% (8%–35%) was achieved in older patients with wild-type BRCA and low HRD scores. This study highlights the importance of BRCA mutations and HRD testing in patients with TNBC and the unusual sensitivity to platinum-based chemotherapy in this subset of patients.[30]

Yuan et al. evaluated neoadjuvant carboplatin with nab-paclitaxel in stage II/III TNBC. The observed pCR rate was 48%, and patients with immune-hot GeparSixto immune signature [G6-Sig]) had higher pCR rates (odds ratio [OR], 7.19; 95% CI, 2.01–25.68; P = 0.002). In addition, patients with defects in DNA repair pathways were found to have higher odds of achieving pCR (OR, 6.93; 95% CI, 1.32–36.47; P = 0.022). This study also highlights the higher immunogenicity of TNBC.[31]

Improvising on the results of the CREATE-X trial, adjuvant olaparib for 1 year was assessed in patients with germline BRCA-mutated human epidermal receptor 2 (HER2)-negative breast cancers not achieving pCR following NACT or in those with pT2 or N1 disease treated with adjuvant chemotherapy. The majority of the patients had TNBC, and after a median follow-up of 2.5 years, the 3-year invasive DFS rate was 85.9% in those who received olaparib maintenance and 77.1% in those who did not (HR, 0.58; 95% CI, 0.41–0.82; P < 0.001); the 3-year distant DFS rate was 87.5% in those who received olaparib maintenance and 80.4% in those who did not (HR 0.57; 95% CI 0.39–0.83; P < 0.001). However, there was no significant difference in the 3-year OS rate (92% vs. 88.3%; HR, 0.68; 95% CI, 0.44–1.05; P = 0.02).[32]

Exploring the role of oral maintenance therapy, the SYSUCC-001 trial evaluated the impact of adjuvant capecitabine at a lower dose of 650 mg/m2 for 1 year in patients with stage Ib–IIIc TNBC following the completion of definitive treatment. There was a 5-year DFS benefit observed in the capecitabine arm in comparison to the observation arm (83% vs. 73%; HR, 0.63; 95% CI, 0.42–0.96; P = 0.027); but, this did not translate into an OS benefit.[33] However, a longer follow-up may delineate the OS benefit. Contrary to the above findings, the GEICAM trial with a similar design but a higher dosage of capecitabine failed to show any DFS benefit with capecitabine.[34] This highlights the fact that low-dose metronomic chemotherapy might have durable effects in TNBC. The beneficial effect of metronomic therapy was highlighted in a retrospective study from the Tata Memorial Hospital (Mumbai, India); in this study, the 5-year DFS was 90% in the metronomic therapy arm and 56% in the observation arm. Metronomic therapy comprised two phases; the initial phase consisted of daily celecoxib and oral cyclophosphamide for 12 weeks along with intravenous cisplatin (25 mg/m2) weekly for 12 weeks, while phase 2 of maintenance therapy consisted of metformin and oral cyclophosphamide daily along with oral methotrexate weekly.[35]

Similarly, platinum compounds (carboplatin, area under the curve-6 or cisplatin 75 mg/m2) were compared to capecitabine in the ECOG-ACRIN EA1131 trial, in patients with TNBC having residual disease following NACT. Platinum-based regimens were neither non-inferior nor superior to capecitabine with a 3-year predicted recurrence-free survival of 46% and 49%, respectively (HR, 0.99; 95% CI, 0.67–1.45) and 3-year predicted OS of 58% and 69%, respectively (HR, 1.13; 95% CI, 0.71–1.79). There were higher hematological toxicities with platinum-based regimes requiring dose reduction in 41.6% of the patients. Hence, capecitabine should remain the standard-of-care in patients who do not achieve pCR.

Even though NACT in TNBC is gaining recognition, adjuvant chemotherapy continues to play an important role. Further improvement in the established standard was attempted in the CBCSG010 trial. In this trial, patients with early-stage TNBC who underwent definitive surgery were randomized to receive either capecitabine with docetaxel followed by capecitabine with epirubicin and cyclophosphamide or docetaxel followed by 5-fluorouracil with epirubicin and cyclophosphamide. Patients in the capecitabine arm fared better with a 5-year DFS of 86.3% than those in the control arm who had a 5-year DFS of 80.4% (HR, 0.66; 95% CI, 0.44–0.99; P = 0.044). However, there was no OS benefit (93.3% vs. 90.7% for capecitabine vs. control; p = not significant). The toxicity profile was similar in both arms.[36]

Adjuvant carboplatin plus paclitaxel (PCb) was compared with cyclophosphamide plus epirubicin plus 5-fluorouracil followed by docetaxel (CEF-T) in the phase III PATTERN trial. Patients treated with PCb had significantly longer DFS than those treated with CEF-T. The 5-year DFS was 86.5% in the PCb arm and 80.3% in the CEF-T arm (HR, 0.65; 95% CI, 0.44–0.96; P = 0.03) after a median follow-up of 62 months. However, PCb did not result in an OS benefit over CEF-T (HR, 0.71; 95% CI, 0.42–1.22; P = 0.22). In an exploratory analysis, the DFS benefit due to PCb was found to be maximum in patients with HRR-deficient tumors (HR, 0.39; 95% CI, 0.15–0.99; P = 0.04). Even though the comparator arm in this trial was not the current standard of care, PCb can be offered to patients with contraindications to anthracyclines.[37]

 Metastatic Disease



Approximately one-third of the patients with TNBC have metastatic disease at presentation or develop metastases during the disease course.[1] Conventionally, chemotherapy has been the mainstay of treatment for metastatic TNBC. However, this decades-long dogma has changed with better understanding of the disease biology and delineation of the molecular subtypes.[2] Nevertheless, chemotherapy continues to play an important role in resource-limited countries like India. Although single-agent chemotherapy is the preferred treatment approach for TNBC, patients with a higher tumor burden and good performance status merit combination chemotherapy.[1],[2],[11] Platinum-based chemotherapy has superior response rates and prolongs the progression-free survival (PFS) in comparison to non-platinum-containing regimens, especially in BRCA-mutated tumors (6.8 vs. 4.4 months; P = 0.002).[38]

Immunotherapy

The IMpassion-130 trial led to the approval of a combination of atezolizumab and nab-paclitaxel for patients with PD-L1 expressing advanced/metastatic TNBC in the first-line setting.[39] To further expand the chemotherapy backbone with atezolizumab, IMpassion131 investigated paclitaxel in combination with atezolizumab. The study failed to meet its primary endpoint, with no PFS benefit in patients with PD-L1 expression ≥1% in the intervention arm (6 vs. 5.7 months; HR, 0.82; 95% CI, 0.60–1.12; P = 0.2). The use of paclitaxel as the chemotherapy backbone and the slightly higher number of taxane pretreated patients in IMpassion131 could explain the lack of any survival benefit.[40]

In KEYNOTE-355, a placebo-controlled, phase III trial, investigator's choice chemotherapy was explored with or without pembrolizumab in patients with advanced TNBC. The trial demonstrated a significant PFS benefit of 7.5 months in the pembrolizumab arm as opposed to 5.6 months in the placebo arm (HR, 0.82; 95% CI, 0.69–0.97). Patients with PD-L1 CPS ≥10 showed maximal benefit with a median PFS of 9.7 months in the pembrolizumab arm and 5.6 months in the placebo arm (HR, 0.65; 95% CI, 0.49–0.86; P = 0.0012). In contrast to the findings of the IMpassion 131 trial, the maximal benefit was derived from the addition of pembrolizumab to paclitaxel, which translated into an objective response rate (ORR) of 63.6% in patients with CPS ≥10. In an exploratory analysis, the beneficial effects improved with an increasing CPS. There was no deviation from the known toxicity profile.[41]

To expand the therapeutic armamentarium beyond the first-line treatment, the KEYNOTE-119 trial compared pembrolizumab monotherapy with palliative chemotherapy. The study did not meet its primary endpoint, and there was no OS benefit in patients with CPS ≥10 with pembrolizumab monotherapy compared to palliative chemotherapy (12.7 vs. 11.6 months; HR, 0.78; 95% CI, 0.57–1.06; P = 0.057). However, in a subgroup analysis, patients with CPS of ≥20 showed better OS with pembrolizumab monotherapy compared to palliative chemotherapy (14.9 vs. 12.5 months; HR, 0.58; 95% CI, 0.38–0.88). Pembrolizumab had a better safety profile than palliative chemotherapy, with fewer grade-3-5 treatment-related adverse events (14% vs. 36%).[42]

Poly-adenosine diphosphate ribose polymerase inhibitors

Both olaparib and talazoparib were approved for previously treated advanced/metastatic HER2-negative breast cancers with germline BRCA mutations based on the results of the OlympiAD and EMBRACA trials.[43],[44] Although in both these trials the comparator arm did not include platinum compounds, olaparib and talazoparib were both found to be effective in patients previously exposed to platinum compounds.

The LUCY trial confirmed the clinical usefulness of olaparib in patients with germline BRCA-mutated, HER2-negative, metastatic breast cancer following a maximum of two prior lines of treatment. Median PFS for the entire cohort and those with TNBC was 8.1 months (95% CI, 6.93–8.67) and 6.8 months (95% CI, 5.52–9.0), respectively. The OlympiAD trial reported a similar PFS of 7 months. This trial further strengthens the clinical efficacy of olaparib in germline BRCA-mutated, HER2-negative, metastatic breast cancer without any new toxicity alerts.[45]

To investigate the addition of PARPi to chemotherapy, the BROCADE3 trial was designed, in which patients with germline BRCA-mutated advanced/metastatic breast cancer post two or more lines of therapy were randomized to receive either veliparib with paclitaxel and carboplatin (TP) or TP alone. The combination demonstrated a better median PFS as compared to TP (14.5 vs. 12.6 months; HR, 0.71; 95% CI, 0.57–0.88; P = 0.0016). There was no OS benefit observed with combination therapy in this interim analysis (median OS was 33.5 vs. 28.2 months in the combination vs. TP arm; HR, 0.95; 95% CI, 0.73–1.23; P = 0.67). The OS benefit may have been diluted because patients in the TP arm were allowed to receive veliparib on progression. In addition, the TNBC subgroup did not show any significant PFS benefit in the combination arm compared to the TP arm (16.6 vs. 14.1 months; HR, 0.72; 95% CI, 0.52–1.01). This study highlights the utility of the combination of active agents (platinum compounds and PARPi) in patients with germline BRCA-mutated tumors.[46]

Sacituzumab govitecan

Sacituzumab govitecan (SG) is an antibody-drug conjugate comprising anti-trophoblast cell-surface antigen-2 (Trop-2) monoclonal antibody and SN-38 (an active irinotecan metabolite). It received accelerated approval for patients with TNBC post two or more lines of treatment on the basis of the results of a phase I/II trial demonstrating an ORR of 33.3%, median PFS of 5.5 months (95% CI, 4.1–6.3) and OS of 13.0 months (95% CI, 11.2–13.7). Toxicities of clinical importance (grade ≥3 toxicities observed in ≥10% of the patients) included neutropenia in 45 (42%) patients, febrile neutropenia in 10 (9.3%) patients, anemia in 12 (11%) patients, and leukopenia in 12 (11%) patients.[47] These results were further verified in the phase III ASCENT trial, that compared SG with single-agent chemotherapy of investigator's choice in patients with metastatic TNBC and without brain metastasis exposed to two or more prior lines of therapy. Patients treated with SG had longer median PFS (5.6 vs. 1.7 months; HR, 0.41; 95% CI, 0.32–0.52; P < 0.001) and OS (12.1 vs. 6.7 months; HR, 0.48; 95% CI, 0.38-0.59; P < 0.001) than those treated with chemotherapy, along with higher myelosuppression and diarrhea but manageable toxicities.[48] Thus, SG is a new for heavily pre-treated patients with metastatic TNBC.

Androgen receptor inhibitors

Androgen receptor (AR) is expressed in about 20%–40% of TNBCs, making it a potentially targetable biomarker.[49] However, trials addressing the role of AR inhibitors have shown only a modest benefit.[50],[51] The LAR subtype of TNBC has activating mutations in the phosphatidylinositol-4,5-biphosphate-3-kinase (PIK3CA) gene in 40%–50% of the cases, and a synergistic effect has been demonstrated by targeting both PIK3CA and AR in LAR TNBC cell lines.[49] This was addressed in a phase Ib/II trial by Lehmann et al., in patients with AR-positive TNBC targeted with enzalutamide plus taselisib (PIK3CA inhibitor). The trial was terminated prematurely because of the poor efficacy of taselisib as shown in the SANDPIPER trial. However, the clinical benefit rate (CBR) at 16 weeks in evaluable patients was 35.7%, and the LAR subtype had better CBR as compared to other subtypes (75% vs. 12.5%; P = 0.06).[49] As the sample size was small, no major conclusion could be drawn from this study. Another phase II study of the combination of enobosarm (selective AR modulator) with pembrolizumab failed to show any meaningful benefit in AR-positive TNBC.[52] Thus, the role of AR inhibitors in TNBC remains investigational.

Other therapies

PI3K/Akt/mTOR is one of the frequently involved cell cycle regulatory pathways in TNBC carcinogenesis, either due to mutations in PI3K/Akt or PTEN alterations.[10] Ipatasertib was the first Akt inhibitor investigated in combination with paclitaxel in the first-line setting in advanced TNBC and demonstrated a modest benefit.[53] Capivasertib is an Akt inhibitor with higher potency and activity against all isoforms of Akt. It was assessed in combination with weekly paclitaxel in the PAKT phase II trial as first-line therapy for metastatic TNBC. The trial demonstrated an improvement in the median PFS from 3.6 to 5.5 months (HR, 0.64; 95% CI, 0.43–0.95; P = 0.01) and median OS from 12.6 to 19.1 months (HR 0.61; 95% CI 0.37–0.99; P = 0.04). In the subgroup of patients with alterations in the PIK3CA/Akt1/PTEN pathway, capivasertib demonstrated a PFS benefit (9.3 vs. 3.6 months; HR, 0.14; 95% CI, 0.05–0.44; P < 0.001).[54]

In the era of precision oncology, cancer vaccines are a major development, and TNBC is one of the malignancies being explored in this field. Potential candidates include the NY-ESO-1 protein cancer vaccine, personalized peptide vaccination, and antigen-presenting cell and dendritic cell-based cancer vaccines. Preclinical data have shown promising results and several vaccines are being explored in various trials.[55]

Bevacizumab with various chemotherapy combinations has been evaluated in the neoadjuvant and metastatic settings. However, the results have been conflicting and its use is still investigational in TNBC.[56]

A suggested algorithm for the management of a patient with TNBC is outlined in [Figure 2].{Figure 2}

 Future Directions



The concept of minimal residual disease in hematological malignancies is being extrapolated to solid malignancies as a method to predict future relapse. Detecting circulating tumor DNA (ctDNA) or circulating tumor cells (CTC) is one of the few established methods to predict relapse. A secondary analysis of the 196 patients randomized in the BRE12-158 trial highlighted that patients with persisting ctDNA and CTC following NACT had dismal outcomes.[57] This strategy has the potential to revolutionize our understanding of disease biology and may help in better risk stratification of patients in future. This marks the beginning of a new era in the management of TNBC and the development of future therapies.

 Conclusion



Molecular studies have revolutionized the understanding of disease biology and the natural history of TNBC. With a better understanding of the disease, the focus has shifted from chemotherapy to novel combination therapies including targeted therapy and immunotherapy. The concepts of ctDNA and CTC may help in predicting early relapse, thus enabling early intervention. Despite these advances, the outcomes of TNBC continue to be poorer as compared to those of other subtypes, and further studies are needed to better understand this enigmatic disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Caparica R, Lambertini M, de Azambuja E. How I treat metastatic triple-negative breast cancer. ESMO Open 2019;4 Suppl 2:e000504.
2Mehanna J, Haddad FG, Eid R, Lambertini M, Kourie HR. Triple-negative breast cancer: Current perspective on the evolving therapeutic landscape. Int J Womens Health 2019;11:431-7.
3Gogia A, Deo SV, Shukla NK, Mathur S, Sharma DN, Tiwari A. Clinicopathological profile of breast cancer: An institutional experience. Indian J Cancer 2018;55:210-3.
4Kulkarni A, Kelkar DA, Parikh N, Shashidhara LS, Koppiker CB, Kulkarni M. Meta-analysis of prevalence of triple-negative breast cancer and its clinical features at incidence in Indian patients with breast cancer. JCO Glob Oncol 2020;6:1052-62.
5Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 2015;21:1688-98.
6Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.
7Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of triple-negative breast cancer molecular subtypes: Implications for neoadjuvant chemotherapy selection. PLoS One 2016;11:1-22.
8Marra A, Trapani D, Viale G, Criscitiello C, Curigliano G. Practical classification of triple-negative breast cancer: Intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies. NPJ Breast Cancer 2020;6:54.
9Núñez Abad M, Calabuig-Fariñas S, Lobo de Mena M, José Godes Sanz de Bremond M, García González C, Torres Martínez S, et al. Update on systemic treatment in early triple negative breast cancer. Ther Adv Med Oncol 2021;13:1-18.
10Park JH, Ahn JH, Kim SB. How shall we treat early Triple-Negative Breast Cancer (TNBC): From the current standard to upcoming immuno-molecular strategies. ESMO Open 2018;3:e000357.
11Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 2016;13:674-90.
12Pilewskie M, Morrow M. Axillary nodal management following neoadjuvant chemotherapy: A review. JAMA Oncol 2017;3:549-55.
13Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275-81.
14von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-804.
15Gray R, Bradley R, Braybrooke J, Liu Z, Peto R, Davies L, et al. Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: A patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet 2019;393:1440-52.
16Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 2014;384:164-72.
17Ding Y, Ding K, Yang H, He X, Mo W, Ding X. Does dose-dense neoadjuvant chemotherapy have clinically significant prognostic value in breast cancer? A meta-analysis of 3,724 patients. PLoS One 2020;15:e0234058.
18Reinisch M, Ataseven B, Kümmel S. Neoadjuvant dose-dense and dose-intensified chemotherapy in breast cancer – Review of the literature. Breast Care (Basel) 2016;11:13-20.
19Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: A comprehensive meta-analysis. Clin Cancer Res 2020;26:2838-48.
20Huang M, O'Shaughnessy J, Zhao J, Haiderali A, Cortes J, Ramsey S, et al. Evaluation of pathologic complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer. J Natl Compr Canc Netw 2020;18:1096-104.
21Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;376:2147-59.
22Liu Z, Li M, Jiang Z, Wang X. A comprehensive immunologic portrait of triple-negative breast cancer. Transl Oncol 2018;11:311-29.
23Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 2018;19:40-50.
24Schmid P, Salgado R, Park YH, Muñoz-Couselo E, Kim SB, Sohn J, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: Results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol 2020;31:569-81.
25Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: An analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol 2020;6:676-84.
26Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-21.
27Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: What's next after PARP inhibitors? Nat Rev Clin Oncol 2018;15:564-76.
28Alba KP, McMurtry E, Vallier AL, Grybowicz L, Copson E, Armstrong A, et al. Abstract P3-10-05: Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. Cancer Res 2020;80 Suppl 4:P3-10-05.
29Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol 2020;38:388-94.
30Masuda N, Bando H, Yamanaka T, Kadoya T, Takahashi M, Nagai SE, et al. Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: A multicenter randomized phase II clinical trial. Breast Cancer Res Treat 2021;188:117-31.
31Yuan Y, Lee JS, Yost SE, Li SM, Frankel PH, Ruel C, et al. Phase II trial of neoadjuvant carboplatin and nab-paclitaxel in patients with triple-negative breast cancer. Oncologist 2021;26:e382-93.
32Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 2021;384:2394-405.
33Wang X, Wang SS, Huang H, Cai L, Zhao L, Peng RJ, et al. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with early-stage triple-negative breast cancer who had received standard treatment: The SYSUCC-001 randomized clinica. JAMA 2021;325:50-8.
34Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, et al. Phase III trial of adjuvant capecitabine after standard neo-/adjuvant chemotherapy in patients with early triple-negative breast cancer (GEICAM/2003-11_CIBOMA/2004-01). J Clin Oncol 2020;38:203-13.
35Bajaj K, Banavali S. Abstract PS11-30: Can Metronomic Maintenance Therapy (MMT) after completion of standard therapy help prevent relapses in Patients (Pts) with non-metastatic Triple-Negative Breast Cancer (TNBC). Cancer Res 2021;81 Suppl 4:PS11-30.
36Li J, Yu K, Pang D, Wang C, Jiang J, Yang S, et al. Adjuvant capecitabine with docetaxel and cyclophosphamide plus epirubicin for triple-negative breast cancer (CBCSG010): An open-label, randomized, multicenter, phase III trial. J Clin Oncol 2020;38:1774-84.
37Yu KD, Ye FG, He M, Fan L, Ma D, Mo M, et al. Effect of adjuvant paclitaxel and carboplatin on survival in women with triple-negative breast cancer: A phase 3 randomized clinical trial. JAMA Oncol 2020;6:1390-6.
38Tutt A, Tovey H, Cheang MC, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT trial. Nat Med 2018;24:628-37.
39Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:2108-21.
40Miles D, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios C, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol 2021;32:994-1004.
41Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817-28.
42Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): A randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:499-511.
43Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523-33.
44Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753-63.
45Gelmon KA, Fasching PA, Couch FJ, Balmaña J, Delaloge S, Labidi-Galy I, et al. Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: Phase IIIb LUCY interim analysis. Eur J Cancer 2021;152:68-77.
46Diéras V, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub JP, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:1269-82.
47Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 2019;380:741-51.
48Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 2021;384:1529-41.
49Lehmann BD, Abramson VG, Sanders ME, Mayer EL, Haddad TC, Nanda R, et al. TBCRC 032 IB/II multicenter study: Molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+metastatic triple-negative breast cancer. Clin Cancer Res 2020;26:2111-23.
50Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res 2013;19:5505-12.
51Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 2018;36:884-90.
52Yuan Y, Lee JS, Yost SE, Frankel PH, Ruel C, Egelston CA, et al. A phase II clinical trial of pembrolizumab and enobosarm in patients with androgen receptor-positive metastatic triple-negative breast cancer. Oncologist 2021;26:99-e217.
53Kim SB, Dent R, Im SA, Espié M, Blau S, Tan AR, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2017;18:1360-72.
54Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: The PAKT trial. J Clin Oncol 2020;38:423-33.
55Li Z, Qiu Y, Lu W, Jiang Y, Wang J. Immunotherapeutic interventions of triple negative breast cancer. J Transl Med 2018;16:147.
56Sun Z, Lan X, Xu S, Li S, Xi Y. Efficacy of bevacizumab combined with chemotherapy in the treatment of HER2-negative metastatic breast cancer: A network meta-analysis. BMC Cancer 2020;20:180.
57Radovich M, Jiang G, Hancock BA, Chitambar C, Nanda R, Falkson C, et al. Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy with Disease recurrence in patients with triple-negative breast cancer: Preplanned secondary analysis of the BRE12-158 randomized clinical trial. JAMA Oncol 2020;6:1410-5.