Metastatic triple-negative breast cancer: Established and emerging treatments
1 | INTRODUC TION
Breast cancer is the most common diagnosed cancer and the second most common cause of cancer-related death in women worldwide.1 Approximately 15%-20% of all breast carcinomas demonstrate lack of estrogen receptor, progesterone receptor, and HER2 by immunohistochemistry and FISH and are classified as TNBC.1 Patients with TNBC have a highly aggressive clinical course, with earlier age of onset, greater metastatic potential, limited therapeutic options, higher relapse rates, lower survival rates, and overall poor clinical outcome.1 The goals of treatment of mTNBC focus on palliation of symptoms, prolonging PFS, OS, and improving the quality of life (QOL). This review provides a com- prehensive approach to a patient with mTNBC and compares stan- dard therapy with newly established therapies, at the same time highlighting key features of the upcoming promising treatments. Figure 1 highlights the molecular classification of TNBC as sug- gested by Lehmann and colleagues,2 and Table 1 lists the biologic markers to be tested in a newly diagnosed TNBC.
2 | TNBC WITHOUT BIOLOGIC SIGNAL
2.1 | Established: Chemotherapy
Sequential single-agent chemotherapy has been the backbone of mTNBC treatment for many years. Albeit in critical situations with bulky, rapidly progressive disease or in visceral crisis, where there is a need of significant treatment response in a time-sensitive man- ner, combination chemotherapy can be used. Other factors that play a role in deciding combined- versus single-agent chemotherapy in- clude performance status, patient preferences, compliance, QOL, and preexisting treatment–related toxicities. Once progressed on a certain chemotherapy, the principle is to switch to another drug, which utilizes a different mechanism of action, and continue treat- ment until limited by adverse effects or progression of disease. Taxanes and anthracyclines are incorporated early in the patient’s treatment course with the caveat that the patient has not received similar adjuvant therapy previously. Anthracyclines are one of the most active drug classes in breast cancer with an ORR between 30% and 50%.3 However due to the risk of cumulative cardiotox- icity, their use in mTNBC is limited to anthracycline-naïve patients. A meta-analysis showed modest superiority among anthracyclines with improved ORR, 38% vs 33%; and PFS, 7 vs 5 months, in an- thracycline vs taxanes, respectively.3 Some other drugs that can be used alone or in combination are capecitabine, gemcitabine, eribulin, ixabepilone, and vinorelbine.
3 | TNBC WITH GERMLINE BRC A 1 /2 MUTATIONS
3.1 | Newly established: PARP inhibitors in BRCA1/2 mutation carriers
BRCA1 and BRCA2 are tumor suppressor genes that encode pro- teins, which are used in the repair of DNA double-strand breaks by way of the homologous recombination repair (HRD) pathway.4 Approximately 5% of breast cancer patients carry a germline BRCA mutation.4 Impaired DNA repair leads to genomic instability called BRCAness, a concept that includes subgroups with BRCA1 methyla- tion, low levels of BRCA1 mRNA, and homologous recombination deficiency (HRD)5 making tumors more susceptible to the antineo- plastic agents such as PARP inhibitors and platinum-based therapies. In the TNT Trial, a phase III study of advanced TNBC patients, car- boplatin was not more active than docetaxel (ORR, 31.4% vs 34.0%, respectively; P = .66).6 In contrast, in the subgroup with gBRCA mu- tations, carboplatin had doubled the ORR as compared to docetaxel (68% vs 33% respectively; P = .01). This benefit was not observed in subjects with BRCA1 methylation, BRCA1 mRNA-low tumors, or a high score in a Myriad HRD assay. Docetaxel also showed greater efficacy as compared to carboplatin in non–basal-like tumors (ORR, 72.2% vs 16.7%; P = .002).6 Thus, BRCA1/2 mutation and gene ex- pression analysis may influence treatment selection.
The PARP family of enzymes are central to the repair of DNA single-strand breaks. Thus, the cells that lack functional BRCA1 or BRCA2 are sensitive to PARP inhibition, due to the unresolved DNA damage and replication arrest that results from physical ob- struction of replication forks by PARP trapping.7 The oral PARP inhibitor olaparib was approved by FDA in 2019 based on a phase III study OlympiAD,7 which compared olaparib with standard sin- gle-agent chemotherapy among patients with HER2-negative met- astatic breast cancer with a gBRCA mutation.7 The study met its primary end point as median PFS was significantly longer in the olaparib group than in the standard chemotherapy group (7 months vs 4.2 months; HR for disease progression or death, 0.58; 95% CI, 0.43 to 0.80; P < .001, median follow-up of 14 months). The ORR was almost double at 59.9% (95%CI, 52%-67.4%) in the olaparib group vs 28.8% (95%CI, 18.3%-41.3%) in the chemotherapy group. Although the overall survival did not differ significantly between the two groups, this trial was not powered to assess these differ- ences. The rate of grade 3 or higher adverse events was lower in the olaparib group than in the chemotherapy group (36.6% vs 50.5%) most commonly being hematological laboratory abnormalities that were not associated with clinical sequelae and did not result in drug discontinuation.7 4 | TNBC WITH PDL1- POSITIVE IMMUNE CELL S 4.1 | Newly established: Immunotherapy TNBC has been associated with tumor-infiltrating lymphocytes8 and higher PD-L1 expression9 as compared to other types of breast cancers, which predicts a favorable response to checkpoint inhibi- tors. Chemotherapy in addition to immunotherapy may enhance the tumor antigen release and antitumor responses to immune check- point inhibitors.10 Taxanes in particular additionally activate Toll-like receptors (TLRs) and promote dendritic cell activity.10 Impassion130, an international, randomized trial of first-line atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel, as compared to placebo plus nab-paclitaxel in patients with locally ad- vanced mTNBC11 noted clinical benefit in the PD-L1–positive pop- ulation, which led to its FDA approval in 2019. This study included 90% treatment-naïve mTNBC patients who were randomized to receive atezolizumab plus nab-paclitaxel or placebo plus nab-pa- clitaxel. PD-L1 expression on tumor-infiltrating immune cells was noted by IHC stains with >1% being classified as PD-L1 positive (40% of the study population). At a median follow-up of 12.9 months, PFS was significantly longer in the atezolizumab-nab-paclitaxel group than in the placebo-nab-paclitaxel group (median, 7.2 months vs 5.5 months, with stratified HR for progression or death being 0.80; 95% CI, 0.69-0.92; P = .002). There was a significant benefit noted in the PD-L1–positive subgroup with median PFS of 7.5 months vs 5 months: stratified HR for progression or death, 0.62; 95% CI, 0.49-0.78; P < .001) but there was no statistically significant ben- efit in median OS. There was a higher ORR in the PD-L1–positive subgroup, 58.9% with atezolizumab-nab-paclitaxel vs 42.6% with placebo-nab-paclitaxel. More patients in the atezolizumab-nab-pa- clitaxel group had complete and durable responses (10.3% vs 1.1%, in the PD-L1–positive subgroup, median duration of response was 8.5 months vs 5.5 months) with comparable adverse events in both groups. 5 | TNBC HE AVILY PRETRE ATED 5.1 | Newly established: Targeted antibody-drug conjugates (ADC) Antibody-drug conjugates are designed to target glycoproteins on the surface of epithelial cancer cells and improve delivery of el- evated concentrations of cytotoxic drugs. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate in which SN-38, an ac- tive metabolite of irinotecan (topoisomerase 1 inhibitor), is coupled to the humanized antitrophoblast cell surface antigen 2 (Trop-2) monoclonal antibody through the cleavable CL2A linker.12 Trop-2, a transmembrane calcium signal transducer, is overexpressed in ap- proximately 70% of TNBC and stimulates cancer growth.12 On bind- ing to Trop-2, SN-38 is internalized into the tumor cells, and because of the cleavable linker, SN-38 is released extracellularly in the tumor microenvironment, thereby causing antitumor effects in the cells to which the conjugate has not bound. In a phase I/II study in heavily pretreated mTNBC, sacituzumab achieved an ORR of 33%, clinical benefit rate (CBR) of 46%, median response duration of 9.1 months, mPFS of 6 months, and mOS of 13 months. Grade 3 or higher neu- tropenia was seen in 41% and anemia in 10% patients.13 SN-38 exhibited a 100-1000 times higher cytotoxic activity than that of irinotecan, facilitated a higher drug concentration in tumor tissue and minimized toxic effects in normal tissues that did express Trop-2. IMMU-132 has now advanced to phase III development studies (ASCENT: NCT02574455) and received FDA approval in 2020 for heavily pretreated mTNBC patients who have failed chemotherapy and immunotherapy.
6 | POTENTIAL THER APIES IN CLINIC AL TRIAL S
6.1 | Luminal androgen receptor blockade
The LAR subtype of TNBC (defined as AR positivity in >1% of tumor cell nuclei by IHC staining) has a prevalence of approximately 32%.14 In 80% of cases, the features overlap with luminal A or luminal B intrinsic subtypes.14 This subtype has a predilection for regional lymph node involvement, metastatic spread to the bone, and a low pCR rate after neo-adjuvant chemotherapy.15 In phase II stud- ies of mTNBC AR-positive patients, single-agent AR blockers such as bicalutamide, enzalutamide, and abiraterone have demonstrated 6-month CBR of 20% and mPFS of 3 months.16 In a phase II trial, an androgen-driven genomic signature Dx predicted improved OS with enzalutamide (mOS 20 months vs 8 months in Dx-positive and Dx-negative patients, respectively).17 This has formed the basis of a phase III trial (ENDEAR), which compares the monotherapy of en- zalutamide, paclitaxel, or as a combination in Dx-positive advanced TNBC patients (NCT02929576).
6.2 | PIK3CA/mTOR/AKT (PAM) pathway inhibitors
Somatic mutations in the TP53, RB1, and PTEN genes play a major role in TNBC, but we have not been able to successfully target these mutations therapeutically to date. The prevalence of other onco- genic alterations in basal-like tumors is low, such as 7% with PIK3CA mutation and 28% with AKT3 amplification.18 In the BELLE-4 trial, a phase II/III study, buparlisib (pan-PI3K inhibitor) added to paclitaxel demonstrated a shorter PFS with the drug in the PI3K-activated mTNBC patients.19 In the phase II LOTUS study, ipatasertib, a highly selective AKT inhibitor, was evaluated in combination with paclitaxel as first-line treatment in mTNBC.20 The results showed improved mPFS in the intention-to-treat population as compared to placebo (6.2 months vs 4.9 months, respectively) including in those with PTEN-low tumors.20 There is an ongoing phase III trial (IPATunity130) studying ipatasertib plus paclitaxel compared with placebo plus pa- clitaxel in patients with activating PIK3CA/AKT1 mutations or PTEN inactivating alterations (NCT03337724).
7 | CONCLUSION
Current treatment paradigms are focusing on targeting the indi- vidual genomic subtypes, for example, mesenchymal subtype with inhibitors of PI3K/AKT/mTOR, MET, TGF-beta, and NOS pathway; luminal androgen subtype by androgen receptor blockade; basal subtype by platinum-based chemotherapy and PARP inhibitors; and immunomodulatory subtype by checkpoint inhibitors. In summary, there has been tremendous growth and development in understand- ing the biologic signaling in mTNBC, which has made a multitude of treatment options available for this challenging subset of patients.