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Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

Authors. ABSTRACT 1. Wendie D den Brok, Background: Triple-negative breast 2. Karen A Gelmon cancer (TNBC) is an aggressive, heterogeneous clinical breast cancer Authors note subtype that currently lacks approved

1. Breast Fellow, Department of Medical targeted therapies. Research aimed Oncology, BC Cancer Agency, Vancouver, at understanding the mutational and Canada transcriptional landscape of TNBC is Email:[email protected] being achieved through gene expression analysis and large-scale 2. Medical Oncologist, Department of genomic projects, resulting in Medical Oncology, BC Cancer Agency, identification of potential drug targets. Vancouver, Canada Design: A review of PubMed and Email:[email protected] conference databases was carried out

to identify randomized clinical trials in TNBC as well as early phase trials of emerging targeted therapies. Results and Discussion: The role of platinums and poly(ADP-ribose) polymerase inhibitors continues to be a focus of clinical trials with attention now on developing a predictive biomarker that identifies “BRCA-like”

tumours. The previously identified six TNBC subtypes has been revised to four and has provided further insight into the role of the androgen receptor and immune system, both of which are emerging as promising targets in select patients either as monotherapy or in combination with other immune therapies, chemotherapy or targeted

therapy. Other novel targets include MET inhibition and signaling pathways such as the MAPK, PI3K and JAK/STAT pathways. Antibody-drug conjugates are also of interest. Targeting the angiogenesis and epidermal growth factor receptor pathways have had limited efficacy in

the treatment of TNBC.

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

Conclusions: As researchers begin to treatment options for patients with understand the underlying biology of TNBC. TNBC and identify predictive Key Words: androgen receptor, biomarkers, more select patient breast cancer, breast cancer molecular populations are being treated with subtypes, cancer treatment, immune targeted therapies, which is a checkpoint blockade, targeted promising step forward in filling the therapy, triple-negative breast cancer. current void of approved targeted

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

Introduction: Triple-negative breast cancer (TNBC), HR pathway,3 either through BRCA defined by lack of estrogen receptor germline mutation or via other (ER), progesterone receptor (PR) and mechanisms, and those without BRCA HER2-neu amplification, remains a mutations (ie. BRCA wild type [WT]) difficult to treat and aggressive clinical are said to be “BRCA-like” or exhibit subtype of breast cancer without “BRCAness”. The base excision repair approved targeted therapies. TNBC (BER) pathway, involved in single- accounts for approximately 15% of all strand DNA repair, is another pathway breast cancer diagnoses affecting a that can be exploited in patients with disproportionate number of young HR defects via the process of synthetic women compared to other breast lethality. Targeting these pathways in cancer subtypes. Researchers are patients with BRCA germline beginning to identify sub- mutations has been promising. classifications of this heterogeneous Researchers are now focused on disease by focusing on the mutational developing a biomarker to identify and transcriptional landscapes of those patients who harbour TNBC tumours. Understanding the “BRCAness”, a subgroup also expected underlying biology allows for the to benefit from drugs targeting these development of predictive biomarkers DNA repair pathways. Whether which in turn will potentially lead to “BRCAness” will give similar the development of targeted therapies responses to targeted therapies as in select TNBC patient populations, a tumours with germline BRCA need that cannot be emphasized mutations is not known. enough given the lack of success in developing targeted therapies in The intrinsic subtypes of breast cancer unselected TNBC patient populations. as determined by PAM50 (luminal A, luminal B, HER2-enriched, and basal- Germline mutations in BRCA1 and like), defined the basal-like subtype, BRCA2 (herein called BRCA), which which overlaps with up to 80% of occur in 20% of patients with TNBC,1 TNBC. Lehmann et al.4 reported on represent the first real biomarkers in gene expression analyses which TNBC. The BRCA genes are involved in initially sub-classified TNBC into 6 the homologous recombination (HR) distinct molecular subtypes (basal-like pathway,2 a high fidelity double- 1 (BL1), basal-like 2 (BL2), stranded DNA repair mechanism, immunomodulatory (IM), which have informed further research mesenchymal (M), mesenchymal around the role of HR in TNBC. It is stem-like (MSL) and luminal androgen now estimated that up to 40% of receptor (LAR) subtypes). These patients with TNBC have defects in the molecular subtypes of TNBC have recently been refined to four distinct

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

molecular subtypes (BL1, BL2, M, Methods LAR) 5 since gene expression profiles PubMed (through July 21 2016), the of the IM and MSL molecular subtypes American Society of Clinical Oncology are now thought to reflect high (2015 and 2016), and San Antonio expression of tumour infiltrating Breast Cancer Symposium (2014 and lymphocytes (TILs) and the 2015) databases were searched at the surrounding stroma, respectively, and title and abstract levels using the not distinct molecular subtypes. These search terms ‘triple negative breast researchers have retrospectively cancer’ or ‘TNBC’ to identify studies examined neoadjuvant chemotherapy investigating targeted therapy or responses from pretreatment biopsies platinum-based therapy in TNBC. of 300 TNBC patients that underwent ClinicalTrials.gov database was subtyping using the TNBC subtype and searched to identify ongoing clinical PAM50. They found differential trials in TNBC. response to neoadjuvant chemotherapy based on the molecular Targeting deficiencies in DNA subtype. These 4 TNBC subtypes and repair: platinum-base agents and the presence of TILs may help identify poly(ADP-ribose) polymerase 1/2- patients who stand to benefit from inhibitors cytotoxic chemotherapy, immunotherapy and other targeted BRCA germline mutations and defects therapies such as anti-androgens. of HR (ie. BRCAness) via other methods such as mutations in other Large scale genomic projects and HR associated genes, epigenetic translational research have also changes such as BRCA1 promotor uncovered other molecular methylation, copy number characteristics in TNBC that show aberrations, or structural promise in early phase clinical trials rearrangements affect approximately including receptor targets and 40% of TNBC patients.3 A number of signaling pathways such as the well studies have shown that patients known MAPK and PI3K pathways but deficient in HR derive greater benefit also other emerging pathways such as from DNA damaging therapies such as the JAK/STAT pathway. platinum salts and PARP inhibitors. Although BRCA germline mutations This updated review on targeting are easily identified using currently TNBC identifies studies performed available methods, a biomarker to since the original article was identify those who are BRCA WT but published in 2012 and highlights still have deficiencies in the HR progress in targeting select patient pathway has been a difficult endeavor. TNBC populations based on Researchers continue to work on mutational and transcriptional developing a robust biomarker of HR analyses. deficiency with the Myriad Genetics

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

myChoice® assay furthest along in Those treated with the addition of terms of development and clinical carboplatin (AUC 6 every 3 weeks) utility. had a statistically significant increase in pCR in both the breast and axilla Platinum-based chemotherapy compared to those who did not In the neoadjuvant setting, platinum receive carboplatin (54% vs 41%, agents combined with chemotherapy p=0.0029). At the 2015 San Antonio have resulted in higher rates of Breast Cancer Symposium updated pathologic complete response (pCR) results reported that pCR was especially in BRCA germline mutated associated with better 3-year event- TNBC but also in a subset of BRCA WT. free survival (74%) and 3-year overall A number of phase 2 trials6–7 have survival (83%). This study did not shown improved pCR rates with report on BRCA mutation status but carboplatin in addition to various biomarker correlates of HR deficiency chemotherapies and targeted are a work in progress with the therapies in BRCA mutated tumours myChoice® assay to try to predict with pCR rates ranging from 45% to those tumours that may benefit from 67%. In the initial analysis of the platinum-based regimens.10,11 GeparSixto trial6 TNBC patients with stage II-III disease who received In patients with advanced TNBC, weekly paclitaxel, non-pegylated objective response rates (ORR) with liposomal doxorubicin and platinum agents have been shown to bevacizumab plus weekly carboplatin be superior to non-platinum (AUC 2, later reduced to AUC 1.5) had chemotherapy for patients with BRCA improved pCR rates, 84/158 (53%) mutated TNBC but not BRCA WT.12 versus 58/157 (37%) who did not ORR was 68% in BRCA mutated TNBC receive carboplatin. In the updated treated with carboplatin compared to analysis presented at SABCS in 2015, 28% in BRCA WT TNBC treated with pCR rates remained higher and had carboplatin. The dichotomized better disease-free survival in the myChoice® assay score failed to carboplatin-treated arm regardless of discriminate between patients who BRCA mutation status.8 would be sensitive to carboplatin versus docetaxel; however, the assay The CALGB 40603 study9 also showed was performed on archival tissue from improvements in pCR rates for 443 the primary tumour suggesting that patients with stage II-III TNBC when advanced TNBC may have different treated with standard weekly underlying biology compared to early paclitaxel followed by dose-dense stage TNBC. doxorubicin/cyclophosphamide (AC) in addition to carboplatin+/- bevacizumab compared to those PARP inhibition treated with standard chemotherapy.

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

A phase III clinical trial of iniparib13 adaptive clinical trial has incorporated failed to show statistically significant two biomarkers of HR deficiency in an differences in PFS and OS, but iniparib attempt to predict those who will exhibits very weak PARP inhibition. benefit from veliparib/carboplatin.18 There is now a resurgence of interest Cisplatin with or without low dose in the more potent and true PARP rucaparib has been studied after inhibitors for the treatment of breast preoperative chemotherapy in cancer. In the advanced setting, patients with TNBC or BRCA germline olaparib showed good results in phase mutations who had residual disease II clinical trials of BRCA mutated (lymph node involvement or >2 cm of cancers but no responses in a small, invasive disease after standard unselected cohort of TNBC with BRCA neoadjuvant chemotherapy). The WT. 14,15 Phase III clinical trials of primary outcome of 2-year DFS was olaparib in BRCA mutated, HER2 not different between the negative breast cancers are underway cisplatin/rucaparib arm versus the in the adjuvant, neoadjuvant and cisplatin arm (63.1% vs 58.3%; advanced settings.16 Reports of the p=0.43) and BRCA mutation status did metastatic trial are expected soon and not impact 2-year DFS. However, the could change clinical practice. dose of rucaparib (24-30 mg IV on days 1-3 every 3 weeks x 4 followed The phase II adaptive randomization by 30 mg IV or 100 mg orally weekly clinical trial, I-SPY 2, has evaluated for 24 weeks) was substantially lower veliparib plus carboplatin in addition than the monotherapy dose used in to standard chemotherapy for patients phase II trials (600 mg orally twice receiving neoadjuvant chemotherapy. daily) and may have resulted in In the subgroup of patients with inadequate PARP inhibition.19 TNBC, pCR rates were estimated to be 51% in the PARP Phase III trials of niraparib inhibitor/carboplatin plus (NCT01905592 ) and talazoparib chemotherapy arm versus 26% in the (NCT01945775) versus physician’s standard chemotherapy arm. A choice in BRCA mutated advanced deleterious or suspected deleterious breast cancer are currently underway. mutation in BRCA was found in 17% of the veliparib/carboplatin arm Immune checkpoint inhibition – compared to 7% of the standard PD-1/PD-L1 monoclonal antibodies chemotherapy arm.17 Although BRCA mutation status may have impacted Immune checkpoint inhibitors rates of pCR, these results suggest that targeting the T-cell inhibitory receptor there is a subgroup of patients who programmed cell death 1 (PD-1) and are BRCA WT that stand to benefit its ligand, PD-L1, have significantly from DNA damaging therapies. This altered the treatment paradigm of various cancers including melanoma,

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

non-small cell lung cancer, renal cell phase II and III clinical trials as cancer and bladder cancer. TNBC is monotherapy (NCT02447003, associated with high levels of genomic NCT02555657) and in combination instability and higher mutational with chemotherapy (NCT02819518). burden which has been shown to be associated with benefit in other Pembrolizumab is also being studied malignancies treated with immune in early phase clinical trials for checkpoint blockade therapies.20,21 patients with metastatic TNBC in TNBC is also associated with higher combination with the PARP inhibitor levels of tumour-infiltrating niraparib (NCT02657889), eribulin lymphocytes (TILs) compared to other mesylate (NCT02513472) and breast cancer subtypes, a finding that carboplatin plus gemcitabine is associated with improved (NCT02755272). outcomes.22 TILs are found in all TNBC molecular subtypes with the highest Atezolizumab, a PD-L1 monoclonal expression in BL2 (in the refined antibody, resulted in ORR of 19% in a molecular TNBC subtype phase I study in patients with PD-L1 classification) and may be considered positive TNBC.24 The combination of representative of the immune state of immune checkpoint inhibitors and the tumour.5 PD-L1 expression is cytotoxic chemotherapy may be measured on TILs but its role alone as synergistic by increasing cancer cell a predictive biomarker has been antigens (neoantigens);25,26 a phase Ib inconsistent and continues to be clinical trial of atezolizumab (800 mg investigated. every 2 weeks) in combination with nab-paclitaxel (125 mg/m2 every One of the first immune checkpoint week for 3 of 4 weeks) in patients inhibitors to be studied in TNBC is with metastatic TNBC and ≤3 lines of pembrolizumab, a PD-1 monoclonal therapy in the advanced setting antibody. In the phase Ib KEYNOTE- resulted in ORR of 42%. Responses 012 Study23 32 of 111 (29%) patients were seen regardless of PD-L1 with advanced TNBC and positive for expression.27 Atezolizumab is now in PD-L1 expression received phase III clinical trials as first-line pembolizumab IV at 10 mg/m2 every therapy for patients with metastatic 2 weeks. In this heavily pretreated TNBC in combination with nab- population (47% of patients had ≥ 3 paclitaxel versus nab-paclitaxel plus lines of therapy in the metastatic placebo with ongoing correlative setting), ORR was 18.5%. Because this biomarker assessment of PD-L1 study enrolled only those patients (NCT02425891). with PD-L1 expression, PD-L1 as a potential biomarker could not be Novel immune checkpoint inhibitors assessed. Pembrolizumab given at are in early phase clinical trials of 200 mg IV every 3 weeks is now in TNBC (NCT02484404, NCT01772004)

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

while other early phase clinical trials clinical studies depending on ER/PR are focusing on dual immune expression with AR expression checkpoint blockade (NCT01928394, thought to have stimulatory effects in NCT02554812) or the combination of TNBC and inhibitory effects in ER/PR immune checkpoint blockade with positive breast cancers.29 In TNBC, immune modulators and vaccines reports of AR expression are highly (NCT02658890, NCT02528357, variable (6.6% to 75%) reflecting NCT02018458). Results of a phase III different methods of testing and trial of the vaccine NeuVaxTM in cutoffs for positivity.30 In the refined patients with high risk, HER2-negative TNBC molecular subtypes described breast cancer after definitive standard by Lehmann et al.,5 16% of tumours local and systemic treatment are were found to be of the luminal pending with 3-year DFS as the androgen receptor (LAR) subtype that primary endpoint (NCT01479244). is biologically driven by the androgen receptor (AR). Patients with the LAR Immune checkpoint inhibitors are subtype had lower grade tumours, generally well tolerated with fatigue, higher degree of nodal involvement at nausea, fever, and diagnosis, more advanced stage and arthralgias/myalgias being the most age at diagnosis and a higher commonly reported side effects in predilection to metastasize to bone clinical trials. As well, a unique compared to other TNBC subtypes. spectrum of immune related adverse The LAR subtype has been associated events are associated with these drugs with a lower pCR rate after including colitis, pneumonitis, neoadjuvant chemotherapy compared pancreatitis, dermatitis, hepatitis and to the BL-1 subtype.5 Although this endocrinopathies. Patients with pre- subtype has been identified via gene existing autoimmune diseases have expression analysis by other been excluded from clinical trials and researcher groups31, 32 and is emerging the risk of potentiating underlying as an important target in a subset of autoimmune disease with the use of TNBC patients, the best method for these drugs is not known. As well, identifying patients who overexpress many trials excluded patients with the AR (IHC versus gene expression brain metastases, a common signatures or both) is not clear.33 occurrence in TNBC. On PAM50 the LAR subtype is frequently associated with the HER2 Anti-androgens enriched or the luminal subtypes. The androgen receptor (AR) is expressed in approximately 60% of all Three phase II trials have reported breast cancer subtypes and associated outcomes in metastatic TNBC with with improved 3- and 5-year OS.28 The anti-androgen therapy and all expression of AR has differential considered AR positivity as >10% effects on tumourigenesis in pre- nuclear staining of the AR by

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

immunohistochemistry (IHC).34,35,37 biomarker work of an androgen- The first by Gucalp et al.34 reported driven gene signature, PREDICT AR, outcomes in patients with TNBC developed via gene expression treated with 150 mg of daily oral profiling found that of the 118 bicalutamide. Of 424 patients with patients who received enzalutamide, advanced TNBC (median number of 56 (47%) were PREDICT AR positive. lines of therapy in the advanced These patients had a superior 24- setting was one, range 0-8), 12% week CBR compared to PREDICT AR tested positive for the AR. The 6- negative (36% [95% CI, 24-49] versus month clinical benefit rate (CBR) in 26 7% [95% CI, 2-16]) and better median evaluable, AR positive patients was PFS (16 weeks [95% CI, 10-32] versus 19% (95% CI 7-39%) and median PFS 8 weeks [95% CI, 7-13]). The 12 weeks (95% CI 11-22 weeks). correlation between AR positivity as Subsequent correlative biomarker defined by IHC versus the gene work by gene expression analysis on expression signature was not 21/26 archival FFPE tissue samples reported. The PREDICT AR gene found there was little correlation of expression signature has AR positivity and LAR positivity as subsequently been shown to have measured by the original TNBC potential prognostic and predictive subtype classification with clinical value in this cohort of TNBC benefit seen in all 6 subtypes with the patients.36 exception of BL-1 and BL-2. However, it is unclear how the AR positivity In a phase II trial of the CYP17A1 would correlate based on the refined inhibitor, abiraterone acetate, plus TNBC molecular subtype classification prednisone in patients with AR where the LAR subtype is identified in positive locally advanced or a slightly higher proportion of TNBC metastatic TNBC, 53 of 138 (37.6%) (12% using the old classification patients were AR positive. The 6- versus 16% using the revised month CBR was 20% (95% CI 7.7- classification). 38.6%) and median PFS 2.8 months Enzalutamide, a more potent AR (95% CI, 1.7-5.4%). Median number inhibitor, was studied in a phase II of lines of therapy in the advanced trial in patients with advanced AR setting was 2.5 (range 1-9).37 At the positive TNBC. Over 50% of patients time of analysis, 5 patients remained received enzalutamide as first or on treatment with CBR lasting second line therapy in the advanced between 6.4 and 24 months. setting. AR expression was identified in 55% of patients. The primary Approxiamtely 80% of patients with endpoint of CBR at 24 weeks in 75 TNBC are basal-like by PAM50 evaluable patients was 29% (95% CI, subtype and are associated with high 20-41%) and median PFS 14 weeks genomic instability, p53 mutations (95% CI, 8-19).35 Correlative and poorer prognosis. The remaining

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

20% are non-basal-like by PAM50, pathway showed promise in with higher frequency of PIK3CA metastatic breast cancer,41–43 phase III mutations and associated with better clinical trials of agents targeting this prognosis.38 Pre-clinical research has pathway in TNBC failed to meet their identified a higher frequency of primary endpoints in the adjuvant and PIK3CA mutations in AR positive TNBC metastatic setting.44,45 compared to AR negative TNBC (40% versus 4%) and that the combination Epidermal growth factor receptor of anti-androgens and PI3K/mTOR (EGFR) inhibitors inhibition has additive effects TNBC is associated with resulting in decreased tumour cell overexpression of the epidermal growth.39 The combination of growth factor receptor (EGFR) in enzalutamide and the PI3K inhibitor, approximately 70% of patients46,47 taselisib, is currently being studied in although EGFR gene mutations are an early phase trial of patients with rare.48,49 Phase II clinical trials of the advanced AR positive TNBC TKIs erlotinib and gefitinib in an (NCT02457910). unselected metastatic breast cancer population have been reported and CDK4/6 inhibitors, involved in cell showed limited efficacy50–52 or were cycle control, are also generating closed early due to poor accrual interest in AR positive TNBC. In pre- (NCT00739063, NCT01272141). clinical studies the LAR subtype was Afatanib, an irreversible TKI, showed especially sensitive to cell cycle minimal activity in a small cohort of inhibition with the CDK 4/6 inhibitor, heavily pre-treated metastatic TNBC palbociclib, and synergy was seen patients53 however, pre-clinical data between PI3K and CDK4/6 inhibition and a phase I trial in patients with in PIK3CA mutated TNBC cell lines.40 A solid tumours showed synergy when phase I/II trial of palbociclib plus afatinib was combined with bicalutamide for patients with AR paclitaxel.54 A phase II trial of positive, metastatic TNBC is currently neoadjuvant afatanib and paclitaxel in recruiting (NCT02605486). TNBC is currently underway (NCT02511847). Anti-angiogenic agents and Epidermal growth factor receptor Cetuximab and panitumumab, (EGFR) inhibitors monoclonal antibody inhibitors of EGFR, have had mostly disappointing Vascular endothelial growth factor results in phase II clinical trials in (VEGF) receptor inhibitors metastatic TNBC with three studies Although initial phase III studies of showing limited benefit with respect bevacizumab which targets the to ORR and median PFS.55–57 One vascular endothelial growth factor randomized phase II trial of cetuximab (VEGF)-mediated angiogenesis with or without cisplatin in metastatic

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

TNBC resulted in a doubling of toxicities included fatigue, diarrhea, response rates with ORR (20% versus mucositis and palmar-plantar 10%) with modest improvement in erthrodysesthesia; no grade 4 PFS and no improvement in OS.58 toxicities were reported. In an update of correlative biomarker work Although targeting the VEGF and presented at ASCO 2016, cabozantinib EGFR pathways in TNBC has not was associated with evidence of shown clinically relevant benefit, immune system activation leading to ongoing research in understanding the hypothesis that the combination of the role of these pathways in TNBC cabozantinib with immunotherapy may rejuvenate this approach. In the may be beneficial and is hypothesis case of targeting EGFR, the role of the generating.62 immune system may prove to be an integral component and synergy with The combination of MET and EGFR drug combinations may prove to be inhibition in TNBC/basal-like breast effective.59 cancer has demonstrated activity in 2 pre-clinical studies where cell lines EMERGING TARGETS resistant to MET inhibition responded to the addition of erlotinib suggesting Receptor tyrosine kinases - MET synergy and is hypothesis MET is a proto-oncogene of the generating.63,64 receptor tyrosine kinase family and becomes overexpressed in a number MAPK pathway of tumour types resulting in activation The MAPK pathway is one of the most of multiple signal transduction aberrantly expressed pathways in pathways including the MAPK and human malignancy resulting in the PI3K pathways that leads to cell growth and survival of tumour cells. growth, proliferation and anti- As part of the MAPK pathway (RAS- apoptosis. RAF-MEK-ERK), MEK kinase is part of a chain of proteins carrying cell Cabozantinib is a multi-targeted TKI surface signals to the nucleus where it against the MET protein amongst results in DNA gene transcription and others such as RET and VEGFR-2. cell proliferation. This pathway MET overexpression is associated appears to be more active in with basal- like breast cancers in pre- TNBC/basal-like breast cancer clinical models and associated with compared to other breast cancer worse outcomes.60 In a phase II subtypes based on pre-clinical study61 of cabozantinib monotherapy work65,66 and inhibition of MEK in in 35 patients with metastatic TNBC TNBC cell lines has shown activity.65,67 and ≤3 lines of therapy in the Taxane resistance is common in TNBC advanced setting, the CBR was 31% and preclinical data suggest this may (95% CI, 17 to 49%). Common be due, in part, to up-regulation of the

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

MAPK pathway.68 The addition of a rates of amplifications or gains at the MEK inhibitor may reverse resistance. 9p24.1 locus, which includes the Janus The phase II COLET trial69 is currently kinase 2 (JAK2), in patients with assessing the role of the MEK residual disease after neoadjuvant inhibitor, cobimetinib plus paclitaxel chemotherapy compared to untreated in the first line treatment of locally TNBC suggesting a causal association advanced/metastatic TNBC. Fourteen with chemotherapy resistance. In cell patients were evaluable in the first lines treated with the general JAK stage of this clinical trial; 8 patients inhibitor, ruxolitinib, tumour growth had a partial response, with stable was not halted but BSK805, a JAK-2 disease and progressive disease in 3 specific inhibitor, resulted in patients each. The most common decreased TNBC tumour growth when toxicities were diarrhea (63%), rash paired with chemotherapy. Early (50%), nausea (44%), alopecia (31%), phase studies of neoadjuvant pyrexia, asthenia, dyspnea, peripheral ruxolitinib plus paclitaxel or edema, stomatitis, vomiting and paclitaxel/AC in inflammatory TNBC constipation (all 25%). Grade 3 are ongoing or pending accrual adverse events (AE) occurred in 9 (NCT02041429, NCT02876302). (56%) patients. No grade 4/5 AEs More JAK-2 specific inhibitors may be were reported. A phase II trial of required for more efficacious results. selumetinib plus docetaxel in addition to AC chemotherapy in the Other pre-clinical work targeting JAK- neoadjuvant setting for patients with 2 by Barrett et al.72 has identified a TNBC is being planned and will assess region of overlap in the 9p24.1 locus pCR rates (NCT02685657). that includes loci for PD-L1, PD-l2 and JAK-2, referred to as the PDJ amplicon. MEK inhibitors have shown synergy in This amplicon was identified in 12/41 pre-clinical models when TNBC but absent in ER+ (0/8) and administered in combination with HER2+ (0/15) breast tumours. other targeted therapies such EGFR Therefore, there may be a role for and AKT inhibitors.70 A phase II combining JAK-2 inhibition with clinical trial is ongoing in metastatic immune checkpoint therapy with the breast cancer with the MEK inhibitor PDJ amplicon a potential biomarker. trametinib plus the AKT inhibitor, GSK2141795 (NCT01964924). PI3K pathway AKT is a protein in the PI3K-mTOR- AKT pathway that is aberrantly JAK/STAT pathway activated in a subset of patients with Targeting the JAK/STAT pathway is TNBC. As part of the adaptive also garnering interest in TNBC. randomization I-SPY 2 trial, the AKT Through next generation sequencing inhibitor, MK-2206, in combination Balko et al.71 have identified higher with standard AC and weekly

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

paclitaxel chemotherapy as leucopenia, lymphopenia, caecitis (all neoadjuvant treatment in the TNBC 3%). cohort resulted in pCR rates of 40% versus 22% in the standard Glembatumumab vedotin (GV), neoadjuvant chemotherapy arm and a another ADC containing predictive probability of success in monomethylauristatin E (MMAE) as phase III trials of 76%.73 A number of the active chemotherapeutic agent, other phase II trials of the AKT showed promise in a phase II clinical inhibitors ipatasertib and AZD5363 in trial75 of patients with heavily pre- combination with paclitaxel are treated metastatic breast cancer. In underway in metastatic TNBC an unplanned analysis, ORR was 40% (NCT02162719, NCT02423603) as (GV arm) versus 0% (investigator’s well as the neoadjuvant setting choice arm) for patients with (NCT02301988). glycoprotein NMB (gpNMB) overexpressing TNBC. This Antibody drug conjugates (ADC) internalizable transmembrane protein Antibody drug conjugates (ADCs) are is overexpressed in up to 40% of composed of an antibody attached to patients with TNBC and associated active cytotoxic chemotherapy via a with poorer prognosis. GV was linker molecule and allows for associated with less hematologic cytotoxic chemotherapy to be directed toxicity than IMMU-132; common to cancer cells bearing a specific toxicities included rash, pruritis, marker thus sparing normal tissue neuropathy and alopecia. GV is from excessive toxicity. currently being investigated in a randomized phase II trial (METRIC) The phase I/II trial results of the ADC, for patients with metastatic gpNMB- sacituzumab govitecan (IMMU-132), overexpressing TNBC versus in patients with heavily pre-treated capecitabine as the comparator arm metastatic TNBC was presented at randomized in a 2:1 fashion. The ASCO 2015.74 This ADC is a primary endpoint is PFS; secondary combination of the humanized anti- endpoints include ORR, OS, duration Trop-2 monoclonal antibody coupled ofresponse, and pharmacokinetics/ to SN-38, the active metabolite of pharmacodynamics (NCT01997333). irinotecan, which targets cells with high expression of Trop-2 which Wnt, NOTCH and STAT3 pathways, includes a high proportion of patients glucocorticoid receptor with TNBC. In the cohort of 48 patients with TNBC, the ORR was 21% The Wnt signaling pathway and CBR (CR+PR+SD ≥6 months) 37%. (NCT01973309), STAT3 pathway Grade 3/4 toxicity included (NCT01325441), NOTCH pathway neutropenia (30%), febrile (NCT02299635) and glucocorticoid neutropenia (3%), diarrhea, anemia, receptor (NCT02014337) represent

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

other potential targets in TNBC with in this area is underway including a early phase clinical trials underway. Stand Up To Cancer Canada collaborative effort actively Discussion developing 3 novel drugs targeting TNBC is an extremely heterogeneous this tumour vulnerability. disease that has made the development of targeted therapies an TNBC is considered an aggressive exceptionally difficult challenge. form of breast cancer that often While patients with hormone sensitive responds well initially to cytotoxic or HER2 amplified breast cancer have chemotherapy. While the majority a number of targeted therapy options, (80%) of TNBC are basal-like by TNBC has yet to see a single approved PAM50, associated with high levels of targeted agent and cytotoxic genomic instability, p53 mutations, chemotherapy remains the standard and poor prognosis, the remaining of care. However, a number of 20% are non-basal like by PAM50, targeted therapies for the treatment of associated with lower levels of TNBC are showing promise, either as genomic instability, PIK3CA mutations, monotherapy, or in combination with less response to cytotoxic other targeted therapy or chemotherapy, and a better prognosis. chemotherapy. The treatment There is evidence that patients who advancements outlined in this review are AR positive have a higher are in large part due to ongoing proportion of PIK3CA mutations and research via gene expression analysis may derive benefit from anti- and other large scale genomic projects androgen based therapy. The LAR that have begun to unravel the subtype by gene expression analysis complex underlying biology of TNBC. appears to overlap to some extent with AR positivity (by IHC) but the Although it has been known for some best method by which to determine time that DNA damaging therapies AR positivity is unknown and is an such as platinum salts and PARP active area of research. inhibitors are active in patients with germline BRCA mutations, assays are TNBC is often associated with high in development to predict BRCA WT levels of genomic instability and TILs, patients who, due to deficiencies in both of which are associated with HR, may benefit from these agents. A sensitivity to immune checkpoint biomarker of HR deficiency will likely blockade. Early phase clinical trials of be available for clinical use in the immune checkpoint blockade as foreseeable future. As we come to monotherapy have yielded modest understand which patients harbor ORR (< 20%) albeit in patients who “BRCA-like” tumours, the next step is were heavily pre-treated. Based on the development of novel therapies results of improved ORR in early that target the HR pathway. Research phase clinical trials, attention is now

Medical Research Archives. Volume 4 Issue 6 Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

focused on combining immune these drugs will be efficacious in select checkpoint blockade with cytotoxic patients with TNBC and satisfy chemotherapy, immune modulators regulatory requirments . and vaccines as well as dual immune checkpoint inhibition. A predictive Conclusions biomarker has not been clearly Ongoing research into the underlying identified and research in this area is biology of TNBC is needed to continue ongoing. the current trajectory of emerging and Many of the emerging targets (eg. promising targeted therapies for this MAPK, PI3K and JAK/STAT pathways) heterogeneous disease. Correlative are in very early phase clinical trials. biomarker research will aid in Although targeting these pathways selecting patients who are likely to has biologic rationale, the results of benefit from novel (and not so novel) clinical trials will determine whether drug therapies.

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