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Advances in the Systemic Treatment of Triple-Negative Breast Cancer

Advances in the Systemic Treatment of Triple-Negative Breast Cancer ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. REVIEW ARTICLE Advances in the systemic treatment of triple-negative breast cancer J.M. Lebert dm sm c,* R. Lester dm ,* E. Powell dm ,* M. Seal dm ,* and J. McCarthy dm * ABSTRACT Triple-negative breast cancer constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. Molecular characterization, while not a standard of care, can further subtype triple-negative breast cancer and prov ide insight into prognostication and behav iour. Optima l chemotherapy regimens have yet to be established; however, there have been advances in the systemic treatment of triple-negative breast cancer in the neoadjuvant, adjuvant, and metastatic settings. In this review, we discuss evidence for the potential benefit of neoadjuva nt plat inum-based chemot herapy, adjuva nt combinat ion chemot herapy w it h week ly paclita xel, and BRCA mutation–directed therapy in the metastatic setting. The role for adjuvant capecitabine in patients who do not achieve a pathologic complete response with neoadjuvant chemotherapy is reviewed. Future directions and data concerning novel targeted agents are reviewed, including the most recent data on parp [poly (adp-ribose) polymerase] inhibitors, antiandrogen agents, and immunotherapy. Key Words Breast cancer, triple-negative breast cancer Curr Oncol. 2018 Jun;25(S1):S142-S150 www.current-oncology.com INTRODUCTION im mu noact ivated is associated w it h t he best prog nosis , which is in keeping with prior research showing that Breast ca ncer cont inues to be t he most com mon solid t u- prognosis is better for tnbc tumours with lymphocytic mou r a f fect i ng women, a nd it is t he second lead i ng cause infiltration . The BRCA-mutated ca ncers tend to be t riple- 1 22 of cancer-related death in women . In triple-negative negative and generally fall into the basal subtype . Tu- breast cancer (tnbc), which accounts for approximately mours that do not have germline mutations in BRCA1/2, 10 % –15% of diag nosed breast ca ncers , ex pression of t he but that display the characteristics of BRCA pathway de- estrogen and progesterone receptors is lacking, and the ficiency a re described as hav ing “ BRCAness” . Those tu- tumour is a lso negat ive for overex pression of her2 (huma n mou rs a re proposed to behave potent ia l ly more sim i la rly 3,4 epiderma l grow th factor receptor 2) . to BRCA-mutated ca ncers in ter ms of natura l histor y a nd Compa red w it h t he hormone receptor–posit ive breast response to systemic t herapy. Molecu la r cha racter i zat ion cancers, tnbc has a worse prognosis, w ith an aggressive of tnbc is an area of active research, but the application natura l histor y , a nd it is more common ly seen in younger a nd releva nce of t hat resea rch to clinica l pract ice has yet a nd obese women, t he average age of onset being 53 yea rs. to be established. The preva lence of tnbc is higher in premenopausa l A fri- At diagnosis, tnbc tumours are more likely to be T2 5 –9 can A merican women . Important ly, tnbc has a strong or T3, to be positive for ly mphovascular invasion, and to cor relat ion w it h BRCA1/2 mutat ion stat us, a nd up to 20 % have a lready metastasi zed to ly mph nodes . The pattern of of tnbc pat ients w ill be ca rriers of a mutat ion . Guidelines spread is dist inct f rom t hat for hormone receptor–posit ive suggest screening for BRCA status in women with tnbc tumours: tnbc has a g reater propensit y for bra in a nd lung diagnosed at 60 years of age or younger (Table i). metastases, and a lower preva lence of bone metastases . Approx imately 70% of tnbcs fall into the basal- In a large observational prospective study of women like subtype, and most basal-like cancers are triple- with stages i–iii breast cancer, women with tnbc were negat ive ; however, t hose cha racter ist ics a re not mut ua l ly found to have worse overa ll sur v iva l (os) compared w it h exclusive . In a recent genomic analysis of tnbc, four those having hormone receptor–positive, her2-negative subtypes were described: luminal androgen receptor, tumours [ha zard ratio (hr): 2.72; p < 0.0001] . The dif fer- mesenchy ma l, basa l-li ke im munosuppressed, a nd basa l- ence was most pronounced in t he first 2 years, t he hr for 20 8 like immunoactivated . Of those subtypes, basal-like os being 8.30 . Correspondence to: Joy McCarthy, Dr. H. Bliss Murphy Cancer Centre, 300 Prince Philip Drive, St. John’s, Newfoundland and Labrador A1B 3V6. E-mail: [email protected] n DOI: https://doi.org/10.3747/co.25.3954 S142 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. breast-conser ving surger y, or for patients for whom sur- SYSTEMIC TREATMENT FOR TNBC 13,24 ger y is temporarily contraindicated . The use of che- mot herapy in t he neoadjuvant setting a llows for a direct Neoadjuvant Setting assessment of t he in vivo response by clinica l exa minat ion Neoadjuvant chemotherapy is used in the treatment or imaging eva luation. of localized early-stage breast cancer w ith a goal of 11–18 TABLE I Excerpts from current guidelines by major organizations for the management of triple-negative breast cancer (BCa) Management Organization Recommendation Level of option evidence Screening and supportive care ASCO In patients with triple-negative or luminal metastatic BCa, genetic counselling and possibly Expert opinion BRCA testing should be discussed with the patient, if the results can affect the treatment decision or clinical trial entry (or both). Risk evaluation and genetic counselling: genetic counselling should be offered if hereditary II, A risk factors are suspected [for example, women with a strong family history of cancer (breast, colon, endometrial) or for those 60 years of age or younger with triple-negative BCa. NCCN In an individual with triple-negative BCa diagnosed at 60 years of age or younger, consider II, A referral to cancer genetics professional. Neoadjuvant treatment ESMO The addition of a platinum compound (carboplatin) to neoadjuvant chemotherapy allows I, B for an increase in the pCR rate in triple-negative tumours, particular those carrying deleterious BRCA1/2 or RAD51 mutations or those occurring in patients with a family history of breast or ovarian cancer. But the effect of those compounds on long-term outcomes is unknown. NCCN The NCCN panel does not recommend the addition of carboplatin to neoadjuvant standard chemotherapy for patients with triple-negative BCa outside a clinical trial setting. Adjuvant treatment ESMO Triple-negative tumours benefit from adjuvant chemotherapy with the possible exception I, A of low-risk “special histologic subtypes” such as secretory juvenile, apocrine, or adenoid cystic carcinomas. ASCO/CCO When considering lymph node–negative tumours with T > 5 mm, these features should be considered high-risk (and thus the patient should be considered a candidate or chemotherapy): n Grade 3 n Triple-negative n Lymphovascular invasion–positive n An Oncotype DX recurrence score that is associated with an estimated relapse risk of 15% or more at 10 years n HER2 positivity In patients who can tolerate it, use of an anthracycline–taxane regimen is considered the optimal strategy for adjuvant chemotherapy, particularly in patients deemed to be high risk. Advanced or metastatic disease ESMO For triple-negative locally advanced BCa, anthracycline–taxane chemotherapy is I, A recommended as initial treatment. In triple-negative advanced BCa patients (regardless of BRCA status) previously treated I, A with an anthracycline with or without a taxane in the neoadjuvant or adjuvant setting, carboplatin (compared with docetaxel) demonstrated comparable efficacy and a more favourable toxicity profile. It is therefore an important treatment option. In patients with BRCA-associated triple-negative or endocrine-resistant metastatic BCa I, A previously treated with an anthracycline with or without a taxane (in the adjuvant or metastatic setting, or both), a platinum regimen, if not previously administered, is the preferred option when no suitable clinical trial is available. ASCO Tumour type should not be used to dictate the choice of first-line treatment. That choice should be based on efficacy, prior treatment, risk of life-threatening disease, relative toxicities, performance statue, comorbid conditions, and patient choice. Refer to the original guidelines for their definitions of level of evidence. ASCO = American Society of Clinical Oncology; NCCN = U.S. National Comprehensive Cancer Network; ESMO = European Society for Medical Oncology; pCR = pathologic complete response; CCO = Cancer Care Ontario. Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S143 ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. Neoadjuvant chemotherapy results in higher rates (1250 mg/m t w ice da i ly for 14 of 21 days) for 6 – 8 c ycles. of pathologic complete response (pcr) in tnbc than T he st udy i ncluded pat ients w it h bot h hor mone receptor– in hormone receptor–positive, her2-negative disease posit ive a nd –negat ive tumours. (28 % –30 % vs. 6.7%) . The rate of pcr va r ies according to The primary endpoint of the study was dfs, and the t he subt y pe of tnbc, w it h t he basa l-l i ke 1 subt y pe hav i ng secondary endpoint was os. Collectively, statistically the highest frequency of pcr (52%) and the basal-like 2 significant improvements in dfs and os were observed and luminal androgen receptor subtypes having the (74.1% vs. 67.6%, p = 0.01, and 89.2% vs. 83.5%, p = 0.01, lowest frequency . In a prospective database analysis, respectively). A hr of 0.59 (95% ci: 0.39 to 0.90 ; p = 0.01) was response to neoadjuva nt t herapy a nd long-term sur v iva l reported for os. On subgroup ana lysis, t he greatest benefit were compa red in patients w it h tnbc a nd non-tnbc . In was obser ved in patients w it h tnbc, w it h t he dfs rate being t hat study, t he rate of pcr was found to be higher in tnbc 69.8% in the capecitabine group compared with 56.1% in than in non-tnbc (22% vs. 11% , p = 0.34); however, tnbc the standard-treatment group. Similarly, os was greater was associated w ith a decreased 3-year progression-free for patients with tnbc in the capecitabine arm (78.8% vs. survival (pfs) and a decreased 3-year os . Patients who 70.3%; hr: 0.52; 95% ci: 0.30 to 0.90). Adverse events were achieved a pcr showed the strongest association with frequent in patients ta k ing capecitabine, w ith 73.4% report- 25,27,28 positive long-term outcomes . ing hand–foot sy ndrome. Dose reductions were required in The optimal chemotherapy regimen for the neoadjuvant 23.9% and 36.7% of the patients assigned to 6 and 8 cycles treatment of tnbc has not been established. Platinum-based of capecitabine respectively. In contrast to the European regimens have been suggested to possibly be more active Societ y for Medica l Oncolog y g uidelines, t he U.S. Nationa l in tnbc . In the Cancer and Leukemia Group B 40603 Comprehensive Cancer Net work guidelines were updated (Alliance) study, the rate of pcr was compared in patients in Februar y 2018 and incorporate the consideration of using receiving carboplatin or bevacizumab (or both) in addition capecitabine in this setting . to weekly paclitaxel, followed by dose-dense doxorubicin A number of studies have examined the potential and cyclophosphamide . Rates of pcr were signic fi antly im - benefit of adjuvant treatment after neoadjuvant chemo - proved with the addition of either carboplatin or bevacizum- therapy. They include a phase iii study examining the use ab in breast-confined disease (60% vs. 44%, p = 0.0018, and of avelumab, a monoclonal antibody inhibitor of PD-L1, 59% vs. 48%, p = 0.0089, respectively). In locally advanced in the adjuvant or post-neoadjuvant setting in high-risk disease involving both breast and axilla, only carboplatin patients (see NCT02926196 at http://ClinicalTrials.gov) and resulted in improved rates of pcr (54% vs. 41%, p = 0.0029). another phase iii tria l assessing pembrolizumab in patients In t he Gepa rSi x to gbg 66 study, pat ients w it h w ith tnbc who have residual disease after neoadjuvant stages ii–iii tnbc or her2-positive breast ca ncer were treat- chemotherapy (see NCT02954874). Table ii presents studies ed w it h neoadjuvant week ly paclita xel and non-peg ylated for tnbc patients that are currently recruiting in Canada. liposoma l doxorubicin, and either bevacizumab for tnbc or For patients who do not receive neoadjuvant chemo- trastuzumab ever y 3 weeks for her2-positive breast cancer, therapy (with the possible exception of those having rare with or without the addition of weekly carboplatin (area histologic subtypes), the European Society for Medical under the curve 1.5) . The study found that pcr was ob- Oncology guidelines suggest treatment with adjuvant ser ved more frequent ly in patients w it h tnbc who received chemotherapy (Table i) . Some controversy surrounds additional carboplatin (53.2% vs. 36.9%, p = 0.005); how- the choice of systemic chemotherapy for small tumours ever, that result came at the expense of greater toxicities. (≤0.5 cm) that are node-negative, and that decision must 13 –16 As did t he Ca ncer a nd Leu kemia Group B 40603 study, therefore be individualized . The optimal adjuvant the GeoarSixto gbg 66 study reported rates of pcr and did regimen for tnbc has not been established, but current not assess disease-free sur v iva l (dfs) a nd os. However, pcr guidelines support the use of regimens that contain an 25,27 13,16 was associated with improved long-term outcomes . anthracycline and a ta xane, if feasible (Table i) . Thus, a lthough dfs and os were not studied, some experts The geicam 9906 tria l compared adjuvant fluorouracil– believe t hat, given t he increased rates of pcr, a n os benefit epirubicin–cyclophosphamide (fec) w ith fec-p (fec can be predicted. However, controversy surrounds that followed by weekly paclitaxel) in lymph node–positive assumption. As investigated in a meta-ana lysis by Corta zar breast cancer . That study found a 23% reduction in the et al. , using pcr as a surrogate endpoint for event-free risk of relapse a nd a 22% reduction in t he risk of deat h w it h sur vival or os could not be validated. the addition of paclitaxel. On subgroup analysis, patients with tnbc were found to experience improved dfs when Adjuvant Setting treated w it h fec plus week ly paclita xel compa red w it h fec As of Februar y 2018, European Societ y for Medica l On- alone (76% vs. 62% , p = 0.0254) . colog y guidelines do not recommend further adjuvant The role of weekly paclitaxel was also studied in the system ic t reat ment i f residua l d isea se is present a f ter com- E1199 phase iii trial . In that study, women w ith stages ii–iii pletion of neoadjuvant chemotherapy . However, that breast cancer were treated with 4 cycles of doxorubicin– principle has recently been cha llenged in the create-x cyclophosphamide followed by paclitaxel or docetaxel tria l . In t hat st udy, pat ients w it h her2-negat ive d isea se every 3 weeks for 4 doses or weekly for 12 doses in a 2×2 who d id not ach ieve a pcr w it h neoadjuva nt chemot her- design . At the 10-year follow-up, significant improve - apy were ra ndom i zed to receive eit her sta nda rd of ca re, ment in dfs and os was observed for the tnbc subgroup wh ich i ncluded hor mona l t herapy or rad iat ion t herapy i f treated with weekly paclitaxel compared with paclitaxel indicated (or bot h), or t he addit ion of ora l capecitabine ever y 3 weeks (hr: 0.69 ; p = 0.01) or w it h doceta xel in eit her S144 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. TABLE II Clinical trials in triple-negative breast cancer (TNBC) currently recruiting in Canada Title ClinicalTrials.gov Phase or Intervention identifier study type A Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RO6870810 and Atezolizumab (PD-L1 Antibody) in Participants with Advanced Ovarian Cancer or Triple Negative Breast Cancer NCT03292172 Phase I Atezolizumab RO6870810 A Study of Atezolizumab and Paclitaxel Versus Placebo and Paclitaxel in Participants with Previously Untreated Locally Advanced or Metastatic Triple Negative Breast Cancer (TNBC) NCT03125902 Phase III Atezolizumab (MPDL3280A), an engineered anti–PD-L1 antibody Atezolizumab placebo Paclitaxel A Study to Investigate Atezolizumab and Chemotherapy Compared with Placebo and Chemotherapy in the Neoadjuvant Setting in Participants with Early Stage Triple Negative Breast Cancer NCT03197935 Phase III Atezolizumab (MPDL3280A), an engineered anti–PD-L1 antibody Placebo Nab-paclitaxel Doxorubicin Cyclophosphamide Filgrastim Pegfilgrastim Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs. Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (MK-3475-355/KEYNOTE-355) NCT02819518 Phase III Pembrolizumab Nab-paclitaxel Paclitaxel Gemcitabine Carboplatin Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants with Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522) NCT03036488 Phase III Pembrolizumab Carboplatin Paclitaxel Doxorubicin Epirubicin Cyclophosphamide Placebo A Study of Ipatasertib in Combination with Paclitaxel as a Treatment for Participants with PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor–Positive, HER2-Negative Breast Cancer NCT03337724 Phase II Ipatasertib Phase III Paclitaxel Placebo Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer NCT02488967 Phase III Carboplatin Cyclophosphamide Doxorubicin Hydrochloride Paclitaxel Laboratory Biomarker Analysis Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S145 ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. TABLE II Continued Title ClinicalTrials.gov Phase or Intervention identifier study type A Study of PDR001 in Combination with CJM112, EGF816, Ilarisa (Canakinumab) or Mekinistb (Trametinib) NCT02900664 Phase I PDR001 ACZ885 CJM112 TMT212 EGF816 A Study to Test the Safety and Effectiveness of Nivolumab Combined with Daratumumab in Patients with Pancreatic, Non–Small Cell Lung or Triple Negative Breast Cancers, That Have Advanced or Have Spread NCT03098550 Phase I Nivolumab Phase II Daratumumab AZD8186 First Time in Patient Ascending Dose Study NCT01884285 Phase I Part A: AZD8186 monotherapy Part B: AZD8186 monotherapy Part C1: Abiraterone acetate combination with AZD8186 Part D1: AZD2014 combination with AZD8186 Part D2: AZD2014 combination with AZD8186 Part C2: Abiraterone acetate combination with AZD8186 A Study of FAZ053 Single Agent and in Combination with PDR001 in Patients with Advanced Malignancies NCT02936102 Phase I FAZ053 PDR001 Study of the Effects of Pembrolizumab in Patients with Advanced Solid Tumors (INSPIRE) NCT02644369 Phase II Pembrolizumab Phase I/II Study of PDR001 in Patients with Advanced Malignancies NCT02404441 Phase I PDR001 Phase II A Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination with Anti–PD-1 Antibody (Nivolumab) in Patients with Select Advanced or Metastatic Solid Tumors NCT02983045 Phase I Combination of NKTR-214 and nivolumab Phase II Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination with Atezolizumab in Advanced Cancers NCT02655822 Phase I CPI-444 CPI-444 plus atezolizumab A Phase 2 Study of Cediranib in Combination with Olaparib in Advanced Solid Tumors NCT02498613 Phase II Cediranib maleate Olaparib A Study of RO7198457 (Personalized Cancer Vaccine [PVC]) as a Single Agent and in Combination with Atezolizumab in Participations with Locally Advanced or Metastatic Tumors NCT03289962 Phase Ia/Ib RO7198457 Atezolizumab Olaparib as Adjuvant Treatment in Patients with Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA) NCT02032823 Phase III Olaparib Placebo Novartis, Basel, Switzerland. GlaxoSmithKline, Brentford, U.K. S146 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. schedu le (hr: 0.69 ; p = 0.019). Those findings suggest t hat a statistical difference in the overall response rate was benefit might accr ue to t he addit ion of week ly paclita xel to evident between the two treatment arms. That finding adjuvant chemotherapy in tnbc; however, that regimen was suggests that “BRCAness” might not be a reliable means not the primar y objective of the study, and thus it is difc fi ult of predicting the clinical response of tnbcs to certain to base recommendat ions on t he subg roup a na lysis a lone. chemotherapy agents. The addition of bevacizumab to chemotherapy was studied in t he adjuvant setting in t he beatrice study . No BRCA Carriers and TNBC invasive dfs or os benet w fi as demonstrated in t hat setting. The treatment of BRCA mutation–associated breast ca ncer Although studies supporting the role of neoadjuvant and the use of directed agents for that patient subset is an and palliative platinum-based chemotherapy in tnbc active area of research. Because the BRCA1 and BRCA 2 have been published, no data in the adjuvant setting are genes code for proteins involved in double-stranded dna currently available. Clinical trials investigating the role break repair, it is hypothesized that BRC A mutation– of platinum-based adjuvant chemotherapy are ongoing associated cancers might be more sensitive to chemot her- (for example, see NCT02488967 at http://Clinica lTria ls. apy agents that cause dna damage, such as the platinums. gov; Table ii). Sensit iv it y of t hat k ind has been show n in vitro ; however, its translation into clinica l application has yet to be estab- Metastatic Setting lished. A small phase ii study of cisplatin chemotherapy Triple-negative breast cancer is associated with a high i n BRC A1 mutation carriers, not selected for hormone risk of distant recurrence, predominantly in the first 2 receptor status, demonstrated high efficacy for cisplatin, 5,8 years after diagnosis . W hen metastases occur, biopsy of with an overall response rate of 80% and 9 of 20 patients the site of distant disease should be attempted to assess achiev ing a complete response . However, the study lacked for discordance in hormone receptor and her2 status . a control group. Further research into the role of cisplatin A retrospective analysis found that 8% of tumours that in the treatment of metastatic tnbc and BRCA mutation– were initia lly estrogen receptor–negative had converted to associated breast cancer is ongoing (NCT02595905 at estrogen receptor–positivity when the metastatic tumour http://ClinicalTrials.gov). deposit was assessed for hormone receptor status . No sta- The impaired dna repair pathway in BRC A1/2 car- tistica l discordance in her2 receptor status was obser ved. riers can also be targeted with parp [poly (adp-ribose) The choice of initial systemic chemotherapy should polymerase] inhibitors, which interfere with the repair of be indiv idua lized based on a number of factors, including single-stranded dna breaks and, when combined with an tumour burden, rate of disease progression, performance already weakened repair process, can result in synthetic status, previous chemotherapy exposure, and patient letha lit y . That activity has been confirmed by in vitro 17,18 preferences . With respect to agent selection, Table i studies, showing that tumours in carriers are in fact sen- 45,46 describes several guideline recommendations. Although sitive to parp inhibitors . Recently, the parp inhibitor combination chemotherapy is generally avoided in the olaparib was studied in the setting of metastatic breast palliative setting, tnbc often results in visceral involve- ca ncer in t he olympiad tria l . That study included 302 pa- ment and a more aggressive course, making combination t ients w it h metastat ic breast ca ncer who had k now n BRCA chemot herapy a more frequent choice in t his population . mutations, who were negative for her2 overexpression, and Platinum-based chemotherapy has been suggested who had received up to 2 prior lines of chemotherapy. The to potentia lly be more ef fective t han non-platinum-based patients were randomized to single-agent chemotherapy chemotherapy in metastatic tnbc. In a retrospective co- (capecitabine, eribulin, or vinorelbine every 3 weeks) or hort study, longer pfs was observed in patients receiving to olaparib (300 mg twice daily). The response rate was platinum-based chemotherapy compared w ith non- 59.9% in the olaparib group compared with 28.8% in the platinum-based therapy in the first line (7.8 months vs. chemotherapy group. Furthermore, pfs was improved in 4.9 months, p < 0.001) . However, no difference in os was the olaparib group (7.0 months vs. 4.2 months; hr: 0.58; observed. No improvement in pfs or os was shown in the 95% ci: 0.43 to 0.80; p < 0.001). Olaparib was approved in preliminary results of the prospective tnt study, which Ja nua r y 2018 by t he U.S. Food a nd Dr ug Administration for compared carboplatin with docetaxel in metastatic or use in BRCA-mutated metastatic breast ca ncer. In Ca nada, recurrent locally advanced tnbc . The tnt study ran- olaparib is currently approved for use only in BRCA-mutated domized 376 patients w it h metastatic tnbc or w it h k now n ovarian, fallopian tube, or primary peritoneal cancers. A BRCA1/2 mutation to either carboplatin (area under the phase iii Canadian Cancer Trials Group study, currently curve 6 every 3 weeks) or docetaxel (100 mg/m every open to accrual, is examining the role of olaparib in the 3 weeks) for 6–8 cycles or until progression. The initial adjuvant setting for carriers of BRCA1/2 mutations (see results, presented at the 2014 San Antonio Breast Cancer NCT02032823 at http://ClinicalTrials.gov). Other parp in- Sy mposium, showed no statistica l difference in pfs or os for hibitors are also actively being investigated in the metastatic the tnbc group (3.1 mont hs vs. 4.5 mont hs and 12.4 mont hs setting, including veliparib and niraparib (for example, vs. 12.3 months respectively). However, on subgroup ana ly- NCT02595905, NCT01905592) . W het her tumours t hat a re sis of BRCA1/2 carriers, pfs was improved in those receiv ing BRCA-proficient or that have BRCA pathway impairment carboplatin (6.8 months vs. 3.1 months). The objective (BRC Aness) will respond to these targeted therapies is response rate was also significantly higher (68.0% vs. currently unknown. 33.3% , p = 0.03). Interestingly, on subgroup analysis of The angiogenesis inhibitor bevacizumab has been basal-like malignancies by immunohistochemistry, no examined in combination with chemotherapy agents in Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S147 ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. 49,50 t he treatment of metastatic breast cancer . A lt hough t he SUMMARY relevant studies demonstrated benefit in pfs , no improve- ment in os was observed. Miles et al. reported a pooled Triple-negative breast ca ncer constitutes a heterogeneous subgroup analysis of bevacizumab use in poor-prognosis group of malignancies that differ in natural history and groups. In the tnbc subgroup, median pfs was signic fi ant ly response to treatment. The mainstay of treatment contin- improved with the use of bevacizumab (hr: 0.63; 95% ci: ues to be chemotherapy; however, optimal chemotherapy 0.53 to 0.76) ; however, that improvement did not trans- regimens for tnbc have yet to be established. late into an os benefit. Thus, no role for bevacizumab is In this article, we have rev iewed the current ev idence accepted at this time. for systemic treatment for tnbc in the neoadjuvant, adjuvant, and metastatic settings. In the neoadjuvant FUTURE DIRECTIONS: IMMUNOTHERAPY setting, the use of platinum agents has been associated AND TARGETED THERAPY w ith improved rates of pcr, but os was not reported in the 30,31 associated studies . In the recently published create-x The role of immunotherapy in the treatment of tnbc is trial, an os benefit was shown for adjuvant capecitabine current ly under investigation in severa l tria ls recr uiting in in patients who do not achieve a pcr with neoadjuvant Ca nada (Table ii). In tnbc, strong ly mphocy tic infiltration chemot herapy . However, that approach has not been or immune response has been associated with improved widely adopted in clinical practice, perhaps because of prognosis . That obser vation suggests t hat harnessing t he the associated toxicity. For adjuvant treatment of tnbc, immune system against this disease might be beneficial. two trials that added weekly paclitaxel to combination 33–35 Pembrolizumab is a PD-1 inhibitor that has been shown chemotherapy showed improvements in dfs . In met- to be effective in the treatment of several other cancers, astatic tnbc, preliminary results show that the response 53–55 including lung, melanoma, and bladder ma lignancies . rate might be higher with platinum than with docetaxel In a phase ib study of pembrolizumab in patients with in BRCA mutation–associated malignancies ; however, advanced tnbc, on ly 18.5% of pat ients ex perienced a com- resea rch to g uide t he optima l choice of systemic treatment plete or partial response , with the duration of response for metastatic disease is limited. Olaparib, a parp inhibitor, varying from 15 to more than 47.3 weeks. A phase iii trial has recently been approved by the U.S. Food and Drug of pembrolizumab in t he treatment of metastatic or loca lly Administration for use in germline BRCA-mutated meta- recurrent inoperable tnbc is ongoing (see NCT02819518 static breast cancer, based on the olympiad trial . at http://Clinica lTria ls.gov) . The anti–PD-L1 antibody As molecular research advances an understanding of atezolizumab is also actively being investigated in the the driver mutations in this disease, more targeted treat- neoadjuvant and metastatic settings (see NCT03197935 and ments could become available. A number of investigationa l NCT03125902). Immunot herapy has show n great potentia l t herapies hold promise, including parp inhibitors, ar pat h- in a number of other disease sites, and thus the results of way inhibitors, and immunotherapy. Given those new de- the foregoing trials are highly anticipated. velopments, t he hope is t hat more ef fective treatments a nd In a subgroup of tnbc, expression of the androgen better outcomes will be achieved for patients with tnbc. receptor (ar) is increased . The clinical relevance of ar status has yet to be established in breast cancer; however, CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncolog y’s policy on disclos- several recent phase ii studies have examined the use ing conflicts of interest, a nd we decla re t he fol low ing interests : RL of anti-androgen agents in this setting. In one study, tu- has received educat ion f unding f rom A mgen a nd Eisa i a nd fees as mours from 242 patients with breast cancer negative for a n adv isor y boa rd member for A st ra Zeneca, Nova r t is, a nd Pfi zer. the estrogen and progesterone receptors were tested for EP has received t ravel f unding f rom Roche a nd fees as a n adv isor y ar expression . Of those tumours, only 12% were found boa rd member for A mgen, Genomic Hea lt h, Nova r t is, a nd Pfi zer. to be ar-positive. Patients whose tumours tested positive MS has received conference funding from Amgen and fees as an received bicalutamide 150 mg daily. The clinical benefit advisory board member for Pfizer and Shire. JM has received rate, defined as complete response, partial response, or conference travel f unding from Astra Zeneca and Roche and fees stable disease for more than 6 months, was 19%, and the as an adv isor y board member from Novartis and Pfizer. median pfs was 12 weeks (95% ci: 11 weeks to 22 weeks) . A phase iii evaluation of bicalutamide is still pending. AUTHOR AFFILIATIONS *Memorial Universit y of New foundland, Saint John’s, NL. En za luta mide is a n ar sig na lling in hibitor t hat is used in t he treatment of metastatic castration-resistant prostate REFERENCES cancer. The effect of enza lutamide has a lso been studied in 59 1. Canadian Cancer Society’s Advisor y Committee on Cancer ar-positive tnbc in a phase ii tria l . In t hat tria l, a ndrogen Stat ist ics. Canadian Cancer Statistics 2017. 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[Available online at: http:// [Available online at: http://ascopubs.org/doi/abs/10.1200/ ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.1003; cited jco.2010.28.15_suppl.1019; cited 9 April 2018] 16 April 2018] S150 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Oncology Multidisciplinary Digital Publishing Institute

Advances in the Systemic Treatment of Triple-Negative Breast Cancer

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Abstract

ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. REVIEW ARTICLE Advances in the systemic treatment of triple-negative breast cancer J.M. Lebert dm sm c,* R. Lester dm ,* E. Powell dm ,* M. Seal dm ,* and J. McCarthy dm * ABSTRACT Triple-negative breast cancer constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. Molecular characterization, while not a standard of care, can further subtype triple-negative breast cancer and prov ide insight into prognostication and behav iour. Optima l chemotherapy regimens have yet to be established; however, there have been advances in the systemic treatment of triple-negative breast cancer in the neoadjuvant, adjuvant, and metastatic settings. In this review, we discuss evidence for the potential benefit of neoadjuva nt plat inum-based chemot herapy, adjuva nt combinat ion chemot herapy w it h week ly paclita xel, and BRCA mutation–directed therapy in the metastatic setting. The role for adjuvant capecitabine in patients who do not achieve a pathologic complete response with neoadjuvant chemotherapy is reviewed. Future directions and data concerning novel targeted agents are reviewed, including the most recent data on parp [poly (adp-ribose) polymerase] inhibitors, antiandrogen agents, and immunotherapy. Key Words Breast cancer, triple-negative breast cancer Curr Oncol. 2018 Jun;25(S1):S142-S150 www.current-oncology.com INTRODUCTION im mu noact ivated is associated w it h t he best prog nosis , which is in keeping with prior research showing that Breast ca ncer cont inues to be t he most com mon solid t u- prognosis is better for tnbc tumours with lymphocytic mou r a f fect i ng women, a nd it is t he second lead i ng cause infiltration . The BRCA-mutated ca ncers tend to be t riple- 1 22 of cancer-related death in women . In triple-negative negative and generally fall into the basal subtype . Tu- breast cancer (tnbc), which accounts for approximately mours that do not have germline mutations in BRCA1/2, 10 % –15% of diag nosed breast ca ncers , ex pression of t he but that display the characteristics of BRCA pathway de- estrogen and progesterone receptors is lacking, and the ficiency a re described as hav ing “ BRCAness” . Those tu- tumour is a lso negat ive for overex pression of her2 (huma n mou rs a re proposed to behave potent ia l ly more sim i la rly 3,4 epiderma l grow th factor receptor 2) . to BRCA-mutated ca ncers in ter ms of natura l histor y a nd Compa red w it h t he hormone receptor–posit ive breast response to systemic t herapy. Molecu la r cha racter i zat ion cancers, tnbc has a worse prognosis, w ith an aggressive of tnbc is an area of active research, but the application natura l histor y , a nd it is more common ly seen in younger a nd releva nce of t hat resea rch to clinica l pract ice has yet a nd obese women, t he average age of onset being 53 yea rs. to be established. The preva lence of tnbc is higher in premenopausa l A fri- At diagnosis, tnbc tumours are more likely to be T2 5 –9 can A merican women . Important ly, tnbc has a strong or T3, to be positive for ly mphovascular invasion, and to cor relat ion w it h BRCA1/2 mutat ion stat us, a nd up to 20 % have a lready metastasi zed to ly mph nodes . The pattern of of tnbc pat ients w ill be ca rriers of a mutat ion . Guidelines spread is dist inct f rom t hat for hormone receptor–posit ive suggest screening for BRCA status in women with tnbc tumours: tnbc has a g reater propensit y for bra in a nd lung diagnosed at 60 years of age or younger (Table i). metastases, and a lower preva lence of bone metastases . Approx imately 70% of tnbcs fall into the basal- In a large observational prospective study of women like subtype, and most basal-like cancers are triple- with stages i–iii breast cancer, women with tnbc were negat ive ; however, t hose cha racter ist ics a re not mut ua l ly found to have worse overa ll sur v iva l (os) compared w it h exclusive . In a recent genomic analysis of tnbc, four those having hormone receptor–positive, her2-negative subtypes were described: luminal androgen receptor, tumours [ha zard ratio (hr): 2.72; p < 0.0001] . The dif fer- mesenchy ma l, basa l-li ke im munosuppressed, a nd basa l- ence was most pronounced in t he first 2 years, t he hr for 20 8 like immunoactivated . Of those subtypes, basal-like os being 8.30 . Correspondence to: Joy McCarthy, Dr. H. Bliss Murphy Cancer Centre, 300 Prince Philip Drive, St. John’s, Newfoundland and Labrador A1B 3V6. E-mail: [email protected] n DOI: https://doi.org/10.3747/co.25.3954 S142 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. breast-conser ving surger y, or for patients for whom sur- SYSTEMIC TREATMENT FOR TNBC 13,24 ger y is temporarily contraindicated . The use of che- mot herapy in t he neoadjuvant setting a llows for a direct Neoadjuvant Setting assessment of t he in vivo response by clinica l exa minat ion Neoadjuvant chemotherapy is used in the treatment or imaging eva luation. of localized early-stage breast cancer w ith a goal of 11–18 TABLE I Excerpts from current guidelines by major organizations for the management of triple-negative breast cancer (BCa) Management Organization Recommendation Level of option evidence Screening and supportive care ASCO In patients with triple-negative or luminal metastatic BCa, genetic counselling and possibly Expert opinion BRCA testing should be discussed with the patient, if the results can affect the treatment decision or clinical trial entry (or both). Risk evaluation and genetic counselling: genetic counselling should be offered if hereditary II, A risk factors are suspected [for example, women with a strong family history of cancer (breast, colon, endometrial) or for those 60 years of age or younger with triple-negative BCa. NCCN In an individual with triple-negative BCa diagnosed at 60 years of age or younger, consider II, A referral to cancer genetics professional. Neoadjuvant treatment ESMO The addition of a platinum compound (carboplatin) to neoadjuvant chemotherapy allows I, B for an increase in the pCR rate in triple-negative tumours, particular those carrying deleterious BRCA1/2 or RAD51 mutations or those occurring in patients with a family history of breast or ovarian cancer. But the effect of those compounds on long-term outcomes is unknown. NCCN The NCCN panel does not recommend the addition of carboplatin to neoadjuvant standard chemotherapy for patients with triple-negative BCa outside a clinical trial setting. Adjuvant treatment ESMO Triple-negative tumours benefit from adjuvant chemotherapy with the possible exception I, A of low-risk “special histologic subtypes” such as secretory juvenile, apocrine, or adenoid cystic carcinomas. ASCO/CCO When considering lymph node–negative tumours with T > 5 mm, these features should be considered high-risk (and thus the patient should be considered a candidate or chemotherapy): n Grade 3 n Triple-negative n Lymphovascular invasion–positive n An Oncotype DX recurrence score that is associated with an estimated relapse risk of 15% or more at 10 years n HER2 positivity In patients who can tolerate it, use of an anthracycline–taxane regimen is considered the optimal strategy for adjuvant chemotherapy, particularly in patients deemed to be high risk. Advanced or metastatic disease ESMO For triple-negative locally advanced BCa, anthracycline–taxane chemotherapy is I, A recommended as initial treatment. In triple-negative advanced BCa patients (regardless of BRCA status) previously treated I, A with an anthracycline with or without a taxane in the neoadjuvant or adjuvant setting, carboplatin (compared with docetaxel) demonstrated comparable efficacy and a more favourable toxicity profile. It is therefore an important treatment option. In patients with BRCA-associated triple-negative or endocrine-resistant metastatic BCa I, A previously treated with an anthracycline with or without a taxane (in the adjuvant or metastatic setting, or both), a platinum regimen, if not previously administered, is the preferred option when no suitable clinical trial is available. ASCO Tumour type should not be used to dictate the choice of first-line treatment. That choice should be based on efficacy, prior treatment, risk of life-threatening disease, relative toxicities, performance statue, comorbid conditions, and patient choice. Refer to the original guidelines for their definitions of level of evidence. ASCO = American Society of Clinical Oncology; NCCN = U.S. National Comprehensive Cancer Network; ESMO = European Society for Medical Oncology; pCR = pathologic complete response; CCO = Cancer Care Ontario. Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S143 ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. Neoadjuvant chemotherapy results in higher rates (1250 mg/m t w ice da i ly for 14 of 21 days) for 6 – 8 c ycles. of pathologic complete response (pcr) in tnbc than T he st udy i ncluded pat ients w it h bot h hor mone receptor– in hormone receptor–positive, her2-negative disease posit ive a nd –negat ive tumours. (28 % –30 % vs. 6.7%) . The rate of pcr va r ies according to The primary endpoint of the study was dfs, and the t he subt y pe of tnbc, w it h t he basa l-l i ke 1 subt y pe hav i ng secondary endpoint was os. Collectively, statistically the highest frequency of pcr (52%) and the basal-like 2 significant improvements in dfs and os were observed and luminal androgen receptor subtypes having the (74.1% vs. 67.6%, p = 0.01, and 89.2% vs. 83.5%, p = 0.01, lowest frequency . In a prospective database analysis, respectively). A hr of 0.59 (95% ci: 0.39 to 0.90 ; p = 0.01) was response to neoadjuva nt t herapy a nd long-term sur v iva l reported for os. On subgroup ana lysis, t he greatest benefit were compa red in patients w it h tnbc a nd non-tnbc . In was obser ved in patients w it h tnbc, w it h t he dfs rate being t hat study, t he rate of pcr was found to be higher in tnbc 69.8% in the capecitabine group compared with 56.1% in than in non-tnbc (22% vs. 11% , p = 0.34); however, tnbc the standard-treatment group. Similarly, os was greater was associated w ith a decreased 3-year progression-free for patients with tnbc in the capecitabine arm (78.8% vs. survival (pfs) and a decreased 3-year os . Patients who 70.3%; hr: 0.52; 95% ci: 0.30 to 0.90). Adverse events were achieved a pcr showed the strongest association with frequent in patients ta k ing capecitabine, w ith 73.4% report- 25,27,28 positive long-term outcomes . ing hand–foot sy ndrome. Dose reductions were required in The optimal chemotherapy regimen for the neoadjuvant 23.9% and 36.7% of the patients assigned to 6 and 8 cycles treatment of tnbc has not been established. Platinum-based of capecitabine respectively. In contrast to the European regimens have been suggested to possibly be more active Societ y for Medica l Oncolog y g uidelines, t he U.S. Nationa l in tnbc . In the Cancer and Leukemia Group B 40603 Comprehensive Cancer Net work guidelines were updated (Alliance) study, the rate of pcr was compared in patients in Februar y 2018 and incorporate the consideration of using receiving carboplatin or bevacizumab (or both) in addition capecitabine in this setting . to weekly paclitaxel, followed by dose-dense doxorubicin A number of studies have examined the potential and cyclophosphamide . Rates of pcr were signic fi antly im - benefit of adjuvant treatment after neoadjuvant chemo - proved with the addition of either carboplatin or bevacizum- therapy. They include a phase iii study examining the use ab in breast-confined disease (60% vs. 44%, p = 0.0018, and of avelumab, a monoclonal antibody inhibitor of PD-L1, 59% vs. 48%, p = 0.0089, respectively). In locally advanced in the adjuvant or post-neoadjuvant setting in high-risk disease involving both breast and axilla, only carboplatin patients (see NCT02926196 at http://ClinicalTrials.gov) and resulted in improved rates of pcr (54% vs. 41%, p = 0.0029). another phase iii tria l assessing pembrolizumab in patients In t he Gepa rSi x to gbg 66 study, pat ients w it h w ith tnbc who have residual disease after neoadjuvant stages ii–iii tnbc or her2-positive breast ca ncer were treat- chemotherapy (see NCT02954874). Table ii presents studies ed w it h neoadjuvant week ly paclita xel and non-peg ylated for tnbc patients that are currently recruiting in Canada. liposoma l doxorubicin, and either bevacizumab for tnbc or For patients who do not receive neoadjuvant chemo- trastuzumab ever y 3 weeks for her2-positive breast cancer, therapy (with the possible exception of those having rare with or without the addition of weekly carboplatin (area histologic subtypes), the European Society for Medical under the curve 1.5) . The study found that pcr was ob- Oncology guidelines suggest treatment with adjuvant ser ved more frequent ly in patients w it h tnbc who received chemotherapy (Table i) . Some controversy surrounds additional carboplatin (53.2% vs. 36.9%, p = 0.005); how- the choice of systemic chemotherapy for small tumours ever, that result came at the expense of greater toxicities. (≤0.5 cm) that are node-negative, and that decision must 13 –16 As did t he Ca ncer a nd Leu kemia Group B 40603 study, therefore be individualized . The optimal adjuvant the GeoarSixto gbg 66 study reported rates of pcr and did regimen for tnbc has not been established, but current not assess disease-free sur v iva l (dfs) a nd os. However, pcr guidelines support the use of regimens that contain an 25,27 13,16 was associated with improved long-term outcomes . anthracycline and a ta xane, if feasible (Table i) . Thus, a lthough dfs and os were not studied, some experts The geicam 9906 tria l compared adjuvant fluorouracil– believe t hat, given t he increased rates of pcr, a n os benefit epirubicin–cyclophosphamide (fec) w ith fec-p (fec can be predicted. However, controversy surrounds that followed by weekly paclitaxel) in lymph node–positive assumption. As investigated in a meta-ana lysis by Corta zar breast cancer . That study found a 23% reduction in the et al. , using pcr as a surrogate endpoint for event-free risk of relapse a nd a 22% reduction in t he risk of deat h w it h sur vival or os could not be validated. the addition of paclitaxel. On subgroup analysis, patients with tnbc were found to experience improved dfs when Adjuvant Setting treated w it h fec plus week ly paclita xel compa red w it h fec As of Februar y 2018, European Societ y for Medica l On- alone (76% vs. 62% , p = 0.0254) . colog y guidelines do not recommend further adjuvant The role of weekly paclitaxel was also studied in the system ic t reat ment i f residua l d isea se is present a f ter com- E1199 phase iii trial . In that study, women w ith stages ii–iii pletion of neoadjuvant chemotherapy . However, that breast cancer were treated with 4 cycles of doxorubicin– principle has recently been cha llenged in the create-x cyclophosphamide followed by paclitaxel or docetaxel tria l . In t hat st udy, pat ients w it h her2-negat ive d isea se every 3 weeks for 4 doses or weekly for 12 doses in a 2×2 who d id not ach ieve a pcr w it h neoadjuva nt chemot her- design . At the 10-year follow-up, significant improve - apy were ra ndom i zed to receive eit her sta nda rd of ca re, ment in dfs and os was observed for the tnbc subgroup wh ich i ncluded hor mona l t herapy or rad iat ion t herapy i f treated with weekly paclitaxel compared with paclitaxel indicated (or bot h), or t he addit ion of ora l capecitabine ever y 3 weeks (hr: 0.69 ; p = 0.01) or w it h doceta xel in eit her S144 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. TABLE II Clinical trials in triple-negative breast cancer (TNBC) currently recruiting in Canada Title ClinicalTrials.gov Phase or Intervention identifier study type A Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of RO6870810 and Atezolizumab (PD-L1 Antibody) in Participants with Advanced Ovarian Cancer or Triple Negative Breast Cancer NCT03292172 Phase I Atezolizumab RO6870810 A Study of Atezolizumab and Paclitaxel Versus Placebo and Paclitaxel in Participants with Previously Untreated Locally Advanced or Metastatic Triple Negative Breast Cancer (TNBC) NCT03125902 Phase III Atezolizumab (MPDL3280A), an engineered anti–PD-L1 antibody Atezolizumab placebo Paclitaxel A Study to Investigate Atezolizumab and Chemotherapy Compared with Placebo and Chemotherapy in the Neoadjuvant Setting in Participants with Early Stage Triple Negative Breast Cancer NCT03197935 Phase III Atezolizumab (MPDL3280A), an engineered anti–PD-L1 antibody Placebo Nab-paclitaxel Doxorubicin Cyclophosphamide Filgrastim Pegfilgrastim Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs. Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (MK-3475-355/KEYNOTE-355) NCT02819518 Phase III Pembrolizumab Nab-paclitaxel Paclitaxel Gemcitabine Carboplatin Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants with Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522) NCT03036488 Phase III Pembrolizumab Carboplatin Paclitaxel Doxorubicin Epirubicin Cyclophosphamide Placebo A Study of Ipatasertib in Combination with Paclitaxel as a Treatment for Participants with PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor–Positive, HER2-Negative Breast Cancer NCT03337724 Phase II Ipatasertib Phase III Paclitaxel Placebo Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer NCT02488967 Phase III Carboplatin Cyclophosphamide Doxorubicin Hydrochloride Paclitaxel Laboratory Biomarker Analysis Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S145 ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. TABLE II Continued Title ClinicalTrials.gov Phase or Intervention identifier study type A Study of PDR001 in Combination with CJM112, EGF816, Ilarisa (Canakinumab) or Mekinistb (Trametinib) NCT02900664 Phase I PDR001 ACZ885 CJM112 TMT212 EGF816 A Study to Test the Safety and Effectiveness of Nivolumab Combined with Daratumumab in Patients with Pancreatic, Non–Small Cell Lung or Triple Negative Breast Cancers, That Have Advanced or Have Spread NCT03098550 Phase I Nivolumab Phase II Daratumumab AZD8186 First Time in Patient Ascending Dose Study NCT01884285 Phase I Part A: AZD8186 monotherapy Part B: AZD8186 monotherapy Part C1: Abiraterone acetate combination with AZD8186 Part D1: AZD2014 combination with AZD8186 Part D2: AZD2014 combination with AZD8186 Part C2: Abiraterone acetate combination with AZD8186 A Study of FAZ053 Single Agent and in Combination with PDR001 in Patients with Advanced Malignancies NCT02936102 Phase I FAZ053 PDR001 Study of the Effects of Pembrolizumab in Patients with Advanced Solid Tumors (INSPIRE) NCT02644369 Phase II Pembrolizumab Phase I/II Study of PDR001 in Patients with Advanced Malignancies NCT02404441 Phase I PDR001 Phase II A Dose Escalation and Cohort Expansion Study of CD122-Biased Cytokine (NKTR-214) in Combination with Anti–PD-1 Antibody (Nivolumab) in Patients with Select Advanced or Metastatic Solid Tumors NCT02983045 Phase I Combination of NKTR-214 and nivolumab Phase II Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination with Atezolizumab in Advanced Cancers NCT02655822 Phase I CPI-444 CPI-444 plus atezolizumab A Phase 2 Study of Cediranib in Combination with Olaparib in Advanced Solid Tumors NCT02498613 Phase II Cediranib maleate Olaparib A Study of RO7198457 (Personalized Cancer Vaccine [PVC]) as a Single Agent and in Combination with Atezolizumab in Participations with Locally Advanced or Metastatic Tumors NCT03289962 Phase Ia/Ib RO7198457 Atezolizumab Olaparib as Adjuvant Treatment in Patients with Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA) NCT02032823 Phase III Olaparib Placebo Novartis, Basel, Switzerland. GlaxoSmithKline, Brentford, U.K. S146 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. schedu le (hr: 0.69 ; p = 0.019). Those findings suggest t hat a statistical difference in the overall response rate was benefit might accr ue to t he addit ion of week ly paclita xel to evident between the two treatment arms. That finding adjuvant chemotherapy in tnbc; however, that regimen was suggests that “BRCAness” might not be a reliable means not the primar y objective of the study, and thus it is difc fi ult of predicting the clinical response of tnbcs to certain to base recommendat ions on t he subg roup a na lysis a lone. chemotherapy agents. The addition of bevacizumab to chemotherapy was studied in t he adjuvant setting in t he beatrice study . No BRCA Carriers and TNBC invasive dfs or os benet w fi as demonstrated in t hat setting. The treatment of BRCA mutation–associated breast ca ncer Although studies supporting the role of neoadjuvant and the use of directed agents for that patient subset is an and palliative platinum-based chemotherapy in tnbc active area of research. Because the BRCA1 and BRCA 2 have been published, no data in the adjuvant setting are genes code for proteins involved in double-stranded dna currently available. Clinical trials investigating the role break repair, it is hypothesized that BRC A mutation– of platinum-based adjuvant chemotherapy are ongoing associated cancers might be more sensitive to chemot her- (for example, see NCT02488967 at http://Clinica lTria ls. apy agents that cause dna damage, such as the platinums. gov; Table ii). Sensit iv it y of t hat k ind has been show n in vitro ; however, its translation into clinica l application has yet to be estab- Metastatic Setting lished. A small phase ii study of cisplatin chemotherapy Triple-negative breast cancer is associated with a high i n BRC A1 mutation carriers, not selected for hormone risk of distant recurrence, predominantly in the first 2 receptor status, demonstrated high efficacy for cisplatin, 5,8 years after diagnosis . W hen metastases occur, biopsy of with an overall response rate of 80% and 9 of 20 patients the site of distant disease should be attempted to assess achiev ing a complete response . However, the study lacked for discordance in hormone receptor and her2 status . a control group. Further research into the role of cisplatin A retrospective analysis found that 8% of tumours that in the treatment of metastatic tnbc and BRCA mutation– were initia lly estrogen receptor–negative had converted to associated breast cancer is ongoing (NCT02595905 at estrogen receptor–positivity when the metastatic tumour http://ClinicalTrials.gov). deposit was assessed for hormone receptor status . No sta- The impaired dna repair pathway in BRC A1/2 car- tistica l discordance in her2 receptor status was obser ved. riers can also be targeted with parp [poly (adp-ribose) The choice of initial systemic chemotherapy should polymerase] inhibitors, which interfere with the repair of be indiv idua lized based on a number of factors, including single-stranded dna breaks and, when combined with an tumour burden, rate of disease progression, performance already weakened repair process, can result in synthetic status, previous chemotherapy exposure, and patient letha lit y . That activity has been confirmed by in vitro 17,18 preferences . With respect to agent selection, Table i studies, showing that tumours in carriers are in fact sen- 45,46 describes several guideline recommendations. Although sitive to parp inhibitors . Recently, the parp inhibitor combination chemotherapy is generally avoided in the olaparib was studied in the setting of metastatic breast palliative setting, tnbc often results in visceral involve- ca ncer in t he olympiad tria l . That study included 302 pa- ment and a more aggressive course, making combination t ients w it h metastat ic breast ca ncer who had k now n BRCA chemot herapy a more frequent choice in t his population . mutations, who were negative for her2 overexpression, and Platinum-based chemotherapy has been suggested who had received up to 2 prior lines of chemotherapy. The to potentia lly be more ef fective t han non-platinum-based patients were randomized to single-agent chemotherapy chemotherapy in metastatic tnbc. In a retrospective co- (capecitabine, eribulin, or vinorelbine every 3 weeks) or hort study, longer pfs was observed in patients receiving to olaparib (300 mg twice daily). The response rate was platinum-based chemotherapy compared w ith non- 59.9% in the olaparib group compared with 28.8% in the platinum-based therapy in the first line (7.8 months vs. chemotherapy group. Furthermore, pfs was improved in 4.9 months, p < 0.001) . However, no difference in os was the olaparib group (7.0 months vs. 4.2 months; hr: 0.58; observed. No improvement in pfs or os was shown in the 95% ci: 0.43 to 0.80; p < 0.001). Olaparib was approved in preliminary results of the prospective tnt study, which Ja nua r y 2018 by t he U.S. Food a nd Dr ug Administration for compared carboplatin with docetaxel in metastatic or use in BRCA-mutated metastatic breast ca ncer. In Ca nada, recurrent locally advanced tnbc . The tnt study ran- olaparib is currently approved for use only in BRCA-mutated domized 376 patients w it h metastatic tnbc or w it h k now n ovarian, fallopian tube, or primary peritoneal cancers. A BRCA1/2 mutation to either carboplatin (area under the phase iii Canadian Cancer Trials Group study, currently curve 6 every 3 weeks) or docetaxel (100 mg/m every open to accrual, is examining the role of olaparib in the 3 weeks) for 6–8 cycles or until progression. The initial adjuvant setting for carriers of BRCA1/2 mutations (see results, presented at the 2014 San Antonio Breast Cancer NCT02032823 at http://ClinicalTrials.gov). Other parp in- Sy mposium, showed no statistica l difference in pfs or os for hibitors are also actively being investigated in the metastatic the tnbc group (3.1 mont hs vs. 4.5 mont hs and 12.4 mont hs setting, including veliparib and niraparib (for example, vs. 12.3 months respectively). However, on subgroup ana ly- NCT02595905, NCT01905592) . W het her tumours t hat a re sis of BRCA1/2 carriers, pfs was improved in those receiv ing BRCA-proficient or that have BRCA pathway impairment carboplatin (6.8 months vs. 3.1 months). The objective (BRC Aness) will respond to these targeted therapies is response rate was also significantly higher (68.0% vs. currently unknown. 33.3% , p = 0.03). Interestingly, on subgroup analysis of The angiogenesis inhibitor bevacizumab has been basal-like malignancies by immunohistochemistry, no examined in combination with chemotherapy agents in Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S147 ADVANCES IN THE SYSTEMIC TREATMENT OF TNBC, Lebert et al. 49,50 t he treatment of metastatic breast cancer . A lt hough t he SUMMARY relevant studies demonstrated benefit in pfs , no improve- ment in os was observed. Miles et al. reported a pooled Triple-negative breast ca ncer constitutes a heterogeneous subgroup analysis of bevacizumab use in poor-prognosis group of malignancies that differ in natural history and groups. In the tnbc subgroup, median pfs was signic fi ant ly response to treatment. The mainstay of treatment contin- improved with the use of bevacizumab (hr: 0.63; 95% ci: ues to be chemotherapy; however, optimal chemotherapy 0.53 to 0.76) ; however, that improvement did not trans- regimens for tnbc have yet to be established. late into an os benefit. Thus, no role for bevacizumab is In this article, we have rev iewed the current ev idence accepted at this time. for systemic treatment for tnbc in the neoadjuvant, adjuvant, and metastatic settings. In the neoadjuvant FUTURE DIRECTIONS: IMMUNOTHERAPY setting, the use of platinum agents has been associated AND TARGETED THERAPY w ith improved rates of pcr, but os was not reported in the 30,31 associated studies . In the recently published create-x The role of immunotherapy in the treatment of tnbc is trial, an os benefit was shown for adjuvant capecitabine current ly under investigation in severa l tria ls recr uiting in in patients who do not achieve a pcr with neoadjuvant Ca nada (Table ii). In tnbc, strong ly mphocy tic infiltration chemot herapy . However, that approach has not been or immune response has been associated with improved widely adopted in clinical practice, perhaps because of prognosis . That obser vation suggests t hat harnessing t he the associated toxicity. For adjuvant treatment of tnbc, immune system against this disease might be beneficial. two trials that added weekly paclitaxel to combination 33–35 Pembrolizumab is a PD-1 inhibitor that has been shown chemotherapy showed improvements in dfs . In met- to be effective in the treatment of several other cancers, astatic tnbc, preliminary results show that the response 53–55 including lung, melanoma, and bladder ma lignancies . rate might be higher with platinum than with docetaxel In a phase ib study of pembrolizumab in patients with in BRCA mutation–associated malignancies ; however, advanced tnbc, on ly 18.5% of pat ients ex perienced a com- resea rch to g uide t he optima l choice of systemic treatment plete or partial response , with the duration of response for metastatic disease is limited. Olaparib, a parp inhibitor, varying from 15 to more than 47.3 weeks. A phase iii trial has recently been approved by the U.S. Food and Drug of pembrolizumab in t he treatment of metastatic or loca lly Administration for use in germline BRCA-mutated meta- recurrent inoperable tnbc is ongoing (see NCT02819518 static breast cancer, based on the olympiad trial . at http://Clinica lTria ls.gov) . The anti–PD-L1 antibody As molecular research advances an understanding of atezolizumab is also actively being investigated in the the driver mutations in this disease, more targeted treat- neoadjuvant and metastatic settings (see NCT03197935 and ments could become available. A number of investigationa l NCT03125902). Immunot herapy has show n great potentia l t herapies hold promise, including parp inhibitors, ar pat h- in a number of other disease sites, and thus the results of way inhibitors, and immunotherapy. Given those new de- the foregoing trials are highly anticipated. velopments, t he hope is t hat more ef fective treatments a nd In a subgroup of tnbc, expression of the androgen better outcomes will be achieved for patients with tnbc. receptor (ar) is increased . The clinical relevance of ar status has yet to be established in breast cancer; however, CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncolog y’s policy on disclos- several recent phase ii studies have examined the use ing conflicts of interest, a nd we decla re t he fol low ing interests : RL of anti-androgen agents in this setting. In one study, tu- has received educat ion f unding f rom A mgen a nd Eisa i a nd fees as mours from 242 patients with breast cancer negative for a n adv isor y boa rd member for A st ra Zeneca, Nova r t is, a nd Pfi zer. the estrogen and progesterone receptors were tested for EP has received t ravel f unding f rom Roche a nd fees as a n adv isor y ar expression . Of those tumours, only 12% were found boa rd member for A mgen, Genomic Hea lt h, Nova r t is, a nd Pfi zer. to be ar-positive. Patients whose tumours tested positive MS has received conference funding from Amgen and fees as an received bicalutamide 150 mg daily. The clinical benefit advisory board member for Pfizer and Shire. JM has received rate, defined as complete response, partial response, or conference travel f unding from Astra Zeneca and Roche and fees stable disease for more than 6 months, was 19%, and the as an adv isor y board member from Novartis and Pfizer. median pfs was 12 weeks (95% ci: 11 weeks to 22 weeks) . A phase iii evaluation of bicalutamide is still pending. AUTHOR AFFILIATIONS *Memorial Universit y of New foundland, Saint John’s, NL. En za luta mide is a n ar sig na lling in hibitor t hat is used in t he treatment of metastatic castration-resistant prostate REFERENCES cancer. The effect of enza lutamide has a lso been studied in 59 1. Canadian Cancer Society’s Advisor y Committee on Cancer ar-positive tnbc in a phase ii tria l . In t hat tria l, a ndrogen Stat ist ics. Canadian Cancer Statistics 2017. 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[Available online at: http:// [Available online at: http://ascopubs.org/doi/abs/10.1200/ ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.1003; cited jco.2010.28.15_suppl.1019; cited 9 April 2018] 16 April 2018] S150 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc.

Journal

Current Oncology – Multidisciplinary Digital Publishing Institute

Published: Jun 1, 2018

Keywords: breast cancer; triple-negative breast cancer

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