Role of Immunotherapy in Triple-Negative Breast Cancer

Authors: Tanya E. Keenan MD, MPH 1 , 2 and Sara M. Tolaney MD, MPH 1 , 2
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  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, and
  • 2 Harvard Medical School, Boston, Massachusetts.

Immune checkpoint inhibitors (ICIs) have led to durable clinical remissions in many metastatic cancers. However, the single-agent efficacy of ICIs in breast cancer is low, including in triple-negative breast cancer (TNBC), which has several key characteristics that enhance ICI responses. Strategies to improve anticancer immune responses in TNBC are urgently needed to extend survival for patients with metastatic disease. This review presents ICI monotherapy response rates and discusses combination strategies with chemotherapy, targeted therapies, and novel immunotherapies. It concludes with a summary of immunotherapy biomarkers in TNBC and a call to action for future directions of research critical to advancing the efficacy of immunotherapy for patients with TNBC.

Triple-negative breast cancer (TNBC), defined by the lack of estrogen and progesterone receptors and HER2, accounts for 15% to 20% of all breast cancers and typically displays aggressive behavior, including earlier recurrence and metastasis.1 The predominant systemic therapy for most metastatic TNBC (mTNBC) is chemotherapy, but responses are often short-lived, and patients have a median overall survival (OS) of 12 to 18 months.1 Therefore, improved therapies are urgently needed.

Immunotherapy has prolonged survival in other solid tumors and represents a promising treatment strategy for TNBC. The most successful immunotherapeutic agents consist of immune checkpoint inhibitors (ICIs), which block immunosuppressive receptors, such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and PD-1, to improve the cytotoxicity and proliferative capacity of tumor-infiltrating lymphocytes (TILs). ICIs, including monoclonal antibodies against PD-1 (ie, pembrolizumab, nivolumab), PD-L1 (ie, atezolizumab, durvalumab, avelumab), and CTLA-4 (ie, ipilimumab), have generated durable responses across many tumor types.29

Several key characteristics make TNBC more likely to respond to immunotherapy than other breast cancer subtypes. First, TNBC has more TILs,10 which correlate with better responses to ICIs in other tumors,11 and high levels of TILs in TNBC associate with improved prognosis in early-stage TNBC.12 Second, TNBC has higher levels of PD-L1 expression on both tumor and immune cells,13,14 providing direct targets for ICIs and also correlating with response to anti–PD-1 therapies in other tumors.2 Finally, TNBC has a greater number of nonsynonymous mutations,15 which give rise to tumor-specific neoantigens that activate neoantigen-specific T cells to mount an antitumor immune response,16 which can be strengthened by ICIs.17

This review presents a framework for understanding the current clinical experience surrounding ICIs and other novel immunotherapy agents in TNBC (Figure 1). In addition, emerging immunotherapy biomarkers are discussed and future directions for immunotherapy development in TNBC are outlined.

Figure 1.
Figure 1.

Immunotherapy and combination agents in triple-negative breast cancer.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 4; 10.6004/jnccn.2020.7554

ICI Monotherapy

Although response rates to ICIs are higher in TNBC than in hormone receptor–positive and HER2-positive breast cancers, the single-agent efficacy is still low, with monotherapy response rates ranging from approximately 5% in unselected patients to approximately 23% in treatment-naïve PD-L1–positive patients (Table 1). The initial phase Ib KEYNOTE-012 study (ClinicalTrials.gov identifier: NCT01848834) of the PD-1 inhibitor pembrolizumab demonstrated an encouraging overall response rate (ORR) of 18.5% in 32 patients with both pretreated and treatment-naïve PD-L1–positive mTNBC.18 However, the subsequent larger phase II KEYNOTE-086 study (NCT02447003) found an ORR of 5.3% in 170 patients with PD-L1–unselected pretreated tumors.19 Notably, in the 84 treatment-naïve patients on this trial, the ORR was 21.4%, suggesting that ICIs have greater efficacy in the first-line metastatic setting.20 In support of this concept, the phase III KEYNOTE-119 trial (NCT02555657) in patients with pretreated mTNBC did not show an improvement in ORR, progression-free survival (PFS), or OS with single-agent pembrolizumab versus single-agent chemotherapy, although patients with the highest levels of tumor PD-L1 expression showed a trend toward greater benefit with pembrolizumab.21

Table 1.

Monotherapy and Chemotherapy Anti–PD-1/L1 Trials in Metastatic TNBC

Table 1.

The PD-L1 inhibitors avelumab and atezolizumab have also been explored as ICI monotherapy in mTNBC. Avelumab demonstrated an ORR of 5.2% in 58 heavily pretreated patients in the phase Ib JAVELIN trial (NCT01772004),22 and the phase I trial of atezolizumab (NCT01375842) led to an ORR of 10% in 115 pretreated patients, with no responses seen in the PD-L1–negative subgroup.23 Both trials underscore the limited single-agent efficacy of ICIs in mTNBC, with particularly low response rates observed in pretreated metastatic disease.

Metastatic Chemotherapy Combination Regimens

Combination regimens of PD-1/L1 inhibitors plus chemotherapy have demonstrated more success in mTNBC than single-agent ICIs (Table 1). Among early trials including both PD-L1–positive and PD-L1–negative tumors, pembrolizumab with eribulin, a microtubule inhibitor that suppresses transforming growth factor β (TGF-β),24 which has been associated with intratumoral CD8-positive T-cell exclusion,25 yielded an ORR of 26.4% in 106 patients treated with 0 to 2 prior lines of therapy for metastatic disease in the ENHANCE-1 trial (ClinicalTrials.gov identifier: NCT02513472).26 Similarly, the smaller phase Ib trial of atezolizumab and nab-paclitaxel (NCT01375842) showed a promising ORR of 39.4% in 33 patients, also treated with 0 to 2 prior lines,27 perhaps related to the ability of taxanes to promote toll-like receptor activity and dendritic cell activation.28 The subsequent randomized IMpassion130 phase III trial (NCT02425891) in treatment-naïve mTNBC showed that atezolizumab added to nab-paclitaxel resulted in a clinically meaningful OS improvement of 7 months in the PD-L1–positive subgroup but not in the entire cohort,29 which is notable because the trial’s hierarchical statistical design required overall benefit to formally test the subgroup effect.28 These results led the FDA and the European Commission to approve atezolizumab and nab-paclitaxel in PD-L1–positive mTNBC, establishing the first immunotherapy approval in breast cancer.

Several ongoing trials will further elucidate the role of chemotherapy in combination with ICIs in mTNBC (Table 2). The KEYNOTE-355 trial (NCT02819518) recently announced in a press release that first-line chemotherapy with pembrolizumab significantly improved PFS compared with chemotherapy alone in patients with mTNBC expressing PD-L1 using the 22C3 antibody with a combined positive score ≥10, defined as the ratio of all PD-L1–expressing cells, including tumor cells, lymphocytes, and macrophages, to the number of all tumor cells.30 In addition, 2 trials of chemotherapy with or without atezolizumab are currently accruing. The IMpassion131 trial (NCT03125902) will investigate whether first-line atezolizumab combined with paclitaxel will improve outcomes compared with paclitaxel alone, whereas IMpassion132 (NCT03371017) will determine whether first-line atezolizumab combined with chemotherapy will improve outcomes compared with chemotherapy alone in TNBC recurring within 1 year of adjuvant therapy.

Table 2.

Ongoing Anti–PD-1/L1 Combination and Novel Immunotherapy Trials in TNBC

Table 2.

Early-Stage Chemotherapy Combination Regimens

The combination of ICIs with chemotherapy in early-stage TNBC has also demonstrated preliminary success (Table 3). Among patients with stage II–III disease, the I-SPY 2 trial (ClinicalTrials.gov identifier: NCT01042379) initially revealed that pembrolizumab added to neoadjuvant paclitaxel followed by doxorubicin and cyclophosphamide nearly tripled the estimated pathologic complete response (pCR) rates from 22% to 60%,31 perhaps related to the known immunostimulatory effects of anthracyclines to increase intratumoral immune effectors,32 as well as antigen uptake and processing.33 However, the GeparNuevo trial (NCT02685059), which included earlier-stage T1b and higher disease, demonstrated that the addition of durvalumab to neoadjuvant nab-paclitaxel followed by epirubicin and cyclophosphamide did not significantly improve pCR rates in the overall trial and only improved pCR rates when durvalumab was started 2 weeks before chemotherapy, which was a subgroup analysis underpowered for significance testing.34 The KEYNOTE-522 trial (NCT03036488) reported that pembrolizumab added to paclitaxel plus carboplatin and then to an anthracycline plus cyclophosphamide as neoadjuvant therapy, followed by surgery plus an additional 9 cycles of adjuvant pembrolizumab, improved pCR rates from 51.2% to 64.8%, and 18-month event-free survival (EFS) rates from 85.3% to 91.3% (hazard ratio [HR], 0.63; 95% CI, 0.43–0.93).35 These results need to be confirmed with extended follow-up data and weighed against long-term immune-related toxicity. In this trial, less benefit was seen in node-negative patients, underscoring the conclusion that the risks of this 5-agent regimen may outweigh the benefits for patients with early-stage node-negative TNBC and TNBC with high TIL levels, who have excellent outcomes with current standard-of-care regimens.12

Table 3.

Anti–PD-1/L1 Combination Therapy Trials in Early-Stage TNBC

Table 3.

Most recently, the NeoTRIPaPDL1 trial (NCT02620280) of atezolizumab added to neoadjuvant carboplatin plus nab-paclitaxel followed by adjuvant cyclophosphamide plus an anthracycline without atezolizumab reported that pCR was not significantly different in patients with early high-risk or locally advanced TNBC treated with versus without atezolizumab (43.5% vs 40.8%; P=.66) (Table 3).36 Similarly, the 8-cycle pembrolizumab cohort without doxorubicin and cyclophosphamide in the neoadjuvant I-SPY 2 trial demonstrated that neoadjuvant pembrolizumab for 4 cycles added to paclitaxel followed by neoadjuvant pembrolizumab alone for 4 additional cycles had an equivalent estimated pCR rate of 27% compared with neoadjuvant paclitaxel, doxorubicin, and cyclophosphamide in patients with high-risk early-stage TNBC.37 Although this regimen did not meet the target threshold pCR rate of 60% required for graduation per I-SPY 2 criteria, these results suggest there may be potential strategies for de-escalation from the 5-agent KEYNOTE-522 regimen that should be further explored. Overall, the contrasting results of KEYNOTE-522 may be explained by different chemotherapy backbones, including the presence of an anthracycline based on the results of the TONIC trial, which showed the superiority of doxorubicin as an induction agent to enhance sensitivity to PD-1 blockade.38 The dissimilar results could also be due to differences in ICI activity, given that PD-1 inhibitors but not PD-L1 inhibitors block PD-L2 inhibitory signaling, but it is unclear whether this mechanistic difference translates into differences in clinical efficacy.39

Several ongoing early-stage disease trials will further clarify the efficacy of ICIs in neoadjuvant and adjuvant regimens for TNBC (Table 3). Two key trials are investigating whether 1 year of adjuvant anti–PD-1/L1 therapy prolongs EFS or disease-free survival (DFS): the SWOG S1418/BR006 trial (NCT02954874) of pembrolizumab for patients with residual disease, and the A-brave trial (NCT02926196) of avelumab for patients with high-risk or residual disease. Similarly, 2 large trials are addressing whether the addition of atezolizumab to both neoadjuvant and adjuvant therapy prolongs EFS or invasive DFS: the placebo-controlled NSABP B-59 trial (NCT03281954) of atezolizumab added to neoadjuvant 4-agent chemotherapy followed by 1 year of adjuvant atezolizumab, and the IMpassion030 trial (NCT03498716) of atezolizumab added to neoadjuvant 3-agent chemotherapy followed by 1 year of adjuvant atezolizumab or observation. Finally, one additional smaller trial is exploring whether atezolizumab added to neoadjuvant chemotherapy alone improves outcomes. The IMpassion031 trial (NCT03197935) will assess whether atezolizumab versus placebo added to neoadjuvant nab-paclitaxel, doxorubicin, and cyclophosphamide results in higher pCR rates.

Targeted Therapy Combination Regimens

Certain targeted therapy combinations are emerging as potential strategies to overcome innate resistance to PD-1/L1 inhibitors in mTNBC (Table 4). Preclinical evidence in BRCA-deficient models of TNBC suggests that PARP inhibitors increase cytoplasmic DNA and activate the STING (stimulator of interferon genes) protein, which increases type 1 interferons and T-cell intratumoral infiltration.40 Translational studies of human breast cancers have also shown that BRCA1/2 mutations negatively associate with markers of immunogenicity, such as immune infiltration and T-cell–mediated cytolysis, the latter calculated as the summed expression of the CD8-positive T-cell effectors PRF1 and GZMA.41 To evaluate the clinical efficacy of combining the PARP inhibitor niraparib with the PD-1 inhibitor pembrolizumab, the phase II TOPACIO trial (ClinicalTrials.gov identifier: NCT02657889) enrolled 55 patients with advanced or mTNBC and found an ORR of 47% and a median PFS of 8.3 months among the 15 patients with tumor BRCA mutations.42 Within the limits of cross-trial comparisons, this ORR was slightly lower than the ORRs of 55% and 62% associated with single-agent PARP inhibitor therapy in patients with TNBC and germline BRCA mutations in the OlympiAD (NCT02000622)43 and EMBRACA44 (NCT01945775) trials, respectively. However, the median PFS was longer than those observed in the TNBC subgroups of these trials, which were 5.5 and 5.8 months, respectively. The MEDIOLA trial (NCT02734004) of olaparib and durvalumab in mTNBC with germline BRCA mutations demonstrated an ORR of 58.8%, more similar to single-agent PARP therapy, with a median PFS of 4.9 months.45 The nonrandomized designs, different PARP inhibitors, and small sample sizes of these initial trials limit definitive conclusions. Ongoing larger trials of olaparib with atezolizumab (ETCTN trial; NCT02849496) or durvalumab (DORA trial; NCT03167619) are in progress (Table 2), as well as an I-SPY 2 cohort of neoadjuvant olaparib with durvalumab ± paclitaxel followed by neoadjuvant doxorubicin and cyclophosphamide (NCT01042379).

Table 4.

Resulted Targeted Therapy and Novel Immunotherapy Agent Anti–PD-1/L1 Trials in Metastatic TNBC

Table 4.

AKT inhibitors constitute another important class of targeted therapy agents currently in development with ICIs in TNBC. Loss of the tumor suppressor PTEN, a negative regulator of AKT, has been linked to immunotherapy resistance,46,47 and AKT inhibition augments expansion of tumor-specific lymphocytes with a memory cell phenotype.48 Preliminary data from a phase Ib trial of taxane chemotherapy plus the AKT inhibitor ipatasertib and atezolizumab demonstrated an impressive ORR of 73% in the first 26 patients, with similar responses irrespective of PIK3CA/AKT1/PTEN alteration status and PD-L1 expression (Table 4).49 These data led to the addition of a paclitaxel, ipatasertib, and atezolizumab arm in the larger phase III IPATunity130 trial (NCT03337724), and the AKT inhibitor capivasertib is being explored in combination with paclitaxel and durvalumab in the BEGONIA trial (NCT03742102; Table 2).

Considerable interest also surrounds MEK inhibitors in combination with checkpoint blockade. Preclinical studies in TNBC showed that MEK inhibition upregulates PD-L1 and major histocompatibility complex expression and enhances the antitumor immune response to PD-1/L1 inhibition.50 The phase II COLET trial (NCT02322814), which investigated the MEK inhibitor cobimetinib, the PD-L1 inhibitor atezolizumab, and taxane chemotherapy in 63 patients with treatment-naïve mTNBC, showed that this triplet combination therapy had modest activity with ORRs of 34.4% and 29.0% and median PFS of 3.8 and 7.0 months in the paclitaxel and nab-paclitaxel cohorts, respectively (Table 4).51 However, this trial was not designed to determine the incremental efficacy of adding PD-1 blockade to combined MEK inhibition and taxane chemotherapy.51 Ongoing (NCT03971409) and future trials of MEK inhibitors combined with PD-1/L1 inhibitors will clarify whether MEK inhibitors enhance responses to checkpoint blockade in TNBC (Table 2).

Novel Immunotherapy Agents

Novel therapeutic strategies to overcome deficient anticancer immunity in TNBC are urgently needed, and some are already in clinical development. One such strategy is the IL-2 pathway agonist bempegaldesleukin (NKTR-214), which preferentially activates the IL-2b receptor to expand effector T cells more than regulatory T cells.5254 The phase I/II PIVOT-02 trial (ClinicalTrials.gov identifier: NCT02983045) evaluated 38 patients with mTNBC treated with bempegaldesleukin in combination with nivolumab and found an ORR of 13.2%, with durable responses regardless of PD-L1 expression (Table 4). Future trials of bempegaldesleukin combined with anti–PD-1/L1 therapies and chemotherapy in TNBC are currently being developed. Another immune priming strategy is the intratumoral toll-like receptor 9 (TLR9) agonist SD-101, which stimulates plasmacytoid dendritic cells to release interferon-α and mature into antigen-presenting cells, thereby increasing CD8+ T-cell infiltration in tumors.55 The I-SPY 2 trial (NCT01042379) is currently investigating the estimated pCR impact of neoadjuvant SD-101 and pembrolizumab added to weekly paclitaxel followed by doxorubicin and cyclophosphamide compared with paclitaxel, doxorubicin, and cyclophosphamide alone (Table 2).

Breast cancer vaccines constitute another novel therapeutic strategy to enhance anticancer immunity (Table 2). By presenting breast cancer peptides to T cells, these vaccines enhance the priming and activation of T cells and strengthen immune recognition of cancer cells. Multiple trials of vaccines with and without PD-1/L1 inhibitors are currently enrolling patients with TNBC in the adjuvant or metastatic setting, including trials of the PVX-410 vaccine (NCT03362060, NCT02826434), folate receptor α vaccine (NCT03012100), and neoantigen vaccines. The PVX-410 vaccine targets the XBP1 and CD138 peptides that are overexpressed in TNBC.56 Similarly, the folate receptor α vaccine also targets a peptide overexpressed in breast cancer, and led to immune responses that persisted at least 12 months in the initial phase I trial of patients with breast and ovarian cancer.57

Rather than targeting peptides overexpressed in tumors but also shared by normal cells, neoantigen vaccines target peptides arising from tumor-specific mutations unique to each patient’s tumor and not present in normal cells, and therefore T-cell responses to these neoantigens are not limited by self-tolerance.58 The randomized phase I trial of a neoantigen vaccine with or without durvalumab is enrolling 24 patients with residual TNBC after neoadjuvant therapy (NCT03199040),59 whereas the randomized phase II trial of nab-paclitaxel and durvalumab with or without a neoantigen vaccine is enrolling 70 patients with treatment-naïve mTNBC who are treated first with gemcitabine and carboplatin for 18 weeks prior to randomization (NCT03606967).60 Using patient-specific neoantigens identified and prioritized by next-generation sequencing and epitope prediction algorithms, these vaccines aim to prime T cells to recognize neoantigens specific to cancer cells.60 Whether these breast cancer vaccines will elicit a sufficient antitumor immune response to improve clinical outcomes remains to be determined.

Other novel immunotherapy strategies currently being explored in TNBC include oncolytic viruses and adoptive cell therapies, such as TIL transfer and CAR T cells. Oncolytic viruses are being developed to target and kill TNBC, such as the phase II trial of in situ oncolytic virus therapy consisting of adenovirus-mediated expression of herpes simplex virus thymidine kinase plus valacyclovir with stereotactic body radiation therapy followed by pembrolizumab (NCT03004183). Likewise, initial studies of TIL transfer in breast cancer are emerging. These therapies activate and expand TILs removed from a patient’s tumor, including T cells that recognize tumor-specific neoantigens. One patient with chemorefractory hormone receptor–positive metastatic breast cancer experienced durable complete remission after adoptive transfer of TILs reactive against 4 tumor-specific mutant proteins,61 and a phase II trial of the autologous TIL transfer therapy LN-145 will enroll 10 patients with mTNBC (NCT04111510).

Finally, CAR T cells, engineered to target tumor antigens, are also being developed in breast cancer, with careful safety measures to prevent potentially life-threatening adverse events. Although preliminary, a phase 0 trial of mRNA-transfected c-MET CAR T cells delivered intratumorally in 6 patients with metastatic breast cancer found no CAR T cell adverse effects greater than grade 1 (NCT01837602),62 and a phase I trial of mesothelin-targeted CAR T cells, which demonstrated responses without toxicity in other tumors,63 will enroll 36 patients with pretreated metastatic breast cancer (NCT02792114). These novel immunotherapies, although preliminary and requiring extensive clinical validation, will enhance understanding of anticancer immunity in breast cancer and contribute to the development of future effective immunotherapies.

Biomarkers of Immunotherapy Response

Biomarkers that predict clinical benefit to immunotherapy in TNBC are needed to select patients most likely to benefit from single-agent ICIs, and to develop combination therapies that overcome ICI resistance. Only 2 validated biomarkers currently exist: mismatch repair deficiency and PD-L1 expression on immune cells.64,65 However, mismatch repair deficiency occurs rarely in breast cancer and more commonly in early-stage disease,64 and most patients with mTNBC are PD-L1–negative by the currently approved SP-142 assay.66 Furthermore, the utility of PD-L1 expression as a reliable biomarker is limited by several issues: its varying expression over time and metastatic sites; the discrepancy among different PD-L1 assays, particularly when staining immune cells67; the observations that some PD-L1–negative patients respond to ICIs 68; and recent trials in the early disease setting that show little to no correlation of PD-L1 expression with benefit specific to ICIs, including the KEYNOTE-522 and NeoTRIPaPDL1 trials.36,69

Emerging potential biomarkers of immunotherapy response in TNBC include high tumor mutational burden (TMB), TILs, and transcriptional signatures of immune infiltration. High TMB with variably defined cutoffs correlates with response to PD-1/L1 inhibitors across various cancer types,7075 but the prevalence of high TMB >10 mutations/Mb in breast cancer is low: 3% of primary tumors and 8% of metastatic tumors.76,77 The TAPUR study (NCT02693535) of single-agent pembrolizumab in patients with heavily pretreated metastatic breast cancer with TMB ≥9 mutations/Mb reported an ORR of 21%,78 which is consistent with improved clinical efficacy of single-agent ICIs in breast cancer with high TMB. In a retrospective study of 62 women with mTNBC treated with anti–PD-1/L1 therapies, TMB ≥10 mutations/Mb was also found to be associated with longer PFS following ICI treatment, whereas PTEN alterations were found to be associated with shorter PFS.79 These findings require validation in future prospective studies, and the predictive versus prognostic role of PTEN alterations needs to be clarified.

Higher levels of TILs have also been associated with better responses to ICI monotherapy,80 and recently TILs ≥5% have been shown to independently predict improved response and survival following pembrolizumab but not chemotherapy in the KEYNOTE-119 trial of pembrolizumab compared with chemotherapy monotherapy in patients with mTNBC treated with 1 to 2 lines of prior systemic therapy, although these results are preliminary and used a one-sided P value for pembrolizumab.81,82 Similarly, a study of neoadjuvant durvalumab concurrent with nab-paclitaxel and dose-dense doxorubicin and cyclophosphamide in 57 patients with early-stage TNBC found that high CD8 cell density and immune gene expression signatures, as well as DNA damage response signatures, correlated with higher pCR rates,83 although these changes were not shown to be specific to ICI therapy compared with chemotherapy alone. Finally, the TONIC trial (NCT02499367) of various induction regimens prior to single-agent nivolumab showed that tumors treated with doxorubicin or cisplatin demonstrated increased expression of genes related to the PD-L1 pathway, T-cell cytotoxicity, and inflammation, suggesting that certain chemotherapy agents induce favorable tumor immune microenvironment changes that promote response to PD-1 blockade.38 Additional translational studies are needed in breast cancer to more thoroughly investigate immunotherapy response correlates found in other tumors, such as antigen presentation and interferon-λ signaling.73,84

Future Directions

Despite the recent approval of atezolizumab and nab-paclitaxel in PD-L1–positive mTNBC, many unanswered questions remain regarding immunotherapy in TNBC. Critical areas in need of development include immunotherapies for PD-L1–negative mTNBC and TNBC refractory to prior PD-1/L1 therapies, as well as strategies that minimize immune-related toxicity. Altogether, clinical trials based on strong preclinical evidence combined with rich translational studies to understand mechanisms of response and resistance are necessary to advance the clinical development of immunotherapy in TNBC.

Acknowledgments

We kindly thank Kate Bifolck for her editorial support on this work.

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If the inline PDF is not rendering correctly, you can download the PDF file here.

Submitted October 21, 2019; accepted for publication February 20, 2020.

Disclosures: Dr. Keenan has disclosed that she has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Tolaney has disclosed that she receives grant/research support from Novartis, Genentech, Eli Lilly, Pfizer, Merck, Exelixis, Eisai, Bristol Meyers Squibb, AstraZeneca, Cyclacel, Immunomedics, Odonate, and Nektar; and that she is a scientific advisor/consultant for Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics, Nektar, Tesaro, Daiichi-Sankyo, Oncopep, Paxman, Athenex, Abbvie, and Nanostring.

Correspondence: Sara M. Tolaney, MD, MPH, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. Email: sara_tolaney@dfci.harvard.edu
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