Novel Agents for Metastatic Triple-Negative Breast Cancer: Finding the Positive in the Negative

View More View Less
  • 1 Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Metastatic triple-negative breast cancer (TNBC) is associated with a poor prognosis, and the development of better therapeutics represents a major unmet clinical need. Although the mainstay of treatment of metastatic TNBC is chemotherapy, advances in genomics and molecular profiling have helped better define subtypes of TNBC with distinct biologic drivers to guide the therapeutic development of targeted therapies, including AKT inhibitors for PI3K/AKT-altered TNBC, checkpoint inhibitors for PD-L1–positive TNBC, and PARP inhibitors for BRCA1/2 mutant TNBC. This progress may ultimately convert TNBC from a disease traditionally defined by the absence of therapeutically actionable receptors to one that is defined by the presence of discrete molecular targets with therapeutic implications. Furthermore, antibody drug conjugates have emerged as an important therapeutic strategy to target genomically complex tumors that lack actionable oncogenes but have overexpressed actionable surface receptors such as trop-2. In this article, we discuss promising novel agents for advanced TNBC, some of which have been incorporated into current clinical practice, and others that will likely change the therapeutic landscape and redefine the TNBC terminology in the near future.

Triple-negative breast cancer (TNBC), conventionally defined as breast cancer that does not express the estrogen receptor, progesterone receptor, and HER2, accounts for approximately twenty percent of breast cancer.1 TNBC often presents in an aggressive manner, with advanced stage at diagnosis in many cases, and a propensity for the development of distant metastases.2 Median overall survival (OS) for metastatic TNBC (mTNBC) is 15 months.3

Although the mainstay of treatment of mTNBC is chemotherapy,48 novel agents are being developed, and some of these agents have been incorporated into clinical practice. This review addresses the molecular heterogeneity of TNBC and discusses novel agents for mTNBC (Table 1).

Table 1.

Summary of Novel Therapeutic Agents in Development for Advanced TNBC

Table 1.

Molecular Heterogeneity of TNBC

Genomic analyses have demonstrated that TNBC is a heterogeneous disease. Molecular profiling has classified TNBC into biologically relevant subtypes with molecular targets.

Lehmann et al9 described 6 discrete subtypes of TNBC based on gene expression profiling: basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR). Each of these subtypes displays different but overlapping clinicopathologic characteristics, heterogenous mutational profiles, and genomic instability. More recently, Burstein et al10 simplified the TNBC classification into 4 distinct subtypes, based on RNA- and DNA-based analyses, given that the previously defined IM and MSL subtypes were attributed in large part to lymphocytes and stromal cells in the bulk sequencing. In the revised classification, subtypes included (1) LAR, characterized by the presence of the androgen receptor and mutations in PI3KCA and AKT1, and biologically similar to the luminal estrogen receptor subtype; (2) mesenchymal, demonstrating expression of mesenchymal genes such as IGF-1, c-kit, and prostaglandin F; (3) basal-like immunosuppressed (BLIS), defined by the presence of SOX transcription factors and VTCN1; and (4) basal-like immune-activated (BLIA), demonstrating cytokine expression. Although the subtype classification can have prognostic implications, with the worst prognosis seen in BLIS tumors, and LAR subtype associated with more indolent features, it does not have predictive implications or clinical utility, and therefore is not used in clinical decision-making. Based on single-cell RNA sequencing, multiple subpopulations within primary TNBC tumors were identified, suggesting that molecular signatures identified through bulk sequencing may not accurately capture the biology of TNBC tumors.11

Although the classifications of TNBC may differ based on the methodology and classification used, clinically the identification of molecular targets in TNBC is most relevant, because this transforms TNBC into potentially actionable disease subsets. Broadly speaking, the actionable targets in mTNBC can be divided into (1) targeting genomic mutations and key intracellular signaling pathways, (2) targeting cell-surface markers for selective delivery of potent agents, and (3) targeting the immune microenvironment, as depicted in Figure 1.

Figure 1.
Figure 1.

Novel targets in triple-negative breast cancer for therapeutic intervention.

Abbreviation: AR, androgen receptor.

aFDA-approved therapy.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 2020; 10.6004/jnccn.2020.7600

Targeting Genomic Mutations and Key Intracellular Signaling Pathways

PARP Inhibition Targeting BRCA1/2 Mutant Cancer

Germline mutations in BRCA1/2 are present in 5% to 10% of breast cancer,12 and often in association with TNBC.13 The current recommendation for mTNBC is to evaluate for a germline BRCA1/2 mutation based on the recent approval of 2 PARP inhibitors for the treatment of patients with advanced breast cancer with deleterious (pathogenic) germline BRCA1/2 mutations. PARP1 and 2 are involved in the cellular response to single-strand DNA breaks.14 DNA lesions caused by PARP inhibition may be repaired through homologous recombination, a pathway mediated by BRCA1/2. In vitro, cells deficient in BRCA1/2 are sensitive to PARP inhibition, via synthetic lethality by which they cannot repair DNA damage via PARP,14 providing support for investigating PARP inhibitors in advanced breast cancer.

In the phase III OlympiAD trial, a significant improvement in progression-free survival (PFS) was seen in patients with HER2-negative advanced breast cancer with germline BRCA1/2 mutations treated with olaparib, a PARP inhibitor, versus chemotherapy (PFS, 7.0 vs 4.2 months; hazard ratio [HR], 0.58; P<.001),15 leading to FDA approval of olaparib. In the EMBRACA study, in which patients with advanced breast cancer and germline BRCA1/2 mutations received talazoparib, another PARP inhibitor with higher potency than olaparib, or chemotherapy,16 median PFS was higher in those treated with talazoparib (8.6 vs 5.6 months; HR, 0.54; P<.001), and the objective response rate (ORR) was also improved (62.6% vs 27.2%; odds ratio, 5.0; P<.001). Talazoparib is FDA approved for HER2-negative advanced breast cancer with germline BRCA1/2 mutations.17 Both olaparib and talazoparib are well tolerated, but toxicity includes myelosuppression, fatigue, and gastrointestinal problems.

The BROCADE 3 phase III study compared veliparib with carboplatin and paclitaxel followed by maintenance veliparib versus chemotherapy in germline BRCA1/2-mutant HER2-negative advanced breast cancer.18 Median PFS improved from 12.6 to 14.5 months with the addition of veliparib, and durable responses were seen with veliparib (3-year PFS rate, 26% with veliparib vs 11% with chemotherapy alone). The FDA’s review of the BROCADE 3 data is awaited, and it is possible that this may become a new standard-of-care option for mTNBC. Notably, this study suggests that perhaps maintenance use of a PARP inhibitor may improve outcomes in germline BRCA1/2 mutant mTNBC.

Additional efforts to broaden the applicability of PARP inhibitors to a larger population are underway, including targeting somatic BRCA1/2 mutations with PARP inhibitors, similar to somatic BRCA1/2-mutant ovarian cancer in which PARP inhibitors are equally as effective as for germline BRCA1/2 mutations,19 and other DNA damage repair genes (ClinicalTrials.gov identifiers: NCT03990896 and NCT03344965). Combination therapy with a PI3K inhibitor and PARP inhibitor is being explored (NCT01623349) based on preclinical data demonstrating that PI3K inhibition can sensitize TNBC to PARP inhibition.20,21 Combining a PARP inhibitor and immunotherapy has demonstrated preliminary efficacy, including in BRCA1/2 wild-type cancer.22

AKT Inhibitors Targeting the PI3K/AKT Pathway

TNBC may overexpress PI3K/AKT.23,24 A subset of TNBC harbors loss of PTEN, a tumor suppressor gene, which may increase AKT pathway activation. Altogether, approximately 45% of breast tumors may harbor mutations in the AKT pathway, including PIK3CA, AKT1, and PTEN. These observations have spurred interest in AKT inhibitors for TNBC.

A randomized phase II trial (LOTUS) in patients with advanced TNBC (aTNBC) evaluated ipatasertib, an AKT inhibitor, with paclitaxel versus paclitaxel alone in the first-line setting (n=124) and demonstrated an improvement in PFS with ipatasertib compared with paclitaxel alone (PFS, 6.2 vs 4.9 months; HR, 0.60; P=.037), particularly in the PTEN-low tumors (median PFS, 6.2 vs 3.7 months; HR, 0.59; P=.18).25 Grade 3 or 4 toxicity with ipatasertib included diarrhea and neutropenia.25 Further investigation with ipatasertib is ongoing in a phase III trial.26

The PAKT trial27 investigated capivasertib, another AKT inhibitor, with paclitaxel versus paclitaxel alone as first-line treatment of mTNBC. With capivasertib, PFS improved (5.9 vs 4.2 months; HR, 0.74; P=.06), and in patients with PIK3CA/AKT1/PTEN alterations, this benefit was prominent (PFS, 9.3 vs 3.7 months; HR, 0.30; P=.01). An improvement in median OS was seen in the entire population (19.1 vs 12.6 months; HR, 0.61; P=.04). Diarrhea, infection, rash, and fatigue occurred with capivasertib. A phase III study of capivasertib and paclitaxel is ongoing for aTNBC (ClinicalTrials.gov identifier: NCT03997123).

Combination therapy with an AKT inhibitor (ipatasertib), taxane, and immunotherapy (atezolizumab) is also being explored for mTNBC (NCT04177108).

Androgen Receptor Inhibitors Targeting the Androgen Receptor Pathway

A subset of TNBC expresses androgen receptor (AR).9,10,28 A phase II study evaluated bicalutamide, an antiandrogen, in patients with AR-positive disease (immunohistochemical positivity >10%).29 The 6-month clinical benefit rate (CBR) was 19% and median PFS was 12 weeks. No significant toxicity was seen.

A second phase II study evaluated the efficacy of enzalutamide, an AR inhibitor, in advanced AR-positive TNBC.30 Patients with AR-positive disease defined by immunohistochemical staining >0% were treated with enzalutamide. Of 118 enrolled patients, the CBR at 16 weeks was 25% in the intent-to-treat population (ITT) and 33% in the evaluable subset. Median PFS was 2.9 months. Enzalutamide was well tolerated, with fatigue being the main grade 3 toxicity. Although these results are modest, they are intriguing for a targeted therapy that is well tolerated. Combination therapy with androgen inhibition is being evaluated. A study evaluated a PI3K inhibitor with an AR antagonist,31 and observed better responses in LAR subtype TNBC, and provided translational insight into tumor subtypes likely to respond to AR antagonists.

An issue that has arisen with targeting AR is the best modality for AR testing. Although both immunohistochemical and genomic assays are available, currently there is a lack of consensus on the best way to define AR positivity given significant variability within these assays and within studies that have been conducted using them.

Targeting Cell Surface Receptors for Selective Delivery of Potent Agents

Antibody–Drug Conjugate Targeting Trop-2

Antibody–drug conjugates (ADCs) selectively deliver a cytotoxic agent to cancer cells through coupling with a monoclonal antibody. Sacituzumab govitecan-hziy is one ADC that combines an irinotecan metabolite (SN-38) to an antitrop-2 monoclonal antibody with a cleavable linker.32 Trop-2 is widely expressed in breast cancer, including TNBC,33 and participates in tumor growth.34

In a phase I/II study, patients with advanced cancer, including 108 with mTNBC (who had received ≥2 prior therapies), received sacituzumab govitecan-hziy.32 Median PFS was 5.5 months and OS was 13.0 months; 3 patients had a complete response and 33 had a partial response, with an overall response rate of 33.3%. Median duration of response was 7.7 months, which is much higher than what has previously been seen with most chemotherapy agents. Common toxicities included myelosuppression, gastrointestinal toxicity, fatigue, electrolyte abnormalities, skin changes, and infection. Accelerated approval of sacituzumab govitecan-hziy for patients with mTNBC who have received at least 2 prior lines of therapy was granted in April 2020. The phase III randomized ASCENT study comparing sacituzumab govitecan-hziy versus chemotherapy for mTNBC will provide additional data (ClinicalTrials.gov identifier: NCT02574455).

ADC Targeting LIV-1

Ladiratuzumab vedotin is an antibody to LIV-1, a breast cancer–associated protein and zinc transporter, which is linked to auristatin.35 LIV-1 is expressed in TNBC.36 In a phase I study, ladiratuzumab vedotin agent was shown to have a preliminary ORR of 32% in TNBC.37 Combination therapy with ladiratuzumab and pembrolizumab for aTNBC is being explored (NCT03310957). Preliminary results showed an ORR of 54% among 26 treated patients, with manageable toxicity.38

Targeting the Immune Microenvironment

Immune Checkpoint Inhibition Monotherapy

Immune checkpoint inhibitors that block interaction of the PD-1 receptor and PD-L1 are being explored in many advanced malignancies. Breast cancer has been viewed as being less immunogenic than other malignancies, such as melanoma and lung cancer, but among breast cancer subtypes, TNBC is considered more immunogenic. The interaction of PD-1 on T cells with PD-L1 and PD-L2 on host tissues was physiologically designed for host tissue protection against immune rejection. Cancer cells may usurp this pathway and evade tumor immune rejection by increasing expression of PD-1 on tumor-infiltrating lymphocytes and/or increasing expression of PD-L1 in cancer cells.39 Prior studies demonstrated the presence of immune infiltration in TNBC.40 By blocking this pathway, immunotherapy agents such as pembrolizumab (anti–PD-1 antibody), atezolizumab (anti–PD-L1 antibody), and durvalumab (anti–PD-L1 antibody) attempt to increase antitumor immunity.

Initial exploration of pembrolizumab as a single-agent therapy occurred in a phase I study of heavily pretreated patients with PD-L1–positive aTNBC.41 Among 27 evaluable patients, the overall response rate to pembrolizumab was 18.5% and median time to response was approximately 18 weeks. Some patients had durable responses. A phase I study of atezolizumab in TNBC was also undertaken.42 An ORR of 24% was seen in the first-line setting, and an ORR of 6% was seen in the second-line or beyond setting, with a median duration of response of 21 months. ORR was higher in patients with tumor immune cell expression of PD-L1 >1%.

These studies demonstrated some preliminary efficacy with immunotherapy for aTNBC. The phase III KEYNOTE-119 study43 compared pembrolizumab versus chemotherapy in patients with mTNBC who had received 1 to 2 prior therapies. The study included a stratification by tumor PD-L1 status defined using a combined positive score (CPS) based on the number of PD-L1–staining cells per total viable tumor cells, with analyses evaluating a CPS score of ≥1, ≥10, and ≥20. Although OS was not significantly improved in the entire population treated with pembrolizumab, there was a trend toward improved efficacy (OS, PFS, and ORR) in patients whose tumors had greater PD-L1 enrichment.

Combination Therapy With Immune Checkpoint Inhibition and Chemotherapy

Other studies are combining immunotherapy agents with chemotherapy, given the potential synergistic activity of combination treatment. In early-stage disease, the combination of pembrolizumab with chemotherapy was shown to result in improved pathologic complete response rates.42,44

In the phase III IMpassion130 study,3 combination atezolizumab + nab-paclitaxel was compared with nab-paclitaxel alone in patients with aTNBC. In the first interim analysis,3 median PFS with atezolizumab + nab-paclitaxel was 7.2 versus 5.5 months in the control arm (HR, 0.80; P=.002) in the ITT population. In the PD-L1–positive population (≥1% PD-L1 immune cell positivity), PFS was 7.5 months with atezolizumab versus 5.0 months in the control arm (HR, 0.62; P<.001). OS was 21.3 versus 17.6 months (HR, 0.84; P=.08) in the atezolizumab and control arms, respectively, in the ITT analysis, but 25.0 versus 15.5 months (HR, 0.62), respectively, in the PD-L1–positive subset. Based on the OS benefit in PD-L1–positive patients, atezolizumab + nab-paclitaxel was FDA-approved for PD-L1–positive aTNBC. In the second interim analysis,45 with a median follow-up of 18.5 months for the atezolizumab arm and 17.5 months for the control arm, median OS in the ITT population was 21 versus 18.7 months (HR, 0.86; P=.078), respectively. In the PD-L1–positive population, OS was improved to 25.0 months with the addition of atezolizumab versus 18.0 months in the control arm (HR, 0.71). The FDA did not specify the treatment line in which atezolizumab + nab-paclitaxel may be prescribed, although data with immunotherapy in breast cancer generally suggest an increased response in the front-line setting for mTNBC. Of note, this study used the Ventana SP142 PD-L1 immunohistochemical assay, which is the companion diagnostic test for the FDA approval. A comparison of this assay with other assays, including the Ventana SP263 and Dako 22C3 PD-L1 assays, did not demonstrate concordance; therefore, ideally the Ventana SP142 assay should currently be used to identify PD-L1–positive patients for treatment with atezolizumab and abraxane.46

The phase III KEYNOTE-355 study similarly evaluated pembrolizumab in combination with chemotherapy for mTNBC as first-line treatment. An improvement in PFS (9.7 vs 5.6 months; HR, 0.65; 95% CI, 0.49–0.86; P=.0012) was noted in patients with PD-L1–positive tumors (defined as a combined positive score ≥10) treated with immunotherapy and chemotherapy versus chemotherapy alone.47

Maintenance immunotherapy is also being explored. In a recent study, patients with mTNBC or hormone receptor–positive breast cancer who received 1 to 2 prior lines of chemotherapy and did not have any actionable mutations were randomized to treatment with durvalumab versus chemotherapy after 6 to 8 cycles of chemotherapy.48 An improvement in OS was seen in patients who received durvalumab compared with chemotherapy (21.7 vs 17.9 months), and this benefit was pronounced in the TNBC (21 vs 14 months; HR, 0.54) and PD-L1–positive populations (26 vs 12 months; HR, 0.42).

Although immunotherapy may have durable responses, a unique toxicity profile is seen. Immune-related adverse events related to hyperactivation of the immune system, such as thyroid disorders, hypophysitis, colitis, myocarditis and pericarditis, and pneumonitis, can sometimes present months after treatment. A multidisciplinary team should manage these types of toxicities, which sometimes may improve or resolve after holding the drug and/or initiation of corticosteroids.

There are many ongoing studies of immunotherapy for mTNBC. Currently, it appears that immunotherapy activity is largely seen in tumors that are PD-L1–positive.

A question that often arises clinically is how to optimally sequence immunotherapy and PARP inhibitors in patients who are germline BRCA1/2 carriers with PD-L1–positive mTNBC. One approach would be to consider using immunotherapy upfront, given that the current literature suggests that immunotherapy often has better responses when sequenced earlier in the disease course, and immunotherapy is associated with an improvement in OS. Patients enrolled in the OlympiAD15 and EMBRACA16 studies also were allowed to have received prior lines of therapy, and PARP inhibitors could be used in the second-line (and beyond) setting, although the sequencing question has not been explicitly evaluated in a clinical trial and further research is needed.

Combination Therapy With Immune Checkpoint Inhibition and AKT Inhibition

The triplet combination of atezolizumab, ipatasertib, and a taxane was investigated as first-line treatment of aTNBC based on data suggesting that the loss of PTEN may contribute to immunotherapy resistance. In 26 patients treated, an ORR of 73% was seen, with common toxicity including diarrhea and rash.49 A phase III trial is further evaluating this combination (NCT04177108).

Other Agents

Oral Taxanes

Although the recent focus in aTNBC has been on the development of therapies targeted to tumor biology, given that chemotherapy is the mainstay of treatment there is also interest in developing oral chemotherapy agents with less toxicity and less burden to patients than intravenous chemotherapy.

One study evaluating oral paclitaxel + encequidar versus intravenous paclitaxel demonstrated an improved response rate of 40% with the oral paclitaxel versus 25.6% for intravenous (P=.005).50 Additionally, a phase II study is ongoing to compare liporaxel, an oral paclitaxel, with intravenous paclitaxel.51 Liporaxel is approved in Korea for the treatment of gastric cancer, with similar efficacy as intravenous paclitaxel, and less neuropathy and no hypersensitivity reactions.52 In the OPTIMAL phase II study of liporaxel, an ORR of 44.4% was seen in mTNBC.53 A third oral taxane, tesetaxel, is being evaluated as a single agent for metastatic HER2-negative breast cancer (ClinicalTrials.gov identifier: NCT01221870) and in combination with immunotherapy in TNBC (NCT03952325).

A significant advantage of the oral formulation is the potential for less neuropathy and absence of infusion reactions compared with intravenous taxanes. The final results of the ongoing studies are eagerly anticipated.

Cell Cycle Inhibition With Chemotherapy

Trilaciclib, a cyclin-dependent kinase 4/6 inhibitor, was studied with gemcitabine and carboplatin, and compared with chemotherapy alone in patients with aTNBC.54 A promising improvement in OS was seen with trilaciclib. An interesting feature of trilaciclib compared with other CDK4/6 inhibitors is that it transiently causes immune and bone marrow cells to be in G1 arrest of the cell cycle, protecting them from the myelosuppressive effects of chemotherapy and thereby enabling the antitumor effect of chemotherapy to be maximized.

Conclusions and Future Directions

Many novel agents are being developed for aTNBC that will transform the therapeutic landscape. A challenge in devising novel agents is the development of resistance, given the high mutation rate of TNBC, leading to the acquisition of new mutations under therapeutic pressure.55,56 Precision medicine initiatives utilizing tumor tissue and blood genotyping to understand tumor biology and evolution in combination with correlative biomarker studies may identify novel targets, elucidate patterns of resistance, and improve therapies for aTNBC. Immunotherapy is a promising direction, but likely requires identification of additional predictive biomarkers to guide therapy. An understanding of heterogeneity in antigen expression, stability of linker, cross-resistance of toxic payload with prior therapy, and bystander effect will help optimize the therapeutic success of ADCs. Additional biomarker-driven clinical trials will lead to validation of novel targets and redefine the therapeutic landscape and molecular classification of TNBC.

At the present time, based on the current body of evidence, we recommend upfront PD-L1 testing on tumor tissue as well as germline BRCA1/2 testing in patients with mTNBC who are eligible for therapy. If the tumor is PD-L1–positive, we recommend consideration of chemotherapy with immunotherapy, such as nab-paclitaxel + atezolizumab (chemotherapy + pembrolizumab is a potential option in the future, if FDA-approved), and if the patient is a germline BRCA1/2 carrier, we recommend consideration of a PARP inhibitor. For PD-L1–negative tumors, standard chemotherapy agents can be considered, such as carboplatin, capecitabine (if the patient is interested in oral therapy), a taxane (if not received within 6 months of metastatic diagnosis), or an anthracycline (if not received within 6 months of metastatic diagnosis). For therapy in the third line and beyond, additional chemotherapy or sacituzumab govitecan can be considered. Clinical trials should always be considered whenever possible in the metastatic setting. Tumor genotyping may help identify actionable mutations and guide enrollment in appropriate clinical trials.

References

  • 1.

    Kumar P, Aggarwal R. An overview of triple-negative breast cancer. Arch Gynecol Obstet 2016;293:247269.

  • 2.

    Dent R, Trudeau M, Pritchard KI, . Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13:44294434.

  • 3.

    Schmid P, Adams S, Rugo HS, . Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:21082121.

  • 4.

    Perez EA, Vogel CL, Irwin DH, . Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 2001;19:42164223.

  • 5.

    O’Brien ME, Wigler N, Inbar M, . Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440449.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Bajetta E, Procopio G, Celio L, . Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23:21552161.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Cortes J, O’Shaughnessy J, Loesch D, . Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914923.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Gradishar WJ, Anderson BO, Abraham J, et al. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2020. Accessed May 18, 2020. For the most recent version, visit NCCN.org

  • 9.

    Lehmann BD, Bauer JA, Chen X, . Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:27502767.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Burstein MD, Tsimelzon A, Poage GM, . Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 2015;21:16881698.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Karaayvaz M, Cristea S, Gillespie SM, . Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nat Commun 2018;9:3588.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum Genet 2008;124:3142.

  • 13.

    Gonzalez-Angulo AM, Timms KM, Liu S, . Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011;17:10821089.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science 2017;355:11521158.

  • 15.

    Robson M, Im SA, Senkus E, . Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523533.

  • 16.

    Litton JK, Rugo HS, Ettl J, . Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753763.

  • 17.

    FDA approves talazoparib for deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. The ASCO Post. Accessed May 18, 2020. Available at: http://www.ascopost.com/News/59372?email=5eaa561b7a8fff95357079f8f4299531bac79763294bc71d3b92bceb75062e97&utm_medium=Email&utm_campaign=TAP%20EN

  • 18.

    Dieras VC, Han HS, Kaufman B, . Phase 3 study of veliparib with carboplatin and paclitaxel in HER2- negative advanced/metastatic germline BRCA-associated breast cancer. Presented at ESMO Congress 2019; September 27–October 1, 2019; Barcelona, Spain.

  • 19.

    Oza AM, Tinker AV, Oaknin A, . Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol 2017;147:267275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Ibrahim YH, García-García C, Serra V, . PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2012;2:10361047.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Rehman FL, Lord CJ, Ashworth A. The promise of combining inhibition of PI3K and PARP as cancer therapy. Cancer Discov 2012;2:982984.

  • 22.

    Vinayak S, Tolaney SM, Schwartzberg L, . Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162). Cancer Res 2019;79(Suppl):Abstract PD5-02.

    • Crossref
    • Export Citation
  • 23.

    Pereira B, Chin SF, Rueda OM, . The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 2016;7:11479.

  • 24.

    Millis SZ, Gatalica Z, Winkler J, . Predictive biomarker profiling of > 6000 breast cancer patients shows heterogeneity in TNBC, with treatment implications. Clin Breast Cancer 2015;15:473481.e3.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Kim SB, Dent R, Im SA, . Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2017;18:13601372.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Dent R, Kim SB, Oliveira M, . IPATunity130: a pivotal randomized phase III trial evaluating ipatasertib (IPAT)+paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered advanced triple-negative (TN) or hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC) [abstract]. J Clin Oncol 2018;36(Suppl):Abstract TPS111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Schmid P, Abraham J, Chan S, . Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol 2020;38:423433.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Vidula N, Yau C, Wolf D, . Androgen receptor gene expression in primary breast cancer. NPJ Breast Cancer 2019;5:47.

  • 29.

    Gucalp A, Tolaney S, Isakoff SJ, . Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013;19:55055512.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Traina TA, Miller K, Yardley DA, . Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 2018;36:884890.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Lehmann BD, Abramson VG, Sanders M, . TBCRC 032 IB/II multicenter study: molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+ metastatic triple-negative breast cancer. Clin Cancer Res 2019;26:21112123.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Bardia A, Mayer IA, Vahdat LT, . Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 2019;380:741751.

  • 33.

    Vidula N, Yau C, Rugo HS. Trop2 gene expression (Trop2e) in primary breast cancer (BC): correlations with clinical and tumor characteristics [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 1075.

    • Crossref
    • Export Citation
  • 34.

    Trerotola M, Cantanelli P, Guerra E, . Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 2013;32:222233.

  • 35.

    Taylor KM, Morgan HE, Johnson A, . Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 2003;375:5159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Sussman D, Smith LM, Anderson ME, . SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther 2014;13:29913000.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Modi S, Pusztai L, Forero A, . Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [abstract]. Cancer Res 2018;78(Suppl):Abstract PD3-14.

    • Crossref
    • Export Citation
  • 38.

    Han H, Diab S, Alemany C, . Open label phase 1b/2 study of ladiratuzumab verdotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer [abstract]. Cancer Res 2020;80(Suppl):Abstract PD1-06.

  • 39.

    McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med 2013;2:662673.

  • 40.

    Mittendorf EA, Philips AV, Meric-Bernstam F, . PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2014;2:361370.

  • 41.

    Nanda R, Chow LQ, Dees EC, . Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 2016;34:24602467.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Emens LA, Cruz C, Eder JP, . Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol 2019;5:7482.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Cortes J, Lipatov O, Im SA, et al. KEYNOTE-119: phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple-negative breast cancer (mTNBC) [abstract]. Ann Oncol 2019;30(Suppl 5):Abstract LBA21.

    • Crossref
    • Export Citation
  • 44.

    Nanda R, Liu MC, Yau C, . Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2 [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 506.

  • 45.

    Schmid P, Rugo HS, Adams S, . Atezolizumab plus nab-paclitaxel as first-line treatment of unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:44–59.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): post-hoc analysis of IMpassion130 [abstract]. Ann Oncol 1029;30(Suppl 5):Abstract LBA20

    • Crossref
    • Export Citation
  • 47.

    Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple negative breast cancer [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 1000

  • 48.

    Dalenc F, Garberis I, Filleron T, . Durvalumab compared with maintenance chemotherapy in patients with metastatic breast cancer: results from phase II randomized trial SAFIR02-IMMUNO [abstract]. Cancer Res 2020;80(Suppl):Abstract GS3-02.

  • 49.

    Schmid P, Loirat D, Savas P, . Phase Ib study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC as first line (1L) therapy for locally advanced/metastatic triple-negative breast cancer (TNBC) [abstract]. Cancer Res 2019;79(Suppl):Abstract CT049.

    • Crossref
    • Export Citation
  • 50.

    Umanzor G, Rugo H, Cutler DL, . Oral paclitaxel with encequidar: the first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a phase III clinical study in metastatic breast cancer [abstract]. Cancer Res 2020;80(Suppl):Abstract GS6-01.

    • Crossref
    • Export Citation
  • 51.

    Pluard TJ, Sharma P, Melisko ME, . A phase II study to evaluate the efficacy, safety and pharmacokinetics of DHP107 (Liporaxel®, oral paclitaxel) compared with IV paclitaxel in patients with recurrent or metastatic breast cancer: OPERA (NCT03326102) [abstract]. Cancer Res 2020;80(Suppl):Abstract OTI-05-02.

    • Crossref
    • Export Citation
  • 52.

    Kang YK, Ryu MH, Park SH, . Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol 2018;29:12201226.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    Ahn J, Lee KS, Lee K, . Phase 2 study of DHP107 (Liporaxel, oral paclitaxel) in first line, HER2 negative recurrent/metastatic breast cancer (OPTIMAL study, NCT03315364) [abstract]. Ann Oncol 2019;30(Suppl 5):Abstract 5083.

    • Crossref
    • Export Citation
  • 54.

    Tan AR, Wright GS, Thummala AR, . Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol 2019;20:15871601.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Wang Y, Waters J, Leung ML, . Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 2014;512:155160.

  • 56.

    Yates LR, Knappskog S, Wedge D, . Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 2017;32:169184.e7.

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

Submitted January 8, 2020; accepted for publication May 28, 2020.

Disclosures: Dr. Vidula has disclosed that she receives honoraria from AbbVie. Dr. Ellisen has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors. Dr. Bardia has disclosed that he is a scientific advisor for Genentech, Immunomedics, Novartis, Pfizer, Merck, Radius Health, Taiho, Diiachi Pharma/Astra Zeneca, Sanofi, Puma Biotechnology, Biothernostics Inc., Phillips, Eli Lilly, and Foundation Medicine; and grant/research support from Genentech, Immunomedics, Novartis, Pfizer, Merck, Sanofi, Radius Health, and Diiachi Pharma/Astra Zeneca.

Correspondence: Neelima Vidula, MD, Massachusetts General Hospital, 55 Fruit Street, Bartlett Hall Extension 1-213, Boston, MA 02114. Email: nvidula@mgh.harvard.edu; and Aditya Bardia, MD, Massachusetts General Hospital, 55 Fruit Street, Bartlett Hall Extension 1-237, Boston, MA 02114. Email: abardia1@mgh.harvard.edu
  • View in gallery

    Novel targets in triple-negative breast cancer for therapeutic intervention.

    Abbreviation: AR, androgen receptor.

    aFDA-approved therapy.

  • 1.

    Kumar P, Aggarwal R. An overview of triple-negative breast cancer. Arch Gynecol Obstet 2016;293:247269.

  • 2.

    Dent R, Trudeau M, Pritchard KI, . Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007;13:44294434.

  • 3.

    Schmid P, Adams S, Rugo HS, . Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:21082121.

  • 4.

    Perez EA, Vogel CL, Irwin DH, . Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 2001;19:42164223.

  • 5.

    O’Brien ME, Wigler N, Inbar M, . Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440449.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Bajetta E, Procopio G, Celio L, . Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23:21552161.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Cortes J, O’Shaughnessy J, Loesch D, . Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914923.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Gradishar WJ, Anderson BO, Abraham J, et al. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2020. Accessed May 18, 2020. For the most recent version, visit NCCN.org

  • 9.

    Lehmann BD, Bauer JA, Chen X, . Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:27502767.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Burstein MD, Tsimelzon A, Poage GM, . Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 2015;21:16881698.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Karaayvaz M, Cristea S, Gillespie SM, . Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nat Commun 2018;9:3588.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum Genet 2008;124:3142.

  • 13.

    Gonzalez-Angulo AM, Timms KM, Liu S, . Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011;17:10821089.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science 2017;355:11521158.

  • 15.

    Robson M, Im SA, Senkus E, . Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523533.

  • 16.

    Litton JK, Rugo HS, Ettl J, . Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753763.

  • 17.

    FDA approves talazoparib for deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. The ASCO Post. Accessed May 18, 2020. Available at: http://www.ascopost.com/News/59372?email=5eaa561b7a8fff95357079f8f4299531bac79763294bc71d3b92bceb75062e97&utm_medium=Email&utm_campaign=TAP%20EN

  • 18.

    Dieras VC, Han HS, Kaufman B, . Phase 3 study of veliparib with carboplatin and paclitaxel in HER2- negative advanced/metastatic germline BRCA-associated breast cancer. Presented at ESMO Congress 2019; September 27–October 1, 2019; Barcelona, Spain.

  • 19.

    Oza AM, Tinker AV, Oaknin A, . Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol 2017;147:267275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Ibrahim YH, García-García C, Serra V, . PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2012;2:10361047.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Rehman FL, Lord CJ, Ashworth A. The promise of combining inhibition of PI3K and PARP as cancer therapy. Cancer Discov 2012;2:982984.

  • 22.

    Vinayak S, Tolaney SM, Schwartzberg L, . Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162). Cancer Res 2019;79(Suppl):Abstract PD5-02.

    • Crossref
    • Export Citation
  • 23.

    Pereira B, Chin SF, Rueda OM, . The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 2016;7:11479.

  • 24.

    Millis SZ, Gatalica Z, Winkler J, . Predictive biomarker profiling of > 6000 breast cancer patients shows heterogeneity in TNBC, with treatment implications. Clin Breast Cancer 2015;15:473481.e3.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Kim SB, Dent R, Im SA, . Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2017;18:13601372.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Dent R, Kim SB, Oliveira M, . IPATunity130: a pivotal randomized phase III trial evaluating ipatasertib (IPAT)+paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered advanced triple-negative (TN) or hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC) [abstract]. J Clin Oncol 2018;36(Suppl):Abstract TPS111.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Schmid P, Abraham J, Chan S, . Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol 2020;38:423433.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Vidula N, Yau C, Wolf D, . Androgen receptor gene expression in primary breast cancer. NPJ Breast Cancer 2019;5:47.

  • 29.

    Gucalp A, Tolaney S, Isakoff SJ, . Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013;19:55055512.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Traina TA, Miller K, Yardley DA, . Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 2018;36:884890.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Lehmann BD, Abramson VG, Sanders M, . TBCRC 032 IB/II multicenter study: molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+ metastatic triple-negative breast cancer. Clin Cancer Res 2019;26:21112123.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Bardia A, Mayer IA, Vahdat LT, . Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 2019;380:741751.

  • 33.

    Vidula N, Yau C, Rugo HS. Trop2 gene expression (Trop2e) in primary breast cancer (BC): correlations with clinical and tumor characteristics [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 1075.

    • Crossref
    • Export Citation
  • 34.

    Trerotola M, Cantanelli P, Guerra E, . Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 2013;32:222233.

  • 35.

    Taylor KM, Morgan HE, Johnson A, . Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 2003;375:5159.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Sussman D, Smith LM, Anderson ME, . SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther 2014;13:29913000.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Modi S, Pusztai L, Forero A, . Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [abstract]. Cancer Res 2018;78(Suppl):Abstract PD3-14.

    • Crossref
    • Export Citation
  • 38.

    Han H, Diab S, Alemany C, . Open label phase 1b/2 study of ladiratuzumab verdotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally-advanced or metastatic triple-negative breast cancer [abstract]. Cancer Res 2020;80(Suppl):Abstract PD1-06.

  • 39.

    McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med 2013;2:662673.

  • 40.

    Mittendorf EA, Philips AV, Meric-Bernstam F, . PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2014;2:361370.

  • 41.

    Nanda R, Chow LQ, Dees EC, . Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 2016;34:24602467.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Emens LA, Cruz C, Eder JP, . Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol 2019;5:7482.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Cortes J, Lipatov O, Im SA, et al. KEYNOTE-119: phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple-negative breast cancer (mTNBC) [abstract]. Ann Oncol 2019;30(Suppl 5):Abstract LBA21.

    • Crossref
    • Export Citation
  • 44.

    Nanda R, Liu MC, Yau C, . Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2 [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 506.

  • 45.

    Schmid P, Rugo HS, Adams S, . Atezolizumab plus nab-paclitaxel as first-line treatment of unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:44–59.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): post-hoc analysis of IMpassion130 [abstract]. Ann Oncol 1029;30(Suppl 5):Abstract LBA20

    • Crossref
    • Export Citation
  • 47.

    Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple negative breast cancer [abstract]. J Clin Oncol 2020;38(Suppl):Abstract 1000

  • 48.

    Dalenc F, Garberis I, Filleron T, . Durvalumab compared with maintenance chemotherapy in patients with metastatic breast cancer: results from phase II randomized trial SAFIR02-IMMUNO [abstract]. Cancer Res 2020;80(Suppl):Abstract GS3-02.

  • 49.

    Schmid P, Loirat D, Savas P, . Phase Ib study evaluating a triplet combination of ipatasertib (IPAT), atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC as first line (1L) therapy for locally advanced/metastatic triple-negative breast cancer (TNBC) [abstract]. Cancer Res 2019;79(Suppl):Abstract CT049.

    • Crossref
    • Export Citation
  • 50.

    Umanzor G, Rugo H, Cutler DL, . Oral paclitaxel with encequidar: the first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a phase III clinical study in metastatic breast cancer [abstract]. Cancer Res 2020;80(Suppl):Abstract GS6-01.

    • Crossref
    • Export Citation
  • 51.

    Pluard TJ, Sharma P, Melisko ME, . A phase II study to evaluate the efficacy, safety and pharmacokinetics of DHP107 (Liporaxel®, oral paclitaxel) compared with IV paclitaxel in patients with recurrent or metastatic breast cancer: OPERA (NCT03326102) [abstract]. Cancer Res 2020;80(Suppl):Abstract OTI-05-02.

    • Crossref
    • Export Citation
  • 52.

    Kang YK, Ryu MH, Park SH, . Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann Oncol 2018;29:12201226.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    Ahn J, Lee KS, Lee K, . Phase 2 study of DHP107 (Liporaxel, oral paclitaxel) in first line, HER2 negative recurrent/metastatic breast cancer (OPTIMAL study, NCT03315364) [abstract]. Ann Oncol 2019;30(Suppl 5):Abstract 5083.

    • Crossref
    • Export Citation
  • 54.

    Tan AR, Wright GS, Thummala AR, . Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol 2019;20:15871601.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Wang Y, Waters J, Leung ML, . Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 2014;512:155160.

  • 56.

    Yates LR, Knappskog S, Wedge D, . Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 2017;32:169184.e7.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1844 1844 320
PDF Downloads 728 728 150
EPUB Downloads 0 0 0