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INTRODUCTION

Triple-negative breast cancer (TNBC) is broadly defined as breast cancer that lacks expression of estrogen and progesterone hormone receptors (HRs) and does not overexpress human epidermal growth factor receptor 2 (HER2) protein. TNBC represents approximately 10% to 15% of all breast cancers. It is generally more aggressive than HR-positive breast cancers. TNBC is more common in younger women, and African-American women have a higher prevalence of TNBC than HR-positive breast cancer.¹ There is also a significant association between TNBC and obesity, particularly in the premenopausal population.² Due to the aggressive nature of TNBC, women are often diagnosed at an advanced stage of cancer, which often includes larger tumors. The presence of lymph node involvement in TNBC has not consistently been shown in large cohort studies.^1,3 TNBC appears more likely to metastasize to the brain and lungs, but less likely to metastasize to bone, than HR-positive tumors.³

Interestingly, TNBC is quite sensitive to traditional chemotherapy when administered in treatment-naïve, early-stage disease. The rates of pathologic complete response (pCR)—defined as the absence of breast cancer at surgery after neoadjuvant chemotherapy—are much higher in TNBC than in HR-positive, HER2-negative breast cancers (28%-30% vs. 6.7%). Nonetheless, after only 3 years, progression-free survival (PFS) and overall survival (OS) tend to be shorter with TNBC. These statistics are disappointing and drive the need to develop better therapies to manage TNBC in early stages, as well as in the metastatic setting.³

Many research accomplishments in the last 5 years have improved clinicians' understandings of the characteristics of TNBC and the biologic mechanisms driving cell growth and metastases. Specifically, there is now known to be a strong correlation between TNBC and BRCA1/2 mutation status. Up to 20% of TNBC patients are carriers of a mutation in BRCA1 or BRCA2; only 5% to 10% of patients with all other breast cancer types carry the same mutation. Also, molecular pathways have been identified as promising targets, such as poly(ADP-ribose) polymerase (PARP), androgen receptor (AR), programmed cell death 1 receptor (PD-1), and programmed cell death receptor 1 ligand (PD-L1).⁴

PARP plays a similar role in cell repair to that of BRCA1/2: PARP repairs single-strand DNA breaks and BRCA1 and BRCA2 repair double-strand DNA breaks. Breakdowns in both of these mechanisms together could be potentially lethal to cancer cells. Functional mutations in BRCA1/2 can predispose cancers to susceptibility to further repair inhibition, which can be accomplished with drug therapies such as the PARP inhibitors.⁴

The AR is a complex steroid hormone receptor that is just beginning to be understood and better characterized. ARs are expressed in a high percentage of TNBCs (10%-50%) and may be another pathway of importance for managing TNBC. There are already several AR inhibitors used for managing prostate cancer, and these agents are being investigated to determine their role, if any, in TNBC, especially in the setting of AR expression.⁵

PD-1 and its ligand, PD-L1, are important immune regulatory components. Inhibitors of these proteins are often referred to as immune checkpoint inhibitors. These inhibitors enable T-cell activation by enhancing costimulatory signals or blocking co-inhibitory signals, producing strong sustained T-cell responses, and triggering the host immune response against cancer cells. Other potential mechanisms to exploit the immune system include vaccines, adoptive T-cell therapies, and antibody-drug conjugates (ADCs).^4,6-8

Decades of experience and research in the management of breast cancer has shown optimal outcomes with traditional management strategies. In patients with TNBC, the intent of regimens used in early-stage disease is curative, and the regimens are the same as those used with other breast cancer tumor types. With metastatic TNBC, incorporation of innovative therapies with unique targets results in new and, occasionally, unexpected adverse events that require management in order to improve patients' quality of life and continue therapy. Many of these therapies are orally administered, so pharmacists are in a unique position to assist with optimizing patient outcomes.

Patient case: JP is a 35-year-old female with metastatic TNBC. She is currently receiving olaparib and her most recent scans demonstrate signs of progression. She is interested in clinical trials as the next step in her next treatment. What agents might be available to her in a study?

TREATMENT OF EARLY-STAGE TNBC

Although there have been many advances made in the treatment of breast cancer, the management of patients with early-stage (Stage I-II) and locally advanced (Stage III) breast cancer has remained relatively unchanged in the past decade. The mainstays of therapy remain a combination of locoregional therapies, including surgery with or without radiation, and combination chemotherapy. Patients who may be spared from chemotherapy include those with small tumors (< 1 cm) and those with node-negative disease. National Comprehensive Cancer Network (NCCN) guidelines state that chemotherapy should be considered in patients with tumors 0.6 to 1 cm and those with tumors up to 0.5 cm in size with micrometastases (axillary node ≤ 2 mm).⁹ Randomized controlled trials have shown no difference in outcomes when chemotherapy is administered preoperatively (neoadjuvant) or postoperatively (adjuvant).^9,10 Advantages to administering chemotherapy preoperatively include improving surgical outcomes, downstaging tumors to allow for breast conservation, and gaining prognostic information from a patient's response to therapy.⁹ Patients, particularly those with TNBC, who achieve a pCR following preoperative chemotherapy have been shown to have improved long-term outcomes compared with those who have less than a pCR.^11,12 Additionally, when chemotherapy is administered preoperatively, it allows patients with residual disease at the time of surgery the option to pursue a clinical trial or additional adjuvant therapy.

The backbone of chemotherapy in the management of TNBC includes anthracyclines and taxanes, and the length of therapy for neoadjuvant/adjuvant therapy ranges from 4 to 6 months. Several acceptable combinations and schedules are recommended by NCCN and the choice of regimen is based on several patient-specific and tumor-specific factors. Two of the 3 preferred chemotherapy regimens recommended by NCCN include doxorubicin/cyclophosphamide (AC) administered every 2 weeks (dose-dense) for 4 cycles followed by paclitaxel administered weekly for 12 weeks or paclitaxel administered every 2 weeks (dose-dense) for 4 cycles.⁹ When AC or paclitaxel are administered in a dose-dense fashion, it is recommended that patients receive myeloid growth factors as primary prophylaxis. It is acceptable for the paclitaxel portion of these regimens to precede AC. The third preferred regimen is an anthracycline-sparing approach that includes docetaxel/cyclophosphamide (TC) administered every 3 weeks for 4 cycles. Several other regimens are listed in NCCN guidelines and include: cyclophosphamide/methotrexate/fluorouracil (CMF), docetaxel/doxorubicin/cyclophosphamide (TAC), epirubicin/cyclophosphamide (EC), and AC administered every 3 weeks (Table 1).⁹

Patient case: ES is a 42-year-old female with a recent diagnosis of Stage II TNBC. Her oncologist recommended she receive dose-dense AC with pegfilgrastim followed by weekly paclitaxel for 12 weeks. She is curious what differences in side effects she can expect if she receives dose-dense AC compared to a conventional schedule. How do you counsel her regarding the differences in side effects related to the different AC dosing schedules?

The concept of dose-density has been evaluated in several different clinical trials to determine if shortening the interval between cycles, particularly AC, will result in better long-term outcomes. A pivotal trial involving more than 2000 node-positive breast cancer (HR-positive and HR-negative) patients demonstrated that patients who received adjuvant chemotherapy every 2 weeks (dose-dense) compared to every 3 weeks (conventional) had significant improvement in both disease-free survival (DFS) (risk ratio [RR] = 0.74; p = 0.010) and OS (RR = 0.69; p = 0.013).¹³ All patients who received dose-dense regimens received myeloid growth factors with all cycles. One criticism of this trial was the 2x2 factorial design, which made it difficult to determine if the benefit was derived from administering paclitaxel, AC, or a combination of both of these regimens in a dose-dense manner. A meta-analysis that combined the results of 8 phase III randomized trials comparing dose-dense to conventional chemotherapy showed that patients who received dose-dense chemotherapy had improved OS and DFS. In a subgroup analysis comparing the results for patients with HR-positive and HR-negative disease, only patients who had HR-negative disease showed a statistically significant OS benefit.¹⁴ When administered with myeloid growth factors, dose-dense chemotherapy did not increase the risk of febrile neutropenia (FN) or grade 3/4 neutropenia, but it was associated with a statistically significant increase in anemia and thrombocytopenia. In clinical practice, the decision to administer dose-dense chemotherapy, particularly AC, should consider several factors. Specifically, in terms of toxicities, patients may experience more anemia, thrombocytopenia, and fatigue with dose-dense administration. Due to the fact that myeloid growth factor support is required, patients are also at risk of side effects (e.g., bone pain) associated with filgrastim and pegfilgrastim.

In addition to the dosing schedule, another important decision for patients and oncologists to consider is whether or not an anthracycline should be included in a patient's chemotherapy regimen. Anthracyclines were shown to be one of the most active single agents in the treatment of metastatic breast cancer and have been included in adjuvant regimens since the early 1990s. Currently, the only preferred regimen recommended by NCCN that spares anthracyclines is TC.⁹ A study conducted by the US Oncology Research Network demonstrated that patients who received TC experienced a statistically significant improvement in DFS compared to patients who received AC.¹⁵ However, data comparing TC to a taxane-plus-anthracycline-containing (TaxAC) regimen were lacking until recently. The Anthracycline in Early Breast Cancer (ABC) trials combined results of 3 phase III, randomized, open-label trials that included more than 4000 patients with high-risk, HER2-negative breast cancer to determine if TC for 6 cycles (TC6) was noninferior to TaxAC.¹⁶ The primary endpoint was invasive disease-free survival (IDFS). The results of the combined trials demonstrated that the TaxAC regimens improved IDFS compared to TC6. Exploratory analysis by stratification variables showed that the benefit of TaxAC was most meaningful in patients with HR-negative disease and in those with HR-positive disease with positive axillary lymph nodes. For patients who do receive an anthracycline-sparing regimen, the optimal number of cycles remains controversial. Patients in the TC arms of the ABC trials were treated with 6 cycles; however, on the basis of previous data, NCCN recommends 4 cycles. The decision to administer 4 versus 6 cycles should be individualized and should consider factors such as stage of disease, patient age, and chemotherapy tolerability.

Patient case: DD is a 50-year-old female with Stage III TNBC who recently completed 4 cycles of neoadjuvant AC. Now, she will receive weekly paclitaxel for 12 weeks. She read online that some patients with TNBC may benefit from carboplatin. She is curious if she will receive this medication. What do you tell her regarding the outcomes related to adding carboplatin in this setting?

Due to the high risk of recurrence in patients with TNBC, researchers are continually evaluating ways to optimize preoperative chemotherapy in order to increase pCR rates and potentially prolong DFS and OS.

One agent that has been extensively evaluated in this population is carboplatin. In a trial of more than 400 patients with Stage II-III TNBC, patients received carboplatin in the preoperative setting in addition to paclitaxel plus AC.¹⁷ The trial also evaluated the benefit of adding bevacizumab in a separate arm. Patients who received carboplatin achieved a statistically significant increase in the rate of pCR compared to patients who did not receive carboplatin. Unfortunately, at a median follow-up of 39 months, the addition of carboplatin did not significantly impact either event-free survival or OS. The trial was not powered to evaluate these outcomes and longer follow-up may have demonstrated a delayed benefit with the addition of carboplatin.¹⁸ In addition, patients treated in the carboplatin arm had increased toxicities and an increased rate of dose delays/modifications.¹⁷ Thus, at this time, NCCN does not recommend carboplatin as part of neoadjuvant/adjuvant chemotherapy regimens outside of a clinical trial.

Platinum agents have also been extensively studied in women with BRCA1/2-related breast cancer. In the metastatic setting, patients with BRCA1/2 mutation treated front-line with carboplatin showed a significant improvement in overall response rate and PFS compared to patients treated with docetaxel.¹⁹ Nonetheless, the role for carboplatin in the curative setting for BRCA-related breast cancer remains unknown and current NCCN recommendations for treatment are not stratified on the basis of BRCA mutational status.

Another recent strategy to decrease the risk of recurrence includes the use of adjuvant capecitabine in patients who have received preoperative chemotherapy. Patients who have residual disease following neoadjuvant chemotherapy, particularly those with TNBC, have been shown to have poor prognoses. In the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial, more than 900 patients with Stage I-III HER2-negative breast cancer who received neoadjuvant chemotherapy and had evidence of residual disease at the time of surgery were randomized to receive capecitabine or no therapy.²⁰ Both arms received standard adjuvant therapy that could include radiotherapy with or without endocrine therapy, if indicated. At trial initiation, capecitabine was administered at a dose of 1250 mg/m² twice daily for 14 days every 21 days for 6 cycles; it was administered before or after completion of radiotherapy and concurrent with endocrine therapy, if indicated. Interim analysis was conducted after the first 50 enrolled patients and a recommendation was made to extend treatment duration from 6 to up to 8 cycles. The primary end point was DFS and the secondary endpoint was OS. Five-year DFS (74.1% vs. 67.6%; HR = 0.70; 95% CI, 0.53 to 0.92; P = 0.01) and OS (89.2% vs. 83.6%; HR = 0.59; 95% CI, 0.39 to 0.90; P = 0.01) were both significantly longer in the capecitabine group than in the control arm. These benefits were more pronounced in the HR-negative population. The rates of DFS (69.8% vs. 56.1%; HR = 0.58; 95% CI, 0.39 to 0.87) and OS (78.8% vs. 70.3%; HR = 0.52; 95% CI, 0.30 to 0.90) were better in the TNBC patients who received capecitabine than in the control group. On the basis of the results of this trial, NCCN recommends considering adjuvant capecitabine for patients with TNBC who received standard neoadjuvant chemotherapy with a taxane and an anthracycline-based regimen and have residual disease at the time of surgery.⁹

One consideration when applying these data is the dose of capecitabine utilized. The population in CREATE-X was composed of Asian women, who are known to metabolize capecitabine better than non-Asian populations. In the metastatic setting, although many of the clinical trials utilized a similar dosing regimen of 2500 mg/m²/day (1250 mg/m² twice daily), oncologists often choose to start closer to 2000 mg/m²/day (1000 mg/m² twice daily) due to improved tolerability (primarily related to diarrhea and hand-foot syndrome) with the lower dose. Data in metastatic breast cancer have shown that starting capecitabine at a daily dose of 2000 mg/m²/day improved tolerability without effecting outcomes.²¹ Dosing should be based on individual patient factors and should be tailored according to tolerability. Another consideration is the timing of capecitabine with radiation therapy. Administration of capecitabine too close to radiation therapy could increase radiation-related skin toxicity. A separation of at least 2 to 3 weeks between the 2 therapies is optimal.

Most patients with early-stage and locally advanced TNBC will receive chemotherapy as part of a multimodal approach to disease management. Chemotherapy may be administered in the neoadjuvant or adjuvant setting, or, potentially, in both. Advantages of administering in the neoadjuvant setting include improving chances of performing breast-conserving surgery, obtaining prognostic information, and allowing patient eligibility for adjuvant capecitabine therapy or a clinical trial if there is residual disease at the time of surgery. Chemotherapy regimens typically contain an anthracycline-and-taxane backbone. Some patients may receive an anthracycline-sparing regimen, although the data in TNBC suggest a benefit for including an anthracycline. Research to improve pCR rates and decrease rates of recurrence utilizing novel agents are ongoing.

TREATMENT OF METASTATIC TNBC

When a patient develops metastatic disease, the goal of therapy changes from cure to palliation and life prolongation. Several chemotherapy agents, administered either as single agents or in combination regimens, have shown activity in the treatment of patients with metastatic disease. However, the ideal sequence of these treatments remains unknown. Factors that affect agent selection include prior therapies used, residual toxicities, comorbid conditions, and organ function. While combination chemotherapy has been shown to produce a higher objective response rate (ORR) and increased time to progression, these benefits come at the cost of significantly increased toxicities.^9,22 Additionally, there is minimal benefit on survival when chemotherapy agents are administered in combination compared to sequential administration. Considering that the goal of treatment for metastatic breast cancer is to enhance quality of life, most oncologists prefer a sequential method of administration in order to minimize toxicities for the patient. Patients with metastatic breast cancer will likely remain on therapy for the remainder of their lives. The decision to change treatment will be based on disease progression and patient tolerability. Examples of single-agent chemotherapy regimens for patients with metastatic disease are listed in Table 2.⁹

Patient case: MR is a 60-year-old female with metastatic TNBC. She is currently receiving capecitabine and her most recent scans show signs of disease progression. She is not interested in receiving intravenous chemotherapy and asks about olaparib. What information do you need to know to determine if MR is an appropriate candidate for olaparib therapy?

Numerous agents have been approved in recent years for metastatic breast cancer patients with HR-positive or HER2-positive disease, but, to date, no agents have been approved specifically for TNBC. Olaparib is an oral PARP inhibitor that was approved in 2018 for the treatment of patients with HER2-negative metastatic breast cancer with a deleterious germline BRCA mutation who have been previously treated with chemotherapy. Approval was based on a single, phase III trial that showed that patients who received olaparib 300 mg twice daily had a significantly prolonged PFS (7.0 vs. 4.2 months; p < 0.001) compared to patients who received standard single-agent chemotherapy.²³ The response rate and incidence of grade 3 or higher adverse events also favored patients treated with olaparib. Because rates of BRCA mutations are higher in the TNBC population, it is likely that olaparib may play a larger role in TNBC than in other HR-positive breast cancers.

Identifying the ideal line of therapy for use of olaparib in the management of metastatic disease is challenging in patients eligible for this therapy. Patients in the clinical trial received prior chemotherapy with a taxane and an anthracycline, but this could have taken place in the neoadjuvant or adjuvant setting. Therefore, for TNBC patients, this agent could be utilized as front-line therapy in the metastatic setting or it could be used after multiple lines of chemotherapy. Patients in the trial were limited to 2 prior lines of chemotherapy in the metastatic setting. It is also important to note that patients with platinum-resistant disease were not assessed in this trial, as patients who had progressed on a platinum agent in the metastatic setting were not eligible for inclusion.

In addition to systemic therapy, there may be a role for local therapy, including radiation and/or surgery in certain situations. Radiation is highly effective for the management of bone pain related to bone metastases, a common site of metastases in patients with metastatic breast cancer. Radiation therapy is also commonly used for patients who develop brain metastases who are not surgical candidates. As previously stated, TNBC has a higher propensity to metastasize to the brain than other breast cancers; it is less likely to spread to the bone than other cancers, but, nonetheless, issues related to bone metastases are still common in patients with TNBC.

INVESTIGATIONAL AGENTS FOR TNBC

Several agents are being investigated for TNBC, including new combinations and sequences of older agents and innovative targeted therapies. Targeted therapies work differently than traditional chemotherapeutic agents: targeted therapies aim to inhibit specific processes within cancer cells to inhibit their growth. Increased understandings of aberrant pathways in cancer cells have established targeted agents as promising strategies for improving outcomes in TNBC.

PARP inhibitors

Multiple PARP inhibitors, in addition to olaparib, are under investigation for the treatment of TNBC. Talazoparib is an exciting compound with dual-mechanism PARP inhibition: it traps PARP-DNA complexes and prevents DNA repair, leading to cell death in BRCA-mutated cancer cells. Recent data demonstrated improved PFS and ORR with talazoparib compared with physician's choice chemotherapy in BRCA-mutated advanced breast cancer.²⁴ While the trial was not specifically designed for TNBC patients, 190 study participants had TNBC and significant benefits were seen in this subset of patients (PFS: HR = 0.596; 95% CI, 0.406-0.874; ORR: HR = 11.89; 95% CI, 4.54-41.37). Interestingly, activity was also seen in a small subset of patients with central nervous system metastases (PFS: HR = 0.322; 95% CI, 0.154-0.675; ORR: HR = 8.95; 95% CI, 1.86-52.26), which are commonly difficult to treat with systemic therapies.

Veliparib, another PARP inhibitor under development, has been studied in combination with carboplatin and paclitaxel, but it failed to demonstrate improvement when used in early-stage breast cancer.⁴ However, veliparib continues to be studied in BRCA-mutated advanced breast cancer in an ongoing phase III trial (NCT02163694). Niraparib and rucaparib are PARP inhibitors approved by the United States Food and Drug Administration for use in ovarian cancer and are also being studied as single agents and in combination with chemotherapy for advanced breast cancer patients. These results are eagerly awaited, since these agents are already approved and on the market and could be quickly adopted in clinical practice if improved activity is demonstrated.⁴

Antiandrogens

Multiple antiandrogens are commercially available in the United States and have widely established clinical activity in patients with metastatic prostate cancer. Agents in this class being studied in breast cancer include bicalutamide, enzalutamide, and abiraterone. While studies with these agents have included patients with HR-positive tumors, some have specifically targeted the TNBC population. All studies require AR "positivity" to be eligible for enrollment, but the level of positivity varies from study to study. It is unclear at this time what percentage of cells needs to be positive for ARs to play a key role in driving tumor growth and metastases for breast cancer. Molecular classification utilizing genomic assessments will likely play a more important role in determining the phenotype associated with response to AR inhibitors, but no genetic tests are yet approved for widespread clinical use. Nonetheless, several studies with antiandrogens included patients with AR-positive TNBC. In a small phase II trial of women with AR-positive TNBC, bicalutamide as a single agent (150 mg daily) demonstrated modest activity with a clinical benefit rate (CBR; stable disease plus objective responses) for at least 6 months of 19% (95% CI, 7%-39%) and a median PFS of 12 weeks (95% CI, 11-22 weeks; range, 6 to > 230 weeks).²⁵

In a phase II trial, enzalutamide (160 mg daily) demonstrated activity and an androgen-driven gene signature was used to stratify outcomes. The CBR was 29% at 24 weeks, and PFS was higher in patients with a positive gene signature (32 vs. 9 weeks) and 7 objective responses were reported.²⁶ Both of these agents were relatively well-tolerated: fatigue, hot flashes, and elevation in liver function tests were the most common treatment-related adverse effects with bicalutamide; fatigue, decreased appetite, and nausea were the most common adverse effects associated with enzalutamide.

Abiraterone inhibits production of testosterone precursors and, thus, inhibits AR differently than the other drugs in this class. It must be administered with supplemental prednisone to avoid symptoms associated with mineralocorticoid deficiency and, therefore, has more toxicity associated with its use than other agents in this class. Abiraterone was studied in a small phase II trial in heavily pretreated women with AR-positive TNBC, and modest results were reported. The CBR at 6 months was 20% and PFS was 2.8 months. The most commonly reported adverse events included fatigue, hypertension, hypokalemia, and nausea.²⁷

Ongoing trials are comparing bicalutamide to traditional chemotherapy in the first-line treatment of metastatic TNBC (NCT03055312). Others are investigating the combination of palbociclib (NCT02605486) or ribociclib (NCT03090165), both CDK 4/6 inhibitors, with bicalutamide in AR-positive metastatic breast cancer (regardless of HR status). Enzalutamide is being studied as a single agent (NCT01597193) and in combination with chemotherapy (NCT02689427) and other targeted agents such as inhibitors of the mTOR/PI3K pathway (e.g., taselisib) (NCT02457910). Abiraterone is involved in dose-finding studies to determine the most effective dose (NCT01884285), but it has yet to be further explored in the TNBC population, likely due to tolerability issues.²⁸

Immunotherapy

Immunotherapy is perhaps one of the most robust areas of research in TNBC and is far too extensive of a topic to cover in its entirety in this manuscript. Some of the more interesting and promising approaches will be reviewed here, but there are many other clinical trials in progress.

Inhibitors of PD-1 and PD-L1 are under investigation for TNBC in both the metastatic and early-stage settings. As single agents, atezolizumab (PD-L1 inhibitor) and pembrolizumab (PD-1 inhibitor) have demonstrated modest activity in heavily pretreated, metastatic TNBC patients with some durable responses. Treating patients earlier or selecting for PD-L1 expression may optimize efficacy with these agents. Combining immune therapies with traditional chemotherapy has demonstrated more impressive results. Atezolizumab combined with nab-paclitaxel demonstrated a 40% ORR in metastatic, pretreated TNBC. These results have led to a phase III clinical trial comparing the combination to single-agent nab-paclitaxel in patients with previously untreated metastatic TNBC (NCT024425891).²⁸ Results from this trial are not expected until 2020.^6,8

Early-stage breast cancer may be the optimal setting to maximize activity with immunotherapy and many clinical trials are ongoing in the neoadjuvant and adjuvant settings. In an exploratory arm of the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY2) neoadjuvant trial, pembrolizumab demonstrated a preliminary pCR rate of 62.4% when combined with paclitaxel followed by traditional anthracycline-containing chemotherapy; the control group achieved a pCR rate of 22.3%.²⁹ These preliminary results, in conjunction with other phase II data, led to the Study of Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants with Triple Negative Breast Cancer (KEYNOTE-522) study, which is currently enrolling patients and evaluating pembrolizumab's place in neoadjuvant and adjuvant therapy of TNBC (NCT03036488).²⁸ Accrual is estimated to be complete towards the end of 2018, but it will be many years before results are available that will substantially answer important clinical questions.

Additional adjuvant studies of administering immunotherapy after curative surgery and traditional chemotherapy are also ongoing with pembrolizumab (NCT03036488), avelumab (NCT02926196), and durvalumab (NCT02826434).²⁸ Combinations of targeted therapies with immunotherapy are also being investigated with PARP inhibitors, vascular endothelial growth factor inhibitors, and MEK inhibitors. Some immunotherapies may also modulate efficacy with radiation therapy, as well. Tolerability of immune therapies varies by agent, but significant endocrinopathies (e.g., hypophysitis, adrenal insufficiency, thyroid abnormalities) have been reported and patients should be closely monitored while receiving these therapies. Recently published guidelines on the management of toxicities related to immune checkpoint inhibitors are very helpful when managing patients in clinical trials with immunotherapies.³⁰

T-cell adoptive therapies and vaccines are in early stages of development as therapies for solid tumors and may further improve outcomes for TNBC patients. Tolerability with T-cell therapies can be problematic and time will tell if the benefits of such therapies outweigh the risks for TNBC patients. Adverse events that are common with this approach to therapy are cytokine release syndrome and cytokine-related encephalopathy syndrome, which can be life-threatening. These serious adverse events are most commonly seen in hematologic malignancies, but the incidence is unknown in solid tumor populations. Careful attention to monitoring and toxicity management is paramount. Refer to an excellent review on toxicity management with these therapies by Neelapu et al for further information.³¹

Antibody-drug conjugates

Glembatumumab vedotin is an ADC comprised of a fully human immune globulin 2 monoclonal antibody targeting the type-1 transmembrane protein gNMB and a microtubule inhibitor, monomethyl auristatin E. Early activity of glembatumumab vedotin in a phase I trial led to further investigation in breast cancer.³² In a phase II randomized trial comparing glembatumumab vedotin to physician's choice chemotherapy in heavily pretreated, gNMB-expressing breast cancer, ORRs in the glembatumumab vedotin and chemotherapy groups were 18% and 0%, respectively, in the TNBC subgroup and 40% and 0%, respectively, in those with gNMB-overexpressing TNBC.³³ These results led to a randomized, phase III trial comparing glembatumumab vedotin to capecitabine in patients with metastatic, gNMB-overexpressing, TNBC (METRIC; NCT01997333).²⁸ Results from this trial are expected in early 2019.

Patient case: RG is a 55-year-old female planning to start neoadjuvant carboplatin plus paclitaxel for early-stage TNBC. During your educational counseling with her, she voices concern about nausea and vomiting with chemotherapy because her mother was very sick with chemotherapy roughly 20 years ago. How would you counsel RG about nausea and vomiting with this regimen?

PHARMACY-DRIVEN STRATEGIES TO IMPROVE OUTCOMES IN TNBC

Traditional chemotherapy for TNBC may contain platinum agents that are typically not administered in other breast cancer populations. Nausea and vomiting are more frequent when platinum agents are included in chemotherapy regimens: a prophylactic antiemetic combination regimen containing a serotonin receptor antagonist, a neurokinin receptor antagonist, and corticosteroids administered prior to the chemotherapy and continued with scheduled dosing for several days (usually 3 days) is important to minimize this adverse event and maintain quality of life. There are many new antiemetics and formulations that allow for less frequent dosing of serotonin and neurokinin antagonists. NCCN guidelines provide details on dosing and administration of recommended antiemetic regimens.³⁴ The addition of olanzapine to combination antiemetic regimens is recommended in national and international antiemesis guidelines and may be useful in the setting of platinum-containing chemotherapy.^34-36 New combination antiemetic regimens have been studied that have added olanzapine to regimens containing serotonin antagonists, neurokinin antagonists, and corticosteroids: the addition of olanzapine significantly improved the rate of nausea control. This is important for many patients receiving chemotherapy for breast cancer, as nausea is often a more frequent complaint than vomiting for these patients.

Neutropenia is a common toxicity associated with many different chemotherapy regimens and the use of myeloid growth factors is occasionally required as primary prophylaxis with some regimens. For example, dose-dense chemotherapy requires a myeloid growth factor with all doses. Other chemotherapy regimens with an incidence of FN of more than 20% require primary prophylaxis with myeloid growth factor according to NCCN guidelines.³⁷ Inclusion of myeloid growth factors in the regimen increases the likelihood of bone pain related to marrow stimulation and some patients may require intervention to manage the pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, opioids, and dose reduction have all been investigated for prevention and/or management of pegfilgrastim-induced bone pain (PIBP). NSAIDs, specifically naproxen 500 mg twice daily, have shown benefits in decreasing the incidence and severity of PIBP when given the day of pegfilgrastim administration and continued for 5 days.³⁸

Research with antihistamines to prevent bone pain associated with myeloid growth factors has demonstrated mixed results. In a recently published review, use of antihistamines (specifically loratadine) was not recommended due to the paucity of data demonstrating benefit. However, due to a more favorable toxicity profile, antihistamines may be a safe option for patients who cannot tolerate or have contraindications to naproxen.³⁹ Opioids do not have any direct evidence to support their benefits in PIBP, but they are reasonable alternatives if other means fail to provide adequate pain control.

While dose reductions may appear to be a remedy to this clinical situation, data from a pooled analysis of pegfilgrastim 3 mg compared to 6 mg appeared to show a higher incidence of PIBP and higher rates of FN in the 3-mg cohort.⁴⁰ Therefore, dose reduction strategies should be avoided due to the risk of FN and lack of benefit in preventing PIBP.

PARP inhibitors are associated with a significant amount of nausea related to their administration (58% of patients receiving olaparib reported nausea; 29.8%, vomiting).²³ While the severity is less than with traditional chemotherapies, nausea with continuous dosing of PARP inhibitors has the potential to substantially impact a patient's quality of life. Serotonin antagonists are the mainstay for the management of nausea related to the PARP inhibitors. Compared with other antiemetics, such as corticosteroids and phenothiazines, the adverse effects associated with serotonin antagonists are less problematic. Nonetheless, constipation and headaches are commonly experienced with long-term use of serotonin antagonists and need to be managed as they occur. Other gastrointestinal toxicities seen with olaparib include diarrhea and stomatitis. Myelosuppression, primarily anemia, is also frequent (incidence of approximately 40%) but is generally mild in severity, with only 16% of patients experiencing grade 3 anemia in the pivotal trial.²³

Pneumonitis is a rare, but serious, toxicity that occurs in less than 1% of patients. Some cases have been fatal and interruption of therapy should be undertaken if pneumonitis is suspected; treatment should be permanently discontinued if confirmed. Common signs and symptoms of pneumonitis include flu-like symptoms, cough, shortness of breath, and fatigue, and definitive diagnosis is confirmed with imaging. Acute myeloid leukemia and myelodysplastic syndrome have also been rarely reported in less than 1.5% of patients receiving olaparib. All cases have been fatal, but causality has yet to be confirmed, as these patients had multiple risk factors for myelodysplasia, including extensive exposure to chemotherapy and/or radiation therapy. It is imperative that patients be appropriately educated about the risks of these serious side effects.⁴¹

An increasing number of therapeutic agents available to treat cancer are oral, self-administered medications, so pharmacists have become important partners in optimizing patient care, including improving adherence and maintaining quality of life. Navigating the medication access process is paramount to helping patients get started on these new medications in a timely manner. Pharmacists, while not the only healthcare provider able to provide this service, are often the ones to facilitate prior authorizations, letters of medical necessity, and appeals, if necessary. There are also many assistance pathways that can be accessed if insurance coverage is suboptimal or if a patient is underinsured or uninsured, and pharmacists can help patients navigate these channels. Once an oral medication is approved and dispensed to the patient, pharmacists are also well-positioned to enhance safety by ensuring the patient is adhering to the monitoring plan and obtaining scheduled refills in a timely manner.

CONCLUSIONS

TNBC represents a minority of breast cancer patients, but it continues to be a challenge for clinicians and researchers. Although patients with early-stage TNBC respond well to traditional chemotherapy, the risk of relapse is high and the need for new agents to reduce this risk is great. Various targets are being investigated as a way to improve outcomes for both early-stage and metastatic TNBC patients. The current treatment options for TNBC mostly involve traditional chemotherapy, but data with newer agents may shift the management to a more targeted approach.

UPDATE: June 14, 2019 Updated overall survival data was presented at ASCO on the Impassion 130 trial. It confirmed clinically meaningful 7 month overall survival benefit with atezolizumab and protein-bound paclitaxel (25.0 months) over protein-bound paclitaxel (18.0 months; HR 0.71, 0.54-0.93). Statistical significance was not met in the IIT population. Reference: https://abstracts.asco.org/239/AbstView_239_252769.html

UPDATE: March 11, 2019 Atezolizumab in combination with paclitaxel protein-bound received accelerated FDA approval for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1 as determined by an FDA-approved companion test, VENTANA PD-L1 (SP142 Assay). The approval is based upon results from the IMpassion130 trial (discussed in December update). (https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm633065.htm=)

UPDATE: December 13, 2018 Study CIBOMA/2004-01_GEICAM/2003-11 presented at San Antonio Breast Conference in 2018 presented conflicting results on the use of adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer. This multicenter phase III trial randomized patients to capecitabine 1000 mg/m2 PO BID on days 1-14 every 21 days or observation following 6-8 cycles of standard anthracycline and/or taxane-containing chemotherapy or 4 cycles of doxorubicin-cyclophosphamide in the neoadjuvant setting. The primary objective of disease free survival was not significantly prolonged in the capecitabine group compared with observation (HR 0.82; 95% CI, 0.63-1.06; p=0.1353). Secondary objectives of overall survival was also not significantly prolonged (HR 0.92; 95% CI, 0.66-1.28; p=06228). (https://www.abstracts2view.com/sabcs18/view.php?nu=SABCS18L_864&terms=) Talazoparib is no longer an investigational agent and was FDA approved on October 16, 2018 for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2 negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on an FDA-approved companion diagnostic for talazoparib. (https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm) Final progression free survival (PFS) results and the initial interim overall survival (OS) results from the Impassion130 trial evaluating atezolizumab and nab-paclitaxel were presented at the European Society for Medical Oncology meeting. At median follow-up of 12.9 months, the trial met its co-primary PFS endpoint in the IIT and PD-L1 positive patients (HR 0.80; 0.69-0.93; p=0.0025; HR 0.62; 0.49-0.78; p< 0.0001 respectively), with clinically meaningful OS benefit at interim analysis in the PD-L1 positive patients (HR 0.62; 0.45-0.86; p=0.0035). (https://www.esmo.org/Press-Office/Press-Releases/IMpassion130-atezolizumab-nab-pac-triple-negative-breast-cancer-Schmid)

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