Shopping Cart

INTRODUCTION

Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression.^1,2 TNBC accounts for approximately 10% to 17% of all breast cancers. It is more common in younger women, and African American women have a higher prevalence of TNBC than of hormone receptor (HR)-positive breast cancer.³ The lack of expression of conventional targets makes it an aggressive disease with no obvious targeted pathway for treatment. In general, TNBC is more chemosensitive than other subtypes of breast cancer particularly the hormone positive, but it is associated with a high relapse rate within the first 3 to 5 years after completion of adjuvant chemotherapy.^4,5 Due to the aggressive nature of TNBC, women are frequently diagnosed at an advanced stage of the disease and present with large tumors. TNBC usually metastasizes to critical visceral organs such as the lung, liver, or brain; it metastasizes to the bone less often than HR-positive disease, leading to a significantly shorter median overall survival (OS).^4-6

In the last decade, extensive efforts have focused on discovering new therapeutic targets in TNBC, but, unfortunately, targeted therapy has achieved little clinical success, rendering most patients with TNBC still mainly dependent on conventional chemotherapy.⁶ Recently, investigators revealed a variety of targets, including molecular pathways such as poly (ADP-ribose) polymerase (PARP), androgen receptor (AR), programmed cell death protein 1 (PD-1) receptor, and programmed death-ligand 1 (PD-L1), that may offer new treatment options for TNBC.^7-10 Data have also shown a strong correlation between TNBC and BRCA1/2 mutation status: approximately 20% of TNBC patients are carriers of BRCA1 or BRCA2 mutations. PARP repairs single-strand DNA breaks, and BRCA1 and BRCA2 repair double-strand DNA breaks. Theoretically, the breakdown in both of these mechanisms could be potentially lethal to cancer cells. PARP inhibitors can play an essential role in causing this lethal process.⁷ The discovery that some (10%-50%) women with TNBC express ARs was also exciting: many anti-androgen agents are already approved for the treatment of prostate cancer and could be utilized in the treatment of AR-positive TNBC.⁸

PD-1 and its ligand, PD-L1, are important immune regulatory components. The inhibition of these proteins enables T-cell activation by enhancing costimulatory signals or blocking co-inhibitory signals, allowing T-cell responses to boost the host immune response against cancer cells. Conventional chemotherapy, small-molecule inhibitors such as PARP inhibitors, and radiation therapy have been shown to increase the efficacy of immune checkpoint inhibitors (ICIs) when used in combination by creating new neoantigens for the immune system to recognize. These new insights into the molecular heterogeneity of TNBC and the manipulation of the immune system offer new therapeutic options for TNBC beyond conventional chemotherapy alone. This review will describe recent scientific and therapeutic progress in TNBC, focusing, in particular, on the role of immunotherapy in combination with conventional therapies in various stages of the disease, including neoadjuvant and adjuvant treatments and metastatic disease.

Patient case #1: ML is a 39-year-old premenopausal Caucasian woman who presents to a medical oncologist for a treatment plan for her newly diagnosed right breast cancer found on screening mammogram and confirmed with ultrasound and core needle biopsy as invasive ductal carcinoma. The tumor is 3.8 cm ´ 3.2 cm, ER negative, PR negative, HER2 immunohistochemistry (IHC) 2+, and fluorescent in situ hybridization (FISH) negative (i.e., TNBC disease). Pathology reveals a nuclear grade of 2 (moderately differentiated) and a high Ki-67 of 55%. She recently underwent a modified radical mastectomy with negative lymph nodes and negative margins (> 1 mm). What therapeutic option would you recommend?

TREATMENT OF EARLY-STAGE TNBC: NEOADJUVANT AND ADJUVANT THERAPY

The intent of treatment for early-stage TNBC is curative. Chemotherapy, small-molecule inhibitors, and lately immunotherapy can all be used at this stage of the disease.

Chemotherapy

Neoadjuvant and adjuvant chemotherapy are employed for the treatment of early-stage TNBC, depending on the size of the tumor, clinical symptoms, and pathologic features of the disease.¹¹ In neoadjuvant trials, achieving pathologic complete response (pCR) has been the standard goal endpoint. Advantages to administering chemotherapy preoperatively are the downstaging of tumors to allow for breast conservation, improving surgical outcomes, and gaining prognostic information from a patient’s response to primary therapy. Patients with TNBC who achieve a pCR following preoperative chemotherapy have been shown to have improved long-term outcomes compared with those who achieve less than a pCR.^12-14 Patients with TNBC showed high response rates to anthracycline- and taxane-based chemotherapy, achieving pCR rates of approximately 30% to 40%. Thus, the anthracycline- and taxane-based chemotherapy regimens had been the standard of care until recently.^14,15

 According to the National Comprehensive Cancer Network (NCCN) guidelines, adjuvant chemotherapy in TNBC is recommended for primary tumors that are larger than 0.5 cm due to their aggressive nature. Due to the frequency of early relapse in TNBC, efforts have been focused on developing more effective chemotherapeutic regimens. Many trials have focused on recombination of a variety of chemotherapeutic agents with various dosing schedules and frequencies, as evidenced by the use of dose-dense doxorubicin and cyclophosphamide (AC regimen) rather than a 21-day regimen. Recently, patients with an initially high tumor burden or residual disease after neoadjuvant chemotherapy (those not achieving a pCR) were identified as candidates for intensive systemic treatment, since they carry a high chance of relapse and metastatic spread. The CREATE-X trial demonstrated the potential survival benefit of adding adjuvant capecitabine in early TNBC with a residual tumor burden after neoadjuvant treatment.¹⁶

The backbone of chemotherapy in the management of TNBC includes anthracyclines and taxanes, and the length of therapy for neoadjuvant and 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. The chemotherapy regimens recommended by NCCN include doxorubicin plus 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.¹⁷ Another regimen is an anthracycline-sparing approach that includes docetaxel plus cyclophosphamide (TC) administered every 3 weeks for 4 cycles. Several other regimens are also recommended, including CMF (cyclophosphamide, methotrexate, and fluorouracil), TAC (docetaxel, doxorubicin, and cyclophosphamide), EC (epirubicin and cyclophosphamide), and AC administered every 3 weeks (Table 1).¹⁷

The concept of dose-density has been evaluated in several different clinical trials to determine if shortening the interval between cycles, particularly in the AC regimen, will result in better long-term outcomes. 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 disease-free survival (DFS).¹⁸ The only preferred regimen recommended by NCCN that spares anthracyclines is the TC regimen.¹⁷ 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.¹⁹

PARP inhibitors

PARP molecules, specifically PARP1 and PARP2, are enzymes that facilitate the repair of double-strand DNA damage at sites of single-strand breaks by activation of various intracellular signaling pathways through auto-poly (ADP)-ribosylation. Inhibiting PARP1 in patients with BRCA mutations induces accumulation of synthetic lethality.²⁰ Early clinical data suggested that a subset of patients with TNBC and BRCA deficiency might benefit from PARP inhibitor treatment. Currently, many PARP inhibitors, including olaparib, talazoparib, niraparib, and rucaparib, are approved by the United States Food and Drug Administration (FDA) for the treatment of patients with breast or ovarian cancer who harbor BRCA1/2 mutations in the advanced/metastatic setting.²¹ The efficacy of these agents has predominantly been demonstrated in the metastatic setting; the use of PARP inhibitors in earlier stages of BRCA-mutated TNBC disease is under investigation but is not currently the standard of care. More research is underway to investigate optimal combination regimens with these agents.

Immunotherapy

TNBC is characterized by genomic instability and high mutational burden, which produces more neoantigens and increased immunogenicity when compared to hormonal positive subtypes of breast cancer.^22,23 The immune system plays a vital role in disease progression of TNBC: the tumor initially induces innate immunity but later suppresses adaptive immunity, ultimately resulting in disease progression. The tumor microenvironment possesses an abundance of infiltrating immune cells, which are actively engaged in the process of immuno-editing.²⁴ Tumor-infiltrating lymphocytes (TILs), mainly CD8+ T-cells, are the most significant immune-related player in breast cancer.^21,25 In TNBC treated with neoadjuvant treatment, TILs reveal an active communication between the immune system and cytotoxic agents and are considered a predictive biomarker of long-term survival. The significance of TILs in the adjuvant setting has also been explored: findings suggest that the presence of TILs may be a criterion for patients to receive adjuvant chemotherapy or immunotherapy. In a recent study in metastatic TNBC, the response rate and OS after pembrolizumab treatment significantly correlated with the level of TILs.²⁶ A lower level of TILs was significantly associated with the activation of Ras-MAPK signaling, which can promote immune evasion in TNBC.

TNBC has a higher expression of PD-L1 than HR-positive subtypes of breast cancer, and a correlation between TILs and PD-1/PD-L1 expression was suggested in recent experiments.²⁷ Several retrospective studies of early-stage TNBC demonstrated significantly worse survival outcomes in patients harboring high PD-L1 expression and a low number of TILs or a high ratio of PD-L1/CD8 expression. Immunogenic factors potentially involved in the expression of neoantigens positively correlated with higher TILs and a more favorable prognosis.²⁷ Consequently, TILs play a significant role in boosting the immune microenvironment and vigorously interact with cytotoxic signals, including both chemotherapy and immunotherapy.

ICIs are a class of monoclonal antibodies that exploit the immune system to target cancer cells. ICIs include the PD-L1 inhibitors atezolizumab, avelumab, and durvalumab; the PD-1 inhibitors nivolumab, cemiplimab-rwlc, and pembrolizumab; and the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor ipilimumab. Several trials have investigated the use of ICIs in both the adjuvant and neoadjuvant settings.

In the I-SPY2 neoadjuvant trial, patients who received pembrolizumab demonstrated a higher preliminary pCR rate than the control group (62.4% vs. 22.3%) when the ICI was combined with paclitaxel followed by traditional anthracycline-containing chemotherapy.²⁸ In the KEYNOTE-522 study, 1174 patients were randomized 2:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy in the neoadjuvant setting followed by pembrolizumab or placebo in the adjuvant setting. Patients received pembrolizumab or placebo every 3 weeks plus weekly paclitaxel and carboplatin, given either weekly or every 3 weeks, for 4 cycles. This was followed by pembrolizumab or placebo, cyclophosphamide, and doxorubicin or epirubicin every 3 weeks for 4 cycles prior to the patient undergoing surgery. After surgery, patients received 9 cycles of pembrolizumab or placebo every 3 weeks as adjuvant therapy. The dual primary endpoints were pCR and event-free survival (EFS), and secondary endpoints included EFS in patients with PD-L1 expression, OS, safety, and patient-reported outcomes. At the interim analysis, there was a significant improvement in pCR in patients who received pembrolizumab (64.8%, 95% CI, 59.9-69.5) versus placebo (51.2%, 95% CI, 44.1-58.3; p=0.00055 for the comparison between the two arms). Benefit was seen in patients who were PD-L1-negative as well (pCR 45.3% with pembrolizumab vs 30.3% with placebo), but not at the same magnitude as in PD-L1+ patients (pCR 68.9% with pembrolizumab vs 54.9% with placebo). EFS also favored the pembrolizumab arm over the placebo arm (HR 0.63, 95% CI, 0.43-0.93). No significant difference was observed in grade 3 or higher treatment-related adverse events (78.0% in the pembrolizumab arm vs 73.0% in the placebo arm).²⁹ Moreover, a phase III trial for high-risk patients with early-stage TNBC is investigating the addition of avelumab for 1 year after standard curative treatment with neoadjuvant chemotherapy.³⁰

In the adjuvant setting, the SWOG1418 phase III trial is evaluating adjuvant monotherapy with pembrolizumab after neoadjuvant chemotherapy followed by curative surgery.³¹ Many approaches and combinations are being studied to improve outcomes for TNBC, including combinations of targeted therapies such as PARP inhibitors with immunotherapy, vascular endothelial growth factor inhibitors, and mitogen-activated protein kinase MEK inhibitors. 

Patient case #2: RK is a 49-year-old premenopausal African American woman who came back to the clinic for new findings on her computed tomography (CT) scans. The patient was diagnosed 3 years ago with early-stage TNBC. She underwent a double mastectomy with breast reconstruction, and she received standard adjuvant treatment with chemotherapy (dose-dense AC followed by weekly paclitaxel) and radiation. She completed her regimen with some mild episodes of emesis despite proper treatment. Lately, she has not been feeling well: she went to her family doctor who advised her to undergo an abdominal and chest CT. CT of her abdomen and chest revealed several nodules in the liver. A biopsy was done and pathology revealed metastatic disease with a tumor that it still negative for all markers. Further diagnostic testing revealed that the tumor is PD-L1 positive. She has no other relevant comorbidities. On the basis of the latest data, what do you recommend as first-line therapy?

TREATMENT OF METASTATIC TNBC: COMBINATION THERAPY

When a patient develops metastatic disease, the goal of therapy changes from cure to palliation and life prolongation. The treatment of metastatic TNBC has conventionally be hallmarked by cytotoxic chemotherapy and palliative radiation, but such treatments continue to have poor outcomes: the prognosis of metastatic TNBC is dismal, with a median OS of 18 months.³² Modern treatment options have aimed at combining conventional therapy with immune checkpoint blockade in hopes of exploiting the neoantigens created by conventional therapy and boosting the immune response to these neoantigens and improving outcomes in this population. 

ICIs and chemotherapy

The phase III IMpassion130 clinical trial examined atezolizumab versus placebo combined with nab-paclitaxel in 902 metastatic TNBC patients who were naïve to therapy for their metastatic disease. The coprimary endpoints of the trial were median PFS and median OS. PFS was significantly improved in the treatment arm for the overall population and for the population that was PD-L1 positive (defined as expression of 1% or higher); however, median OS was better in only the PD-L1-positive cohort at the interim analysis.³³ Outcomes were preserved in the BRCA-mutated and wild-type cohorts as long as the patients were also PD-L1 positive.

The results of IMpassion130 led to the first FDA approval of an ICI in TNBC. Atezolizumab is FDA approved in combination with nab-paclitaxel in first-line advanced/metastatic TNBC for patients who are at least 1% positive for PD-L1 according to the VENTANA PD-L1(SP142) assay, the FDA-approved companion diagnostic test for PD-L1 positivity for atezolizumab. The KEYNOTE-355 clinical trial, analogous to IMpassion130, is currently ongoing and examining pembrolizumab with chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) versus chemotherapy alone as first-line treatment of metastatic TNBC. Results are expected in 2020.³⁴

ICIs and PARP inhibitors

Recent approvals of the PARP inhibitors olaparib and talazoparib for BRCA-mutated cancer were based on modest improvement in median PFS seen in the OlympiAD and EMBRACA trials, respectively, which included both TNBC and HR-positive breast cancer subtypes.^20,21 OS data are still premature in the case of the EMBRACA trial with talazoparib, and the OlympiAD study was not powered to detect an OS difference with olaparib.^20,21 Immune checkpoint blockade is also being studied in combination with PARP inhibitors to exploit the DNA damage caused by PARP inhibitors as a neoantigen. Olaparib is being studied in combination with durvalumab, a PD-L1 antagonist, in metastatic BRCA-mutated breast cancer.³⁵ Preliminary results from the phase II MEDIOLA trial in BRCA-mutated patients (57% of whom had TNBC) showed a disease control rate of 80% at 12 weeks in the entire study population, which was the primary endpoint of the study. Further results revealed an overall response rate of 63%, a median duration of response of 9.2 months, and a median PFS of 8.2 months. Notably, observed response rates were greater when the combination was used earlier in the course of the disease with 0 to 1 previous lines of therapy in the metastatic setting.³⁵

A separate phase II study of olaparib in combination with durvalumab in metastatic BRCA wild-type TNBC is being conducted to examine if this benefit is extended beyond just BRCA-mutated patients.³⁶ Similarly, the TOPACIO trial, an open-label, single-arm, phase II study examined niraparib in combination with pembrolizumab in advanced/metastatic TNBC regardless of BRCA and PD-L1 statuses. The overall response rate was 21% in the entire population; the objective response rate (ORR) was 47% in patients with BRCA mutations and 11% in patients with wild-type BRCA.³⁷ 

ICIs and radiation

While systemic cytotoxic therapy and small-molecule inhibitors play a key role in managing metastatic TNBC, radiation therapy is still frequently used, especially for focal progression, such as that seen in the bones, liver, and brain, and for symptom relief. There is increasing evidence that radiation therapy generates an antitumor immune response. Radiation therapy modulates tumor cell surface expression of cell death receptors, tumor-associated antigens, and adhesion molecules. This process of immunomodulation sensitizes tumor cells to immune-mediated killing.³⁸ Further, this process can lead to immune-mediated rejection of nonirradiated metastatic lesions after irradiation of the primary lesion in a process known as the abscopal effect.³⁸ This could be a promising approach for patients who have few treatment options. Such effect was examined in the phase II basket TONIC trial in patients with metastatic TNBC who received 3 or fewer lines of previous therapy. Patients were randomized to receive radiation therapy or 1 of 3 regimens of low-dose chemotherapy or no induction treatment; then, all patients received nivolumab, a PD-1 antagonist. A modest ORR of 8% was observed in the radiation therapy arm, which trailed that of the no-induction arm (17%) and the low-dose chemotherapy arms (cyclophosphamide: 8%, cisplatin: 23%, and doxorubicin: 35%).³⁹

MANAGEMENT OF IMMUNE-MEDIATED ADVERSE EVENTS

The main toxicities associated with ICIs are immune-mediated adverse events (imAEs): these events manifest when the ICI stimulates the immune system, which then attacks normal, healthy tissue in an autoimmune fashion. CTLA-4 inhibitors (e.g., ipilimumab), which are not currently used in the treatment of TNBC, have a higher incidence of imAEs than PD-1 inhibitors; PD-L1 inhibitors have the lowest incidence of imAEs among ICIs. The organs and organ systems most commonly affected by imAEs are the skin, gastrointestinal tract, endocrine system, lungs, and kidneys; rare imAEs have been reported to affect the musculoskeletal system, neurologic system, blood cells, and heart.⁴⁰ Recently, the American Society of Clinical Oncology (ASCO) and the NCCN have each published practice guidelines on the management of imAEs, but the data included in the guidelines predate the use of ICIs in TNBC.^40,41 The ASCO and NCCN guidelines are helpful tools for grading each imAE with respect to each organ/organ system and give parameters for appropriate intervention and follow-up.

Currently, there is no prophylaxis recommended for the prevention of imAEs. Early recognition of imAEs is paramount for reversal and prevention of progression to higher-grade and more difficult-to-manage symptoms. Effective patient counseling is a cornerstone in identifying imAEs in outpatients. Patients should be counseled about when to call the office to report physical manifestations and educated about signs and symptoms. Patients should be routinely assessed at each oncology clinical encounter with appropriate laboratory monitoring and symptom assessment inquiry. Laboratory assessments should include complete blood count (CBC) with differential; comprehensive metabolic panel (CMP) including liver, renal, and metabolic parameters; hemoglobin A1C; adrenocorticotropic hormone; thyroid-stimulating hormone; and free T4; laboratory assessments should be completed at baseline and periodically throughout treatment and more often if clinically indicated. Qualitative in-clinic assessments or patient questioning should allow for the ability to recognize changes in neurologic function, mood, libido, fatigue, and pulmonary function and to assess the presence and/or changes in rashes and diarrhea/bowel habits.

The clinical onset and incidence of imAEs vary widely; select imAEs are described in Table 2.^40,42-45 ImAEs can present as early as cycle 1 or 2 of ICI therapy or as late as years after the start of therapy: they can occur during treatment or even after therapy is completed. The management of imAEs is complex and varies according to the organ system affected. Dose decreases or increases of any ICI are not currently recommended. Instead, in most cases, ICIs are held when patients experience imAEs of grade 2 or worse. Supportive care measures should always be considered up-front in conjunction with increased quantitative (laboratory) and qualitative (patient-reported) monitoring. In the case of moderate imAEs, corticosteroids (0.5-1 mg/kg prednisone or equivalent) serve as the backbone of therapy for most grade 2 or higher events, and higher doses (1-2 mg/kg prednisone or equivalent) may be considered for moderate to severe imAEs. Short-course pulse-dose corticosteroids may be considered in severe imAEs, including Guillain-Barre syndrome, encephalitis, transverse myelitis, and myocarditis/pericarditis. For patients with imAEs that are worsening or not improving after 3 to 5 days of corticosteroid doses of less than 2 mg/kg/day and supportive care, doses should be escalated up to 2 mg/kg/day. If patients do not respond to 2 mg/kg/day prednisone or equivalent, steroid adjuncts should be added in combination with a specialist consultation to gain control of the imAE and prevent patient morbidity (Table 3).^37-39 

As the use of ICIs expands to combination therapy with cytotoxic chemotherapy, small-molecule inhibitors, and radiation therapy in TNBC, overlapping toxicities must be taken into consideration. Rash and diarrhea are 2 common side effects of cytotoxic chemotherapy, particularly for the taxanes, and are the leading imAEs for ICIs, as well. The taxanes are currently the leading compounds used in combination therapy with ICIs in TNBC. Peripheral neuropathy, while less commonly seen as a result of ICI therapy, is very common in patients treated with microtubule-targeting agents in TNBC, such as vinorelbine, eribulin, and the taxanes, and with platinum analogs. Standard dose modulation of microtubule targeting agents and platinums should be employed for peripheral neuropathy. If peripheral neuropathy worsens in the context of dose changes, an imAE should be considered. Other concomitant toxicities of ICIs and conventional therapy in TNBC, including rare events, are listed in Table 4.

To date, experience with ICI combination therapy in TNBC is limited, but the addition of ICIs to conventional cytotoxic therapy, small-molecule inhibitors, or radiation therapy has not been shown to worsen side effects of such therapies. Trials of ICI therapy in TNBC did not show new or unexpected toxicities from standard therapy or newly emergent imAEs. As ICIs are increasingly used in combination with conventional therapies, it will become increasingly important to distinguish toxicities due to ICIs from those due to conventional therapy: patients must be spared unnecessary steroid therapy if conventional therapy is the culprit or inappropriate dose modulations of conventional therapy if the ICI is the culprit. Disease features, particularly progression of disease in the case of advanced/metastatic TNBC or disease recurrence in the neoadjuvant and adjuvant settings, should always be considered as a possible cause of new adverse events, particularly in the case of elevated liver enzymes and bilirubin, as the liver is a frequent site of metastatic disease in breast cancer. 

ROLE OF THE PHARMACIST

Pharmacists are important in the treatment of patients with TNBC. Not only can pharmacists optimize patient education and facilitate compliance, they can help guide selection of patients, planning of treatments, procurement of drugs, and management of adverse events. Pharmacists are critical members of cancer care teams who are well poised to improve patient care and outcomes.

Patient education

Patient education and counseling by pharmacists are exceedingly important for managing patient expectations, encouraging adherence and compliance, ensuring attendance at clinic visits/infusion center appointments, and facilitating early detection of imAEs. Pharmacists should emphasize the goals of therapy (curative intent in the neoadjuvant setting and disease control/palliation in the metastatic setting), which will help to reinforce the messages conveyed by other medical team members. In the case of metastatic disease, patients frequently do not understand that their treatment is not going to achieve a cure, despite this message being explained by various members of the healthcare team.⁴⁶ Lack of disease insight could compromise patients’ abilities to make informed decisions, and further efforts to increase understanding might come at the cost of patient satisfaction.⁴⁶ Thus, the healthcare team must engage in a delicate balancing act and decide what and how to communicate outcomes data to patients: should it be shared only when asked by the patient or should prognostic information be offered up-front during counseling? Successful interactions will likely arise from long-term pharmacist-patient relationships.

A variety of patient education materials are readily available online or in handout format, courtesy of drug manufacturers, and 1 smart phone application for imAEs exists. Patients should be encouraged to carry identification cards notifying others that they are receiving an ICI in case an emergency should occur in order not to confuse care management with that of cytotoxic chemotherapy. Patient calendars are often helpful for preventing absences in clinics or infusion centers on treatment days. For instance, the treatment schedule for atezolizumab with nab-paclitaxel includes an infusion of atezolizumab and nab-paclitaxel on day 15 of each cycle that often does not coincide with a clinic visit. Pharmacists can also monitor patients on off-clinic days for treatment-emergent toxicities by way of chart checks, counseling in the infusion center, and/or telepharmacy programs.

Optimal patient selection

Pharmacists can also aid in identifying special populations of TNBC patients, often through patient workups, interviews, or medication reviews/reconciliations, who might not be optimal candidates for ICI-based therapy or who may be at increased risk for imAEs. For instance, according to the National Cancer Institute, 10% to 30% of cancer patients have a baseline autoimmune disease. The ultimate decision to treat patients with a personal history of autoimmune disease with an ICI-based therapy must include a risk/benefit assessment and considerations of the severity of the autoimmune condition, active versus remissive disease, and concurrent immunosuppressive therapies, which may theoretically decrease the efficacy of ICI-based therapy, especially those that are long-acting agents, such as select biologics. Standard chemotherapy and supportive care frequently employed in TNBC, including cyclophosphamide and corticosteroids, are inherently immunosuppressive and may play a role in suppressing underlying autoimmune conditions. Therapy should proceed in collaboration with a patient’s primary provider for care of the autoimmune disorder. Two recent series have characterized the use of ICI therapy for the treatment of cancer in patients with autoimmune disease. Jounson and colleagues found a 10% to 62.5% incidence of autoimmune exacerbation or flare while on ICI therapy.⁴⁷ Cortellini and colleagues reported a significantly higher overall incidence of imAEs in patients who had an autoimmune disease and received ICI therapy compared to those without an autoimmune disease (65.9% vs. 39.9%, p=0.0162), but there was no difference in grade 3 to 4 imAEs between the groups.⁴⁸ These results must be considered in the risk/benefit assessment to proceed with ICI-based therapy in patients with autoimmune disease. 

ICIs increase immune system activity, so patients who previously received a solid organ transplant also might not be optimal candidates for ICI-based therapy. A recent real-world study reported an allograft rejection rate of 41% after receipt of an ICI: overall, 81% of patients who experienced ICI-mediated allograft rejection ultimately lost their allograft and 46% of patients subsequently died as a result.⁴⁹ The effects of concomitant immunosuppression on efficacy of ICI therapy in TNBC in allograft recipients is currently unknown, but coadministration could, in theory, decrease ICI efficacy. While there are no overt drug interactions listed for the ICIs, medications that impair T-cell function and medications that impair immune response, including steroid premedications for cytotoxic chemotherapy, could theoretically decrease the efficacy of ICIs. Currently, there are no data in TNBC about the effects of steroid use on outcomes of therapy in patients treated with ICIs, but nab-paclitaxel was specifically chosen for the IMpassion130 trial due to its lack of steroid premedication requirement. Concomitant organ toxicity of ICI-based therapy should also be taken into consideration: specifically, platinums plus ICIs in patients with kidney allografts and anthracyclines plus ICIs in patients with heart allografts confer a risk of not only primary chemotherapy toxicity but imAEs related to those vital organs. 

TNBC is more common in younger patients than other breast cancer subtypes. Therefore, some women who need systemic therapy are of child-bearing potential and some women are, unfortunately, diagnosed during pregnancy. While some conventional cytotoxic chemotherapy has been reported to have been used successfully in pregnant patients with breast cancer,⁵⁰ data are lacking with ICIs. All ICIs are immunoglobulin G monoclonal antibodies that cross the placenta and are excreted in breast milk: therefore, there is a theoretical increased risk of the fetus developing immune-mediated disorders. Patients with autoimmune disease, those who are receiving concomitant immunosuppressive therapy, those who have received an allograft, and those who are pregnant and/or breastfeeding are routinely excluded from clinical trials involving ICI-based therapy.

Patient access

Pharmacists are uniquely positioned to facilitate access to and procurement of ICI therapy for TNBC patients. Pharmacists, particularly those who work alongside the medical team in clinics, frequently play a role in submitting documentation for precertification of therapy. In cases in which payors initially deny patients financial access to therapy, such as in cases of off-label use, pharmacists can facilitate appeals and peer-to-peer conversations or negotiate procurement and interpretation of information to reverse the denial (e.g., tumor profiling results).

There are currently several tumor profiling tests and companion diagnostics that are routinely employed in screening TNBC patients for ICI-based therapy.⁴⁸ Atezolizumab was FDA approved for the treatment of TNBC in conjunction with the VENTANA PD-L1(SP142) assay.⁵¹ Pembrolizumab, while not currently FDA approved for TNBC, requires a different PD-L1 assay, the IHC 22C3 pharmDx, for its FDA-approved indications.⁵¹ Olaparib and talazoparib, which are being studied in combination with ICIs, were FDA approved in conjunction with the BRACAnalysis CDx.⁵¹ Other more comprehensive tumor profiling tests are routinely available for solid biopsies and liquid biopsies, which measure cell-free DNA. FoundationOne is the only FDA-approved tumor profiling panel that assesses for PD-L1-positive status and microsatellite instability. Guardant360 and CGP+ by Caris are other common tumor profiling tests that are routinely used in practice, though neither are currently FDA approved. Pharmacists can play a role in interpreting these test results and appropriately identifying TNBC patients who are eligible for ICI-based therapy in addition to supplying precertification/prior authorization personnel and payors with results that will allow for approval of financial access to ICIs. If payor financial access is ultimately denied, pharmacists can facilitate compassionate use of the medication through the FDA and/or manufacturer programs. 

Supportive care

Pharmacists serve a key role in the management of imAEs through the provision of supportive care. Pharmacists can facilitate optimal steroid dosing and slow tapering over 4 to 6 weeks to prevent imAE recurrence. They can also facilitate monitoring to identify patients who have a repeat or flare of an imAE in the setting of a taper. Tapering should begin when imAEs have resolved to grade 1 or lower.^40,41 Steroid tapering calendars are helpful educational tools that promote adherence to the care plan. Pharmacists can also assess patients for restarting ICI therapy after holding for an imAE. In general, ICIs can be restarted when the imAE has resolved to grade 1 or lower and patients are on a steroid dose of 10 mg per day or less of prednisone or equivalent corticosteroid.^40,41

Telepharmacy consultations in conjunction with routine lab monitoring, ordering of labs and medications in states that offer collaborative practice agreements, and/or pharmacist clinic visits can facilitate imAE management and resolution, as well as re-initiation of therapy when possible. In this role, pharmacists are uniquely positioned to provide continual reassessment and support to patients who develop imAEs while receiving ICI-based therapy. Patients on long steroid tapers should be provided with stress ulcer prophylaxis, calcium and vitamin D supplementation to prevent bone loss, and antimicrobial prophylaxis as indicated. Fungal prophylaxis is indicated if patients receive 20 mg per day or more of prednisone for 6 weeks or longer. Prophylaxis against Pneumocystis jiroveci pneumonia is indicated in patients who receive 20 mg per day or more of prednisone for 4 weeks or longer, and herpes simplex virus (HSV) prophylaxis should be considered in patients who are seropositive.⁴¹

CONCLUSIONS

Persistent negative historic outcomes in TNBC have stimulated the search for new therapeutic targets. TILs, PD-L1 status, genomic instability, and tumor mutational burden have been shown to be predictive and prognostic, especially in the setting of immunotherapy. BRCA continues to be an evolving target, and research is actively being done to examine other tumor markers and mutations. Combining immune therapy with conventional therapy has shown promise in the curative-intent and metastatic settings. Combination therapy with ICIs and conventional chemotherapy, small-molecule inhibitors, or radiation therapy has not identified any new signals of toxicity, but overlapping toxicities must be considered, and recurrence or progression of disease must be ruled out for patients who present with new symptoms. New guidelines for the management of imAEs are helpful, practical tools, but they are based not only on toxicities of PD-1 and PD-L1 inhibitors but also on CTLA-4 inhibitors. Currently, CTLA-4 inhibitors are not at the forefront of treatment of TNBC, and the guidelines were published ahead of most of the experience with immunotherapy in TNBC. Therefore, pharmacists must use clinical judgement when managing imAEs.

Pharmacists are uniquely positioned to provide patient counseling, continually reassess patients, and facilitate drug access and procurement of the latest therapies for TNBC. Pharmacists can also play a key role in identifying optimal TNBC patients for therapy with ICIs. With the growing body of evidence in immunotherapy combinations, it is likely that immunotherapy will become mainstream in the management of TNBC, and pharmacists can facilitate optimal management and outcomes for patients receiving ICI-based therapies.

REFERENCES

1. Zaharia M, Gómez H. Triple negative breast cancer: a difficult disease to diagnose and treat. Rev Peru Med Exp Salud Publica. 2013;30(4):649-56.
2. Schmadeka R, Harmon BE, Singh M. Triple-negative breast carcinoma: current and emerging concepts. Am J Clin Pathol. 2014;141(4):462-77.
3. Lin NU, Vanderplas A, Hughes ME, et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. 2012;118(22):5463-72.
4. Guarneri V, Dieci MV, Conte P. Relapsed triple-negative breast cancer: challenges and treatment strategies. Drugs. 2013;73(12):1257-65.
5. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938-48.
6. Lebert JM, Lester R, Powell E, et al. Advances in the systemic treatment of triple-negative breast cancer. Curr Oncol. 2018;25(Suppl 1):S142-50.
7. Tong CWS, Wu M, Cho WCS, To KKW. Recent advances in the treatment of breast cancer. Front Oncol. 2018;8:227.
8. Gerratana L, Basile D, Buono G, et al. Androgen receptor in triple negative breast cancer: a potential target for the targetless subtype. Cancer Treat Rev. 2018;68:102-10.
9. Li Z, Qiu Y, Lu W, et al. Immunotherapeutic interventions of triple negative breast cancer. J Transl Med. 2018;16(1):147.
10. Hu ZI, McArthur HL. Immunotherapy in breast cancer: the new frontier. Curr Breast Cancer Rep. 2018;10(2):35-40.
11. Moran MS. Should triple-negative breast cancer (TNBC) subtype affect local-regional therapy decision making? Am Soc Clin Oncol Educ Book. 2014;e32-6.
12. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol. 2008;26(5):778-85.
13. Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275-81.
14. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-72.
15. Earlyer Breast Cancer Trialists’ Collaborative Group (EBCTCG); Peto R, Davies C, Godwin J, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432-44.
16. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147-59.
17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 3.2019. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Published September, 2019. Accessed September 15, 2019.
18. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of intergroup trial C9741/Cancer and leukemia group B Trial 9741. J Clin Oncol. 2003;21(8):1431-9.
19. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006;24(34):5381-7.
20. Robson M, Im SA , Senkus E, et al. Olaparib for metastatic breast cancer in patients with germline BRCA mutation. N Engl J Med. 2017;377(6):523-33.
21. Litton J, Rugo H, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-63.
22. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.
23. Adams S, Gray R, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959-66.
24. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949-55.
25. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373-80.
26. Schmid P, Park YH, Muñoz-Couselo E, et al. Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173. J Clin Oncol. 2017;35(Suppl 15):abstract 556.
27. Tomioka N, Azuma M, Ikarashi M, et al. The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumorinfiltratinglymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC). Breast Cancer. 2018;25(1):34-42.
28. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017;35(15_suppl):abstract 506.
29. Schnid P, Cortes J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs placebo as adjuvant therapy for triple negative breast cancer (TNBC). Ann Oncol. 2019;30(suppl_5):v851-v934. DOI 10.1093/annonc/mdz394.
30. S. National Library of Medicine. NCT 02926196: Adjuvant Treatment for High Risk Triple Negative Breast Cancer Patients with Anti-PD-L1 Antibody Avelumab (A-Brave). https://clinicaltrials.gov/. Accessed October 15, 2018.
31. Pusztai L, Barlow WE, Ganz PA, et al. SWOG S1418/NRG-BR006: A randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with > 1 cm residual invasive cancer or positive lymph nodes (>pN1mic) after neoadjuvant chemotherapy. Cancer Res. 2018;78(4 Suppl):abstract OT1-02-04.
32. Zeichner S, Ambros T, Zarvinos J, et al. Defining the survival benchmark for breast cancer patients with systemic relapse. Breast Cancer (Auckl). 2015;9:9-17.
33. Schmid P, Adams, Rugo, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-21.
34. Cortes J, Guo Z, Karantza V, Aktan G. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2018;36(5_Suppl):abstract TPS18.
35. Domchek SM, Postel-Vinay S, Im SA, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Presented at San Antonio Breast Cancer Symposium; December 5-7, 2018; San Antonio, TX. Abstract PD5-04.
36. Mitri ZI, Vuky J, Kemmer KA, et a. A phase II trial of olaprib and durvalumab in metastatic BRCA wild type triple-negative breast cancer. J Clin Oncol. 2019;37(15_Suppl):abstract TPS1111.
37. Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5(8):1132-40.
38. Wattenberg MM, Fahim A, Ahmed MM, Hodge JW. Unlocking the combintion: potentiation of radiation-induced antitumor responses with immunotherapy. Radiat Res. 2014;182(2):126-38.
39. Voorwerk L, Slagter M, Horlings H, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med. 2019;25(6):920-8.
40. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-68.
41. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published April 8, 2019. Accessed August 27, 2019.
42. Lee H, Hodi FS, Giobbie-Hurder A, et al. Characterization of thyroid disorders in patients receiving immune checkpoint inhibition therapy. Cancer Immunol Res. 2017;5(12):1133-40.
43. Haissaguerre M, Hescot S, Bertherat J, Chabre O. Expert opinions on adrenal complications in immunotherapy. Ann Endocrinol (Paris). 2018;79(5):539-44.
44. Barroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):173-82.
45. Solinas C, Porcu M, De Silva P, et al. Cancer immunotherapy-associated hypophysitis. Semin Oncol. 2018;45(3):181-6.
46. Weeks JC, Catalano PJ, Cronin A, et al. Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med. 2012;367(17):1616-25.
47. Jounson DB, Beckermann KE, Wang DY. Immune checkpoint inhibitor therapy in patients with autoimmune disease. Oncology (Williston Park). 2018;32(4):190-4.
48. Cortellini A, Buti S, Santini D, et al. Clinical outcomes of patients with advanced cancer and pre-existing autoimmune disease treated with anti-programmed death-1 immunotherapy: a real-world transverse study. 2019;24(6):e327-37.
49. Abdel-Wahab N, Safa H, Abudayyeh A, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer. 2019;7(1):106.
50. Mir O, Berveiller P, Goffinet F, et al. Taxanes for breast cancer during pregnancy: a systematic review. Ann Oncol. 2010;21(2):425-6.
51. S. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools. Published August 2, 2019. Accessed August 27, 2019.

Back Top