Breast cancer research continues to extend survival across all subsets and settings of the disease, according to Sandra Cuellar, PharmD, BCOP, Director, PGY-2 Oncology and Clinical Oncology Pharmacist and Clinical Assistant Professor, University of Illinois Hospital and Health Sciences System, Chicago.
At the 2019 Hematology/Oncology Pharmacy Association (HOPA) annual meeting, Dr Cuellar discussed new and practice-changing drug therapies, noting that trends continue toward tailoring treatments based on tumor biology and characteristics.
“To give you an idea of the magnitude of research in this disease state, between the years 2017 and 2018, over 20,000 articles were published in breast cancer,” she said. “My presentation will only scratch the surface of updates.”
Adjuvant Chemotherapy for Early-Stage Node-Negative Disease
It has been established that adding chemotherapy to treatment reduces recurrence by 25% in estrogen receptor–positive, HER2-negative, node-negative breast cancer, and approximately 50% of patients have this type of disease.
“But what we also know, unfortunately, is that the classical clinical and histopathological factors that we use to predict recurrence of disease really don’t apply to this patient population,” Dr Cuellar said. “So, things like tumor size, mitotic rate, and biomarker expression really don’t correlate in predicting who’s going to benefit from chemotherapy,” she added.
Because clinical and histopathological factors are not particularly sensitive in this patient population, the National Institute of Health Consensus Panel recommends chemotherapy for the majority of this population. However, up to 85% of these women do not benefit from additional chemotherapy and are adequately managed with localized endocrine therapy.
The multigene Oncotype DX assay can predict who is going to benefit from chemotherapy and who is likely going to have a recurrence. This assay looks at 16 breast cancer–related genes and 5 reference genes, and places patients in 1 of 3 categories related to adjuvant chemotherapy based on a disease recurrence score ranging from 0 to 100. A low score (<18) indicates minimal benefit from adjuvant chemotherapy and a high score (≥31) indicates significant benefit from adjuvant chemotherapy.
But the benefit of adjuvant chemotherapy was unclear in the intermediate group (ie, recurrence score, 18-30). This led to the TAILORx clinical trial, which established that adjuvant endocrine therapy and chemotherapy plus endocrine therapy showed similar efficacy in women with hormone receptor (HR)-positive, node-negative breast cancer who had intermediate risk scores.
Therefore, endocrine therapy was determined to be sufficient in this patient population, with the caveat that younger women (aged ≤50 years) may still benefit from adding chemotherapy to hormone therapy.
Extended Adjuvant Therapy in HER2 Disease
The introduction of trastuzumab in the adjuvant setting led to remarkable improvements among patients with HER2-positive breast cancer, but according to Dr Cuellar, there is still room for improvement. Approximately 25% of patients with HER2-positive disease who receive chemotherapy plus trastuzumab still have disease recurrence.
The addition of pertuzumab to chemotherapy and trastuzumab had previously demonstrated improved outcomes in the metastatic and the neoadjuvant settings. The addition of pertuzumab in the adjuvant setting was later explored in the APHINITY clinical trial, which demonstrated a significant benefit among patients with node-positive disease. The addition of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, node-positive, HER2-positive breast cancer was part of a 2018 update to the American Society of Clinical Oncology (ASCO) guidelines.
The ASCO guidelines were also updated to include extended adjuvant neratinib therapy after trastuzumab in patients with early-stage, HER2-positive breast cancer, with preferential use in patients with HR-positive and node-positive breast cancer, based on results from the ExteNET clinical trial.
“One caveat to this is that none of these patients received pertuzumab, so we still don’t know the role of pertuzumab in this patient population,” Dr Cuellar said. Diarrhea management is mandatory with this drug regimen, she said, and the overall survival rate is expected to mature this year.
In the phase 3 KATHERINE clinical trial, T-DM1 significantly prolonged invasive disease-free survival compared with trastuzumab alone in patients with HER2-positive breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy and surgery. The benefit of T-DM1 was consistent across all subgroups, the extent of benefit was equal, and no new safety signals were identified. The study investigators concluded that T-DM1 will likely represent a new standard of care in this population. “These are very exciting data,” Dr Cuellar observed.
CDK4/CDK6 Inhibitors in Metastatic Breast Cancer
According to Dr Cuellar, the landscape for HR-positive metastatic breast cancer continues to evolve over time.
“We can offer our patients a number of endocrine therapies, and over the past few years other targeted agents have been approved, such as everolimus,” she said. “But more important, and more impactful, is the approval of the CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib.”
All 3 agents have been studied with endocrine therapy in the first-line setting, and have led to significant improvements in progression-free survival, but abemaciclib is the only agent indicated as monotherapy in disease refractory to endocrine therapy.
According to Dr Cuellar, providers often wonder which of these CDK4/CDK6 inhibitors is superior; however, opinion leaders report that in the absence of direct comparative trial data, all 3 agents show equivalent efficacy. The decision could come down to the dosing schedule that is most conducive to a patient’s lifestyle. For example, palbociclib and ribociclib have an intermittent dosing schedule, so a patient who struggles to remember that dosing schedule may benefit most from abemaciclib.
With palbociclib and ribociclib, the dose-limiting toxicity is neutropenia, whereas abemaciclib causes more diarrhea. All 3 drugs cause alopecia. The neutropenia seen with palbociclib and ribociclib is noncumulative, setting it apart from neutropenia caused by chemotherapy.
“But with simple dose adjustments, these patients recover relatively quickly,” Dr Cuellar said. “I find it very hard to find a patient who wouldn’t benefit from these agents, because of their remarkable progression-free survival in the frontline setting,” she added.
The combination of CDK4/CDK6 inhibitors plus endocrine therapy is now the standard of care for patients with metastatic HR-positive, HER2-negative breast cancer.
PARP Inhibitors in Metastatic Breast Cancer with BRCA Mutation
Currently, 2 poly (ADP ribose) polymerase (PARP) inhibitors are approved for breast cancer—olaparib and talazoparib. These 2 agents used as monotherapy significantly prolonged PFS versus chemotherapy in previously treated patients with HER2-negative, metastatic breast cancer and germline BRCA mutation.
According to Dr Cuellar, the objective response rate (a secondary end point) in the EMBRACA clinical trial of talazoparib versus chemotherapy was particularly noteworthy.
“When we think about these women who are symptomatic or have visceral disease and we want to give them something that’s going to elicit a rapid response, I think our go-to, historically, has always been chemotherapy,” she said. “But, when you look at the objective response rate with an oral PARP inhibitor, you see a response rate of 62%. That is extremely high compared with the response rate with chemotherapy: 27.2%. That is statistically significant, and I think clinically significant, for our patients.”
Compared with chemotherapy, olaparib and talazoparib showed lower rates of adverse event–related discontinuations, although talazoparib has significantly more hematologic toxicity than olaparib. These agents also often cause gastrointestinal toxicities, so supportive care in the form of antiemetics and antidiarrheals is necessary, she said.
Historically, BRCA testing was not done in this setting, but with the approval of PARP inhibitors, germline BRCA testing is now recommended at the time of diagnosis of metastatic breast cancer.
Immune Checkpoint Inhibitors in Advanced Triple-Negative Breast Cancer
Triple-negative breast cancer in the advanced setting has a very poor prognosis: the overall survival is approximately ≤18 months. The primary therapy for patients with triple-negative breast cancer remains systemic chemotherapy, with international guidelines supporting the use of a single-agent taxane or anthracycline.
“What’s unique about some of the heterogeneity of triple-negative breast cancer is that PD-L1 is expressed in tumor infiltrating immune cells rather than the tumor cells,” Dr Cuellar said. “That really allows for the investigation into, and possible benefit of, checkpoint inhibitors, specifically atezolizumab in combination with nab-paclitaxel.”
In the practice-changing IMpassion130 clinical trial, atezolizumab plus nab-paclitaxel resulted in a median overall survival of 25 months in patients with PD-L1 expression compared with 15 months with nab-paclitaxel alone.
“That is absolutely incredible and never seen before in the triple-negative breast cancer population,” she said. The combination regimen also led to a significant progression-free survival benefit in the intent-to-treat and PD-L1 populations, which was clinically meaningful in the PD-L1 group. According to Dr Cuellar, considering this “outstanding” efficacy, the side effects were manageable.
This was the first phase 3 clinical trial to demonstrate a benefit of first-line immunotherapy in metastatic triple-negative breast cancer. For patients with PD-L1 tumors, these data establish atezolizumab plus nab-paclitaxel as a new standard of care.
Based on the results of the IMpassion130 study, on March 18, 2019, the US Food and Drug Administration granted accelerated approval to atezolizumab plus nab-paclitaxel for the treatment of patients with unresectable, locally advanced or metastatic triple-negative breast cancer with PD-L1 expression.