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Advances in Personalized Therapy for Early-Stage and Metastatic Breast Cancer

TOP - May 2019, Vol 12, No 2 - HOPA

Fort Worth, TX—Breast cancer research continues to improve survival across all subsets and settings of the disease, according to Sandra Cuellar, PharmD, BCOP, Director, PGY-2 Oncology; 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 Conference, Dr Cuellar discussed new and practice-changing 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,” Dr Cuellar said. “My presentation will only scratch the surface of updates.”

Adjuvant Chemotherapy in Node-Negative, Early-Stage Disease

It has been established that adding chemotherapy to treatment reduces recurrence by approximately 25% in patients with estrogen receptor–positive, HER2-negative, node-negative breast cancer.

“But what we also know, unfortunately, is that the classical clinical and histopathologic factors that we use to predict recurrence of disease really don’t apply to this patient population,” Dr Cuellar explained. “So, things like tumor size, mitotic rate, and biomarker expression really don’t correlate in predicting who’s going to benefit from chemotherapy.”

Since clinical and histopathologic factors are not especially predictive in these patients, the National Institute of Health Consensus Panel recommends chemotherapy for the majority of this population. However, up to 85% of these patients do not benefit from additional chemotherapy, and can be adequately treated with surgery with or without radiation and hormonal therapy.

A multigene assay can be used to more accurately predict which patients are more likely to have disease recurrence and potentially benefit from chemotherapy. The Oncotype DX Breast Recurrence Score test examines the activity of 21 genes (16 breast cancer–related genes and 5 reference genes) in breast tumor tissue to provide personalized information for tailoring treatment based on the biology of a patient’s individual disease. The results are presented as a recurrence score (RS), based on a scale from 0 to 100, which places patients into 1 of 3 risk categories: low (RS <18), intermediate (RS ≥18-30), or high (RS ≥31).

Although studies have shown that patients in the low-risk category are not likely to benefit from adjuvant chemotherapy and patients in the high-risk category are likely to reap significant benefit from this approach, until recently, it was unclear what the benefit would be for those in the intermediate-risk category. This prompted investigators to initiate the phase 3 TAILORx clinical trial, which showed similar efficacy with adjuvant endocrine therapy versus chemotherapy plus endocrine therapy in patients with hormone receptor (HR)-positive, node-negative breast cancer with intermediate risk scores. As a result, endocrine therapy was determined to be sufficient in this patient population, with the caveat that women aged 50 years or younger may still benefit from the addition of chemotherapy.

Extended Adjuvant Therapy in HER2-Positive Disease

The introduction of trastuzumab in the adjuvant setting has led to remarkable improvements in outcomes for patients with HER2-positive breast cancer. However, according to Dr Cuellar, there is still room for improvement. Approximately 25% of patients in this population who receive chemotherapy plus trastuzumab still have disease recurrence.

The addition of pertuzumab to chemotherapy plus trastuzumab previously demonstrated improved outcomes in the metastatic and neoadjuvant settings. Adding pertuzumab in the adjuvant setting was later explored in the phase 3 APHINITY clinical trial, which demonstrated a significant benefit among patients with node-positive breast cancer. The addition of adjuvant pertuzumab to trastuzumab-based chemotherapy in high-risk, node-positive, HER2-positive breast cancer was included in a 2018 update to the American Society of Clinical Oncology (ASCO) guidelines.

Another update to the ASCO guidelines was the inclusion of extended adjuvant neratinib after trastuzumab in patients with early-stage, HER2-positive breast cancer, with preferential use in patients with HR-positive and node-positive disease, based on results from the phase 3 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. She also noted that diarrhea management is mandatory with this drug regimen, and that overall survival (OS) data are expected to mature this year.

In the phase 3 KATHERINE clinical trial, trastuzumab emtansine (T-DM1) significantly prolonged invasive disease-free survival compared with trastuzumab alone in HER2-positive patients with 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. “This is very exciting data,” Dr Cuellar noted.

CDK4/6 Inhibitors in Metastatic Breast Cancer

According to Dr Cuellar, the landscape for hormone-positive metastatic breast cancer continues to evolve.

“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,” Dr Cuellar said. “But more importantly, and more impactful, is the approval of the CDK4/6 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 (PFS), but abemaciclib (Verzenio) is the only agent indicated as monotherapy in breast cancer that is refractory to endocrine therapy.

According to Dr Cuellar, providers often speculate which of these CDK4/6 inhibitors is superior, but opinion leaders report that, in the absence of direct comparative trial data, all 3 agents appear to have equal efficacy. The decision could come down to the dosing schedule that is most conducive to a patient’s lifestyle. For example, palbociclib (Ibrance) and ribociclib (Kisqali) require intermittent dosing, so a patient who struggles to remember this type of dosing schedule may benefit most from abemaciclib.

The dose-limiting toxicity associated with palbociclib and ribociclib is neutropenia, whereas abemaciclib tends to cause more diarrhea. All 3 drugs are associated with alopecia. The neutropenia observed with palbociclib and ribociclib is a noncumulative toxicity, setting it apart from the neutropenia frequently associated with chemotherapy.

“But with simple dose adjustments, these patients recover relatively quickly,” Dr Cuellar said.

“I find it very hard to find a patient that wouldn’t benefit from these agents, because of their remarkable progression-free survival in the frontline setting,” she added.

CDK4/6 inhibitors in combination with endocrine therapy is now standard of care for hormone-positive, HER2-­negative, metastatic breast cancer.

PARP Inhibitors in BRCA-Positive Metastatic Breast Cancer

Two PARP inhibitors are approved for use in the treatment of breast cancer—olaparib (Lynparza) and talazoparib (Talzenna). Both of these agents, used as monotherapy, significantly prolonged PFS versus chemotherapy in patients with previously treated HER2-negative, germline BRCA-mutated metastatic breast cancer.

According to Dr Cuellar, the objective response rate (a secondary end point) in the phase 3 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 seen 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 appears to be associated with significantly more hematologic toxicity than olaparib. These agents also tend to cause gastrointestinal toxicities, requiring supportive care in the form of antiemetics and antidiarrheals, 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 (TNBC) in the advanced setting has a very poor prognosis—OS of approximately 18 months or less. Primary treatment for patients with TNBC 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 TNBC is that PD-L1 is expressed in tumor infiltrating immune cells rather than the tumor cells,” Dr Cuellar explained. “That really allows for the investigation into—and possible benefit of—checkpoint inhibitors, specifically atezolizumab in combination with nab-paclitaxel.”

In the IMpassion130 clinical trial, atezolizumab (Tecentriq) plus nab-­paclitaxel (Abraxane) led to a median OS of 25 months in a PD-L1–positive subgroup of patients, 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 PFS benefit in the intent-to-treat and PD-L1 populations, which was clinically meaningful in the PD-L1 group. According to Dr Cuellar, considering the “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 TNBC. For patients with PD-L1 tumors, these data establish atezolizumab plus nabpaclitaxel as a new standard of care.

Based on the results of the IMpassion130 clinical trial, on March 18, 2019, the FDA granted accelerated approval to atezolizumab plus nab-­paclitaxel for the treatment of patients with unresectable, locally advanced or metastatic, PD-L1–positive, TNBC.

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Last modified: June 14, 2019