This story was corrected on May 13. We regret the errors.

By Marcus A. Banks

New treatments for early-stage hormone receptor–positive (HR+) breast cancer—the most common subtype—are emerging, with some of the treatments being potential cures. But supportive care issues, including how best to manage adverse reactions, require having hem/onc pharmacists on the care team, a panel noted during the 2024 ACCP Annual Meeting, in Phoenix.

“We have some good opportunities to obtain a cure, and for a complete pathologic response, when we start out with chemotherapy,” said Julia Ziegengeist, PharmD, BCOP, a clinical pharmacist coordinator at Atrium Health Levine Cancer, in Charlotte, N.C. “Depending on the size of their tumor and whether they have lymph node positivity, not everyone will need chemotherapy. But there are some high-risk patients that do.” 

The treatment goal for all patients, regardless of how advanced their cancer may be, is to prevent recurrence. Lymph node–negative premenopausal women with a score of less than 16 on the Oncotype DX Breast Recurrence Score (Exact Sciences) can start with endocrine therapy and forgo chemotherapy unless their tumor grows or spreads, Dr. Ziegengeist said. A recurrence score of more than 16 in this same group is indicative of starting with chemotherapy before beginning endocrine therapy combined with treatments to slow or stop estrogen production (J Clin Oncol 2022;40[16]:1816-1837).

Postmenopausal women with negative lymph nodes and an Oncotype DX score of less than 26 may start with endocrine therapy, but a score higher than 26 suggests chemotherapy, she added.

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Not everyone eligible for chemotherapy will agree to it; Dr. Ziegengeist’s role is to guide patients through various treatment options in a shared decision-making process. “Some people want to do everything they can to avoid recurrence. Others want to avoid anything [they view as] toxic, or that they think will decrease their quality of life,” she said.

If premenopausal women are lymph node–positive, some providers may forgo the Oncotype DX test; chemotherapy is the clear first-line therapy, assuming a patient agrees to it, she noted. The same is true for postmenopausal women with at least four positive lymph nodes—usual chemotherapy applies.

Neoadjuvant chemotherapies offered before surgery are not all the same, Dr. Ziegengeist stressed. In most cases, dose-dense doxorubicin plus cyclophosphamide followed by paclitaxel, or a course of anthracycline-sparing docetaxel plus cyclophosphamide, is recommended. These approaches yield longer disease- and recurrence-free survival than offering other forms of doxorubicin plus cyclophosphamide or cyclophosphamide, methotrexate and fluorouracil (J Clin Oncol 2003;21[8]:1431-1439; 2009;27[8]:1177-1183).

Immunotherapies and Checkpoint Inhibitors 

In Dr. Ziegengeist’s view,immunotherapy with immune checkpoint inhibitors show promise for increasing response rates in early-stage HR+ breast cancer. . “We’ve typically reserved immunotherapies and checkpoint inhibitors for the metastatic setting,” she said.

The use of these therapies in the early-stage HR+ setting is still investigational. More clinical trial evidence still needs to accrue for immunotherapies and checkpoint inhibitors to become part of routine care in the early stage for HR+ breast cancer, Dr. Ziegengeist noted. As of now, for instance, the immunotherapy pembrolizumab (Keytruda, Merck) is only FDA approved for treating early-stage or metastatic triple-negative breast cancer.

Dr. Ziegengeist highlighted promising research for pembrolizumab in HR+ breast cancer at the ACCP meeting. The KEYNOTE-756 trial combined pembrolizumab with paclitaxel before surgery to remove an invasive ductal carcinoma, and then pembrolizumab plus endocrine therapy after surgery. Compared with placebo, people who received pembrolizumab enjoyed greater rates of pathologic complete response (pCR) (Ann Oncol 2023;34[suppl 2]:S1259-S1260). Specifically, the pCR for pembrolizumab was 24.3% (95% CI, 21.0%-27.8%) versus 15.6% for placebo (95% CI, 12.8%-18.6%); estimated difference, 8.5 percentage points (95% CI, 4.2-12.8 percentage points; P=0.00005).

However, more data are needed about event-free and overall survival before pembrolizumab is added to standard of care in the early stages, Dr. Ziegengeist said.

Some CDK4/6 inhibitors for treating early-stage HR+ breast cancer are further along. In the MonarchE trial, combining abemaciclib (Verzenio, Eli Lilly) with an endocrine therapy increased rates of relapse-free (hazard ratio [HR], 0.675; 95% CI, 0.588-0.774) and disease-free survival (HR, 0.680; 95% CI, 0.599-0.772) compared with endocrine therapy alone (J Clin Oncol 2024;42[9]:987-993). This combination now has FDA approval.

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The CDK4/6 inhibitor ribociclib (Kisqali, Novartis and Astex Pharmaceuticals) was another noteworthy 2024 FDA approval, based on the positive NATALEE trial (mini oral presented at ESMO Breast 2024; May 15-17, 2024; Berlin). In NATALEE, ribociclib plus endocrine therapy had superior disease-free survival (HR, 0.749; 95% CI, 0.628-0.892; P=0.0006) than endocrine therapy alone.

The NATALEE trial results are significant because breast cancer “is rapidly changing” toward a trend of longer survival rates Dr. Ziegengeist said. She added that pharmacists are critical in managing treatment toxicities for this drug class, which include interstitial lung disease/pneumonitis, severe cutaneous adverse reactions and QT interval prolongation.

Metastatic HR+ Breast Cancer

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Farah Raheem, PharmD

 

Farah Raheem, PharmD, BCOP, a hematology/oncology pharmacist at Mayo Clinic in Arizona, Phoenix, reviewed treatment options for patients with metastatic HR+ breast cancer. “We prefer endocrine therapy plus CDK4/6 inhibitors up front, plus/minus PI3K inhibitor in PIK3CA-mutated tumors including in patients presenting the with extensive visceral involvement,” Dr. Raheem said. Upfront chemotherapy is still recommended by treatment guidelines in the presence of true visceral crisis defined as rapid progression of disease leading to severe organ dysfunction and compromise (Ann Oncol 2020;31:1623-1649). 

The efficacy of first line endocrine therapy plus CDK4/6 inhibitors versus chemotherapy in patients with extensive visceral involvement  was investigated in the RIGHT Choice (J Clin Oncol 2024;42[23]:2812-2821) and PADMA (Loibl S, et al. SABCS 2024; abstract SESS-3616) clinical trials, Dr. Raheem said. In the RIGHT Choice trial, combining ribociclib with letrozole or anastrozole plus/minus goserelin had superior progression-free survival (PFS) than investigator’s choice of combination chemotherapies. The median PFS was 21.8 months for ribociclib plus endocrine therapy (95% CI, 17.4-26.7 months) and 12.8 months (95% CI, 10.1-18.4 months) for combination chemotherapy (HR, 0.61; 95% CI, 0.43-0.87; P=0.003). 

“This has changed our practice in clinic. It was a nice surprise,” Dr. Raheem said.

In the PADMA trial, endocrine therapy (aromatase inhibitors or fulvestrant plus/minus gonadotropin-releasing hormone agonists) plus the CDK4/6 inhibitor palbociclib also outperformed chemotherapy as first-line treatment in patients with high-risk metastatic HR+ breast cancer with symptomatic visceral disease (Loibl S, et al. SABCS 2024; abstract SESS-3616). The combination of palbociclib and endocrine therapy resulted in a significantly longer median time to treatment failure at 17.2 versus 6.1 months with chemotherapy (HR, 0.46; 95% CI, 0.31-0.69). Endocrine therapy plus palbociclib versus chemotherapy also led to significant PFS improvement at 18.7 versus 7.8 months (HR, 0.45; 95% CI, 0.29-0.70). 

Sometimes insurance barriers, such as prior authorizations, prevent the immediate use of CDK4/6 inhibitors plus endocrine therapies, Dr. Raheem noted. In such cases, providers would start patients with chemotherapy in the presence of extensive, symptomatic visceral metastases and then switch to endocrine therapy once payment issues have resolved. Manufacturers sometimes offer a temporary supply of CDK4/6 inhibitors for free to bridge patients while awaiting insurance authorization, she added.


Dr. Raheem reported financial relationships with AstraZeneca and Eli Lilly. Dr. Ziegengeist reported no relevant financial disclosures.

This article is from the March 2025 print issue.