An emerging focus is aligning targeted, safe, and effective therapies with patient goals.
Although treatment outcomes for patients with breast cancer have improved in recent years, data have shown that 1 in 8 women is likely to develop breast cancer in their lifetime.1 In 2021 alone, the United States recorded 281,550 new cases of invasive breast cancer, 49,290 new cases of noninvasive breast cancer, and 43,600 deaths from the disease.2 Currently, the evolving treatment approaches center on manipulating and targeting each tumor’s molecular identity to effectively treat the disease.
With the use of more sensitive screening protocols and sophisticated molecular testing, survival rates of patients with breast cancer are favorable. When breast cancer is localized, survival rates can approach 99%; when the cancer is regional (eg, metastasis to neighboring/surrounding tissues), survival rates are approximately 86%.3
However, when cancer metastasizes to the lung, liver, bone, or brain, survival rates for patients with breast cancer drop to 28%. For this reason, early detection, prompt treatment, individualized therapy, and more tolerable and effective regimens are crucial to improve patient outcomes.3
The majority (approximately 72%) of breast cancers are hormone sensitive (hormone receptor [HR]+/HER2-).4 The second most common subtype (approxi- mately 13%) is aggressive triple-negative breast cancer (TNBC, or HR-/HER2-), followed by hormone-sensitive/HER2- sensitive breast cancer (HR+/HER2+) at approximately 10%, and HR-/HER2+ breast cancer at 5%.4
When directing next steps in a treatment plan, staging is often the most important factor. Once oncologists determine the stage and main genotype, the clinical team will work collaboratively with the patient to decide the best treatment strategy.
Breast Cancer Treatment
Clinicians use a few core therapies alone or, for greater efficacy, in combination with another therapy for breast cancer treatment (See Table 14); Table 24 provides further examples of breast cancer thera- pies used for treatment.
Patients with early-stage breast cancer (stages 0, I, II, or III) generally undergo primary surgery followed by adjuvant treatment. When the cancer is late, advanced, or metastatic at stage IV, surgical interventions are usually not an option and medication therapy is the mainstay.
Molecular targets and potential future changes for combatting breast cancer are as follows:
• HR—Recent studies found that when started early, HR regimens can be as effective as traditional chemotherapy options and minimize adverse events.5
• HER2—The success of trastuzumab (Herceptin; Genentech USA, Inc) and pertuzumab (Perjeta; Genentech USA, Inc) has sparked interest in exploiting HER2 as a target. Recently, the FDA approved margetuximab-cmkb (Margenza; MacroGenics, Inc), which may be effective for select patients as well.6 Additionally, cytotoxic drug conjugates have made significant progress, with more agents undergoing clinical trials.
• PD-1/PD-L1—The immunotherapy space, including investiga- tion into the PD-1/PD-L1 pathway, is exploding due to findings that it may deter or treat brain metastases.7
• PARP—Mutations such as BRCA1/2 and PALB2 have been identified as PARP inhibitor targets, especially in the treat- ment of metastatic TNBC.8
• Cyclin-dependent kinase 4 and 6 (CDK4/6)—More research efforts are combining CDK4/6 agents with endo- crine therapies in metastatic HR+ breast cancers, which may enable patients to avoid traditional chemotherapy if proven effective.9
• Tyrosine kinase inhibitors (TKIs)—Oral medications such as tucatinib (Tukysa; Seagen Inc), lapatinib (Tykerb; Novartis Pharmaceuticals Corporation), neratinib (Nerlynx; Puma Biotechnology, Inc), and newly developed TKIs may protect against brain metastases and have a role in HER2+ meta- static breast cancer treatment.10
• PI3K—Alpelisib (Piqray; Novartis Pharmaceuticals Corpora- tion) has shown promise in the SOLAR-1 (NCT02437318)11 and BYLieve (NCT03056755)12 clinical trials and may benefit patients with PIK3CA-mutated tumors or HR+ metastatic breast cancer.
• VEGF-A—Antiangiogenesis drugs such as bevacizumab (Avastin; Genentech USA, Inc) have returned to clinical trials combined with chemotherapy/immunotherapy, which may have potential in the treatment of metastatic HR+ breast cancer.13
• HDAC (histone deacetylase)—Entinostat and tucidinostat are both in clinical trials for various cancers. Tucidinostat is also currently recruiting for a phase 2 clinical trial for metastatic HR+ breast cancer treatment.14
• TROP2 (tumor-associated calcium signal transducer 2)—The FDA approved sacituzumab govitecan-hziy (Trodelvy; Gilead Sciences, Inc) in 2021 for the treatment of metastatic disease in TNBC; currently, more agents in this novel class are being developed, studied, and assessed.15
Chemotherapy often has off-target effects due to its cytotoxic nature, but it still has a place in treatment as a monotherapy or in a combination treatment. Moving forward, investigators are formulating chemotherapy in more tolerable, convenient, and effective vehicles such as oral dosage forms or drug-antibody conjugates with targeted payload deliveries that exhibit less off-target effects.
During the clinical decision-making process around treatments, breast cancer subtypes have a direct impact on therapy options. Table 3 summarizes treatment approaches for the common HR+/ HER2- subtype.4
Most breast cancer is hormone sensitive, which implies that both the estrogen receptor and progesterone receptor can be targeted to inhibit tumor growth.
Additionally, shifting from traditional chemotherapy to a more effective targeted endocrine therapy, especially when resistance to endocrine therapy develops, can have a significant impact. Comparative research, early detection, and an optimized medication repertoire may make this shift a possibility soon. Regardless, results from the TAILORx trial (NCT00310180) and guidance from the National Comprehensive Cancer Network support the integration of chemotherapy and endocrine treatment when recurrence potential is high.16
Patients with both the HR+ subtype and HER2+ subtype (triple positive) can receive all the endocrine therapy options shown in Table 3; these patients can also receive all chemotherapeutic options in addition to HER2+ guided treatment plans.4 In Table 4, treatment approaches for the HER2+ subtype are included.4
In HR+/HER2+ patients, trastuzumab can be combined with fulvestrant or aromatase inhibitors (AIs) with or without lapatinib, and AIs can be used with lapatinib and without trastuzumab. However, endocrine therapy is not indicated for HR- subtypes.
Cancers that lack estrogen receptor, progesterone receptor, or HER2 are difficult. Because TNBC lacks targets, the most effective treatments for early and late stage are identical to options found in Table 3.4 In any stage, clinicians may use adjunctive therapy options, such as atezolizumab (Tecentriq; Genentech USA, Inc) with albumin-bound paclitaxel (with PD-L1 expression), pembrolizumab (Keytruda; Merck Sharp & Dohme Corp; with PD-1 expression), platinums, capecitabine, or sacituzumab govitecan-hziy.15,17,18
The growing trend is targeted, safe, and effective therapy that aligns with the patient’s goals. Currently, there are unmet needs for therapy options that target HER2, for antibody-drug conjugates, and for more advanced-stage therapies for those with TNBC. However, it seems likely that in the future, we can expect to see more effective oral therapy options for HER+ cases.
Today, research is primarily focusing on reducing progression, propagation, and treatment-resistant genotypes; however, clinicians should remain open to the de-escalation of chemotherapy and/or invasive surgical procedures because other options may be as effective or superior.
Robert Mownn, PharmD, is a pharmacist and sterile products coordinator at St Vincent’s Medical Center in Bridgeport, Connecticut. He is a graduate of
the University of Connecticut’s School of Pharmacy.