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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Fulvestrant (FaslodexTM) is a synthetic steroidal ER antagonist developed by AstraZeneca (Figure 8.11) for use in ER+ve metastatic breast cancer in postmenopausal women with disease progression following previous antiestrogen therapy, and was the first molecule of its type to be approved. It is also used in combination with palbociclib in HR+ve/HER2-ve advanced breast cancer in women with disease progression after endocrine therapy. Fulvestrant has also been evaluated in the clinic for use in endometrial cancer but development was halted in 2016 for this indication.
Hormone Receptors and Endocrine Therapy in Breast Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Nancy E. Davidson
Encouraged with the results in the metastatic setting, a CDK inhibitor in combination with endocrine therapy is currently studied in adjuvant and neoadjuvant settings. Palbociclib collaborative adjuvant study is a randomized phase III trial of palbociclib with adjuvant endocrine therapy compared to endocrine therapy alone for HR+/HER2-early breast cancer (PALLAS; NCT02513394 at clinicaltrials.gov). Ribociclib plus adjuvant endocrine therapy is being tested in a phase III, randomized, double-blind, placebo-controlled clinical trial in patients with HR+, HER2-, and high-risk breast cancer (EarLEE-1; NCT03078751). MonarchE is a randomized, open-label, phase III study of abemaciclib in combination with standard adjuvant endocrine therapy versus endocrine therapy alone in patients with high risk, node-positive, early stage, HR+/HER2-breast cancer (NCT03155997). However, in a recent preplanned interim analysis, the PALLAS trial did not demonstrate a significant improvement in the primary endpoint endpoint of invasive disease-free survival.
Breast Surgery
Published in Tjun Tang, Elizabeth O'Riordan, Stewart Walsh, Cracking the Intercollegiate General Surgery FRCS Viva, 2020
Gaural Patel, Lucy Kate Satherley, Animesh JK Patel, Georgina SA Phillips
What other drugs are being developed to treat breast cancer?CDK4/6 inhibitors (e.g. palbociclib, ribociclib, abemaciclib) disrupt cancer cell growth by inhibiting CDK4 and CDK6, which are enzymes involved in cell division. Adverse effects include neutropenia, infections, fatigue and GI toxicity. They have been recommended by NICE in combination with an aromatase inhibitor for locally advanced or metastatic ER+, HER2 –ve cancers and are being evaluated in combination with fulvestrant for women who have had previous endocrine therapy.PARP inhibitors – targeted therapy for BRCA gene carriers (HER2 –ve)Bevacizumab (Avastin): This antiangiogenic monoclonal antibody inhibits vascular endothelial growth factor A (VEGF-A).It slows progression of metastatic disease but has no effect on overall survival or quality of life, and has significant side effects including hypertension.It is not recommended by NICE for metastatic breast cancer.It can be prescribed off licence via the Cancer Drugs Fund for triple-negative recurrent tumours and cancers which have progressed despite prior taxane treatment.Trastuzumab emtansine (Kadcyla): Recurrent HER2 +ve cancers, given with a taxane.NeuVax: This is a combination of a synthetic derivative of HER2 peptide and GMCSF which targets CD4 T cells to HER2-overexpressing cells.Phase 3 clinical trials are ongoing.Serum HER2 levels can be used to monitor response to treatment.43PI3K/Akt/mTOR pathway has been implicated in trastuzumab resistance in HER2+ breast cancer. There are a number of trials of mTOR and Akt inhibitors ongoing.Several other novel therapies targeting cellular signalling proteins including PD-L1, tyrosine kinase and TGFβ R1 are currently being evaluated in clinical trials.
A retrospective, non-interventional study of breast cancer patients diagnosed with ER+/HER2 negative, locally advanced or metastatic breast cancer treated with palbociclib in Denmark
Published in Acta Oncologica, 2023
Rasmus Garly, Tobias Berg, Maj-Britt Jensen, Ann Knoop, Lone Volmer, Vesna Glavicic, Humma Khan, Peter Bo Poulsen, Jens Olsen, Iben Kümler
A limited number of real-world studies have investigated the efficacy of palbociclib. One study investigated the efficacy on 1324 patients from the US who initiated palbociclib and AI treatment as first-line therapy. Endocrine resistance was not reported. The study reported a median OS of 49.1 months (95% CI, 45.2–57.7) and a median PFS of 19.3 months (95% CI, 17.5–20.7) [22]. Another study included 165 advanced BC patients who were treated with palbociclib and endocrine therapy as first-line treatment. These patients had a median PFS of 24.2 months (95% CI, 18.9 – NA) and most (85.5%) of them received letrozole as the endocrine backbone [23]. A retrospective analysis of US electronic health records of 772 patients receiving palbociclib and letrozole in a first-line setting found a median PFS of 19.7 months (95% CI, 17.3–21.9) [24]. A different study included 233 patients with advanced BC who initiated treatment with palbociclib and letrozole as first-line therapy. A median PFS of 21.2 months (95% CI, 17.9-NA) was found [25]. A smaller study including 88 patients in a Scandinavian setting found a median PFS of 13.3 months (95% CI, 11.4–15.2) with 38.6% of the patients previously receiving multiple lines of endocrine therapy [26]. The outcomes of these real-world studies indicated a similar efficacy of first-line palbociclib treatment compared to our real-world study.
Review of cyclin-dependent kinase 4/6 inhibitors in the treatment of advanced or metastatic breast cancer
Published in Journal of Drug Assessment, 2021
Lakyn Husinka, Pamela H. Koerner, Rick T. Miller, William Trombatt
Adherence rates related to oncolytic agents is a challenge given the various types of cancers treated with oncolytic agents, the variable mechanisms of actions of oncolytic agents, the variations in administration and dosing, and the difficulty in measuring dose adjustments or held doses. Abemaciclib which is dosed continuously twice daily, no rest periods per cycle, had consistent adherence rates across all patient subgroups. Palbociclib and ribociclib both consist of dosing that includes three weeks of therapy followed by a week without medication. Patients on these medications experienced high adherence rates in the monotherapy and combination with hormone therapy subgroups. However, these rates decreased in the subgroups that included another oncolytic, potentially due to conflicting or varying dosing regimens being a challenge for some patients.
An evaluation of palbociclib as a breast cancer treatment option: a current update
Published in Expert Opinion on Pharmacotherapy, 2021
Gregory T. Gallanis, Ramon I. Pericas, Anna T. Riegel, Paula R. Pohlmann
Palbociclib is an effective, safe, and well-tolerated treatment for patients with HR+/HER2- metastatic breast cancer. Current clinical research is exploring the potential expansion of palbociclib use into new subtypes of breast cancer and earlier clinical stages, as well as in different sequences with existing approved therapies or in combination with experimental compounds. Anti-estrogen endocrine therapies for patients with metastatic HR+/HER2- breast cancer synergize with CDK4/6 inhibition owing to estrogen signaling biology (Figure 1). In HER2+ breast cancer, anti-HER2 therapy and CDK4/6 inhibition were shown to synergize in preclinical models, providing rationale for combining palbociclib with HER2-directed therapies such as anti-HER2 antibodies, receptor tyrosine kinase inhibitors and antibody-drug conjugates. In TNBC, combination treatment with enzalutamide provides hope for targeted therapy against the LAR subtype, which is AR+; however, cytotoxic chemotherapy and immune therapy rather than palbociclib remain the mainstay of treatment in metastatic TNBC. Interestingly, the novel intravenous CDK4/6 inhibitor trilaciclib is under evaluation in combination with cytotoxic chemotherapy for its potential effects in preventing chemotherapy-induced myelosuppression and its potential to alter the tumor-immune microenvironment, in addition to a potential impact on response rates and survival [61].