How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story

Abstract

CDK4/6 inhibitors in association with endocrine therapy represent the best therapeutic choice for either endocrine-sensitive or resistant hormone-receptor-positive advanced breast cancer patients. On the contrary, the optimal therapeutic strategy after the failure of CDK4/6 inhibitors-based treatment still remains an open question worldwide. In this review, we analyze the most studied mechanisms of resistance to CDK4/6 inhibitors treatment, as well as the most significant results of retrospective and prospective trials in the setting of progression after CDK4/6 inhibitors, to provide the reader a comprehensive overview from both a preclinical and especially a clinical perspective. In our opinion, an approach based on a deeper knowledge of resistance mechanisms to CDK4/6 inhibitors, but also on a careful analysis of what is done in clinical practice, can lead to a better definition of prospective randomized trials, to implement a personalized sequence approach, based on molecular analyses.

Edaravone: A Novel Possible Drug for Cancer Treatment?

“…Targeted therapy aims to deliver drugs to specific genes or proteins that are found only in cancerous cells or in the tissue microenvironment that is driving tumor growth. It is often used in combination with other types of cancer treatment, such as chemotherapy [13,21,71]. Targeted therapy involves developing drugs that inhibit cancer proliferation, promote cell cycle regulation, induce apoptosis or autophagy, or deliver harmful substances only to cancer cells to eliminate them [72].…”

“…Despite various screening programs aimed at reducing tumor incidence, numerous cancer cases are diagnosed at advanced stages, making surgical removal impossible. Current cancer therapies face several challenges related to their selectivity, specificity, complexity, side effects, and most importantly, drug resistance [12,13]. Considering these factors, it is crucial to continue making ongoing efforts to reassess therapeutic approaches and develop more efficient cancer medications that can overcome these existing obstacles [14].…”

Filling the Gap after CDK4/6 Inhibitors: Novel Endocrine and Biologic Treatment Options for Metastatic Hormone Receptor Positive Breast Cancer

“…The continuation of CDK4/6 inhibitor beyond progression remains controversial given the conflicting data discussed above [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. This approach is not standard clinical practice and the mentioned research studies are likely to provide more information about the efficacy of this approach and on patient selection.…”

“…PFS on first line CDK4/6 inhibitor ranges from 2–3 years; however, the median OS of about five years suggests limited efficacy of subsequent anti-cancer treatments. For instance, several recent trials have shown that fulvestrant achieves a median PFS of 2–3 months after progression to CDK4/6 inhibitors, warranting the development of better treatment strategies to extend the endocrine treatment window before moving to cytotoxic chemotherapy [ 19 , 20 , 21 ] Importantly, in the past few years, the mechanisms of resistance to CDK4/6 inhibitors and endocrine therapy are starting to be unraveled, allowing for an expansion in the pipeline of effective agents in this setting [ 22 , 23 ]. Multiple randomized phase 2 and 3 trials have recently reported positive results, leading to significant changes in treatment algorithms for HR-positive MBC.…”

Navigating next-generation HR+/HER2− metastatic breast cancer therapies: a critical commentary on abemaciclib vs. tucidinostat after palbociclib progression

“…Following ET + CDK4/6i progression, limited data compared standard treatments with chemotherapy ( Figure 2 ). Cogliati et al reviewed these experiences and concluded that continuing CDK4/6i or switching to another CDK4/6i can remain effective post-progression ( 22 ). Additionally, ‘chemotherapy-like’ treatments like antibody-drug conjugates (ADCs) such as trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) expand treatment options for HR-resistant and HER2 − low/negative MBC ( 23 , 24 ).…”