CDK4/6 and PI3K inhibitors: A new promise for patients with HER2‐positive breast cancer

Abstract

Background HER2‐positive (HER2+) breast cancer represents a heterogeneous breast cancer subtype, including both oestrogen receptor (ER) positive and negative tumours. A deeper understanding of the crosstalk between ER and HER2 receptor pathways has led to the development of treatment strategies consisting of a simultaneous blockade of both signalling pathways, as a reasonable approach to prevent the onset of mechanisms of resistance. Methods This review was based on the material searched on PubMed, MEDLINE and Embase databases and on conference proceedings from major oncology conferences up to 15 December 2020. The search strategy included the following keywords: ‘HER2‐positive breast cancer’, ‘CDK4‐6 inhibitors’ and ‘PI3K inhibitors’, and was adapted for use with different bibliographic databases. Results CDK4/6 and PI3K inhibitors are two classes of agents already approved in patients with hormone receptor positive, HER2‐negative breast cancer. Recently, promising data with their use have been also shown in HER2+ disease. Results from preclinical and clinical studies are shedding light on the role of these classes of agents in HER2+ breast cancer, and are paving the road for a forthcoming change in clinical practice. Conclusions Treatment landscape for HER2+ breast cancer is rapidly changing, and CDK4/6 and PI3K inhibitors represent a new promising strategy to improve patients’ outcomes.

Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors

“…It is also notable that CU-OP-20 with a PIK3CA mutation but not an FGFR3 mutation is also somewhat sensitive to the PI3K inhibitor, but not to the FGFR inhibitor at the low doses used herein. We, therefore, suggest that is possible that a higher sensitivity to a single dose of an inhibitor may mask the synergy obtained as sometimes noted previously [42]. However, the fact that by combining different inhibitors one can obtain synergy against relatively resistant cell lines such as CU-OP-2 and CU-OP-3, that also are both radioresistant [59] is encouraging for the pursuit of personalized medicine.…”

“…Notably, however, by combining 5 μM of PD-332991 with low doses of 0.5 and 1 μM of BYL719, gave for CU-OP-3 a remarkable decrease in the inhibition of viability and proliferation and could in fact be clinically useful, as for example as already initiated and shown for breast cancer [ 35 ]. However, despite the promises of using these drugs in combination, the safety of using these drugs alone or combined or in combination with endocrine therapies must also be accounted for and scrutinized on a molecular basis [ 42 , 43 , 44 ].…”

Impact of Age on Clinical Outcomes and Efficacy of Adjuvant Dual Anti-HER2 Targeted Therapy

“…However, these data highlight the need to further investigate the best adjuvant endocrine therapy in patients with HER2-positive and hormone receptor–positive breast cancer. Proper subgroup analyses according to age are important to be conducted in the upcoming adjuvant trials investigating targeted treatments in combination with endocrine therapy in the HER2-positive setting ( 24 ).…”

Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma

“…Many of the above, but not all, of the clinical trials are still ongoing, but it is impossible to distinguish any positive effects specifically for HPV + TSCC, BOTSCC, and OPSCC. Nevertheless, positive effects with prolonged progression-free survival with some of the above treatments have been documented for other types of solid tumors, such as for breast cancer, but there are also considerable side effects accompanying these treatments [ 116 , 117 , 136 , 137 , 138 , 139 , 140 ].…”

“…In metastatic breast cancer, to avoid rapid resistance development, PI3K inhibitors, anti HER2, PI3K, and CDK4/6 inhibitors are being used clinically in combination and also explored experimentally [ 136 , 141 ]. Consequently, to avoid some of these side effects, i.e., to be able to decrease the inhibitor doses and to avoid resistance development, some of these inhibitors have been combined.…”