- Dr. Mark Pegram
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
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Special Issue Introduction
According to the World Health Organization (WHO), cancer is the first or second leading cause of death under 70 years in 112 of 183 countries, and in a further 23 countries, it ranks third or fourth. In 2020, breast cancer was the most commonly diagnosed cancer in women, with 2,261,419 breast cancer cases diagnosed worldwide, and was the leading cause of cancer mortality in women -- 684,996 deaths. These are prominent improvements in early detection and significant improvements in systemic adjuvant (and neoadjuvant) therapeutic approaches, including endocrine therapy for hormone receptor (HR) positive breast cancers (about 75% of all breast cancers), chemotherapeutic approaches, as well as molecularly-targeted therapeutics, particularly those targeting human epidermal growth factor receptor-2 (HER2) – HER2+ breast cancer accounting for about 15%-20% of all newly diagnosed breast cancers. A major barrier to improving clinical outcomes in breast cancer is drug resistance. Drug resistance in breast cancer can be either de novo or acquired following selection pressure from drug treatment. The discovery of the activity of CDK 4 and CDK6 inhibition against HR+ breast cancer has been a significant therapeutic advance. Numerous mechanisms of drug resistance have been proposed, including retinoblastoma gene mutation, increased CDK2 activity, activation of FGF/FGFR1 signaling, basal-like intrinsic breast cancer phenotype, YAP (yes-associated protein-1) activation via the Hippo pathway, and sequestration of CDK4/6 inhibitors into tumor cell lysosomes. In HER2+ breast cancer, the advent of HER2-directed antibody-drug conjugates (ADCs) has revolutionized treatment, with improvements in both progression-free and overall survival in metastatic diseases and invasive disease-free survival in patients with residual disease following neoadjuvant HER2-targeted therapy[9,10]. Recently, Tsui and colleagues used CRISPR-Cas9 screens to identify genes that control the toxicity of ADCs. Their results demonstrate critical roles for a range of known and novel endolysosomal trafficking regulators in ADC toxicity. In particular, they identified and characterized C18orf8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Finally, triple-negative breast cancer (TNBC), accounting for ~15% of all breast cancers, lacks the classical therapeutic targets of steroid hormone receptors and HER2. Therefore, chemotherapy remains a mainstay of treatment. Mechanisms of chemotherapy resistance in TNBC have been characterized previously. However, at present, significant efforts are underway to integrate immunotherapeutic approaches with PD-(L)1 checkpoint antibodies, along with chemotherapy, as a treatment for TNBC[13,14]. In melanoma and non-small cell lung cancer, a myriad of mechanisms have been offered to explain clinical resistance to immune checkpoint therapeutic antibodies, but the phenomenon of resistance to immune checkpoint inhibition in breast cancer is less well studied. In this special issue of Cancer Drug Resistance, we will discuss the molecular mechanisms of targeted therapy resistance in breast cancers. It is hoped that this issue will suggest future opportunities to overcome targeted therapy resistance in breast cancer, leading ultimately to the goal of eradicating the disease.
1. Bray F, Laversanne M, Weiderpass E, Soerjomataram I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer, Published online 4 June 2021.
2. Sung, H, Ferlay, J, Siegel, RL, Laversanne, M, Soerjomataram, I, Jemal, A, Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209- 249.
3. O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, André F, Loibl S, Loi S, Garcia-Murillas I, Cristofanilli M, Huang Bartlett C, Turner NC. The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov 2018;8:1390-1403.
4. Pandey K, Park N, Park KS, Hur J, Cho YB, Kang M, An HJ, Kim S, Hwang S, Moon YW. Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence. Cancers (Basel) 2020;12:3566.
5. Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun 2019;10:1373.
6. Prat A, Chaudhury A, Solovieff N, et al. Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA Phase III studies. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract GS1-04.
7. Li Z, Razavi P, Li Q, Toy W, Liu B, Ping C, Hsieh W, Sanchez-Vega F, Brown DN, Da Cruz Paula AF, Morris L, Selenica P, Eichenberger E, Shen R, Schultz N, Rosen N, Scaltriti M, Brogi E, Baselga J, Reis-Filho JS, Chandarlapaty S. Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway. Cancer Cell 2018;34:893-905.e8.
8. Fassl A, Brain C, Abu-Remaileh M, Stukan I, Butter D, Stepien P, Feit AS, Bergholz J, Michowski W, Otto T, Sheng Q, Loo A, Michael W, Tiedt R, DeAngelis C, Schiff R, Jiang B, Jovanovic B, Nowak K, Ericsson M, Cameron M, Gray N, Dillon D, Zhao JJ, Sabatini DM, Jeselsohn R, Brown M, Polyak K, Sicinski P. Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Sci Adv 2020;6:eabb2210.
9. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-91.
10. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019;380:617-628.
11. Tsui CK, Barfield RM, Fischer CR, Morgens DW, Li A, Smith BAH, Gray MA, Bertozzi CR, Rabuka D, Bassik MC. CRISPR-Cas9 screens identify regulators of antibody-drug conjugate toxicity. Nat Chem Biol 2019;15:949-958.
12. Echeverria GV, Ge Z, Seth S, Zhang X, Jeter-Jones S, Zhou X, Cai S, Tu Y, McCoy A, Peoples M, Sun Y, Qiu H, Chang Q, Bristow C, Carugo A, Shao J, Ma X, Harris A, Mundi P, Lau R, Ramamoorthy V, Wu Y, Alvarez MJ, Califano A, Moulder SL, Symmans WF, Marszalek JR, Heffernan TP, Chang JT, Piwnica-Worms H. Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci Transl Med 2019;11:eaav0936.
13. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 2018;379:2108-2121.
14. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817-1828.
Submission Deadline28 Feb 2022