Targeting the HER/EGFR/ErbB family to prevent breast cancer

Abstract

Preventing breast cancer is possible with selective estrogen receptor (ER) modulators and aromatase inhibitors, which reduce the risk of invasive disease by up to 65% (up to 73% for ER-positive and no effect for ER-negative cancer) and the risk of preinvasive disease [ductal carcinoma in situ (DCIS)] by up to 50%. Clearly, approaches for preventing ER-negative, and increased prevention of ER-positive breast cancers would benefit public health. A growing body of work (including recent preclinical and clinical data) support targeting the HER family [epidermal growth factor receptor (EGFR), or human epidermal growth factor receptor (HER) 1 or ErbB1) and HER2, HER3, and HER4] for preventing ER-negative and possibly ER-positive breast cancer. Preclinical studies of HER family-targeting drugs in mammary neoplasia show suppression of (i) ER-negative tumors in HER2-overexpressing mouse strains, (ii) ER-negative tumors in mutant Brca1/p53(+/-) mice, and (iii) ER-positive tumors in the methylnitrosourea (MNU) rat model; tumors arising in both the MNU and mutant Brca1/p53(+/-) models lack HER2 overexpression. Clinical trials include a recent placebo-controlled phase IIb presurgical trial of the dual EGFR HER2 inhibitor lapatinib that suppressed growth of breast premalignancy [including atypical ductal hyperplasia (ADH) and DCIS] and invasive cancer in patients with early-stage, HER2-overexpressing or -amplified breast cancer. These results suggest that lapatinib can clinically suppress the progression of ADH and DCIS to invasive breast cancer, an effect previously observed in a mouse model of HER2-overexpressing, ER-negative mammary cancer. The preclinical and clinical signals provide a compelling rationale for testing HER-targeting drugs for breast cancer prevention in women at moderate-to-high risk, leading perhaps to combinations that prevent ER-negative and ER-positive breast cancer.

Figure 1

HER-family targeting for breast cancer prevention. A, potential clinical preventive applications of lapatinib (along with known applications of trastuzumab, SERMs, and AIs). The major circle segments reflect HER2-positive cancer (violet; ~20% of total disease) and HER2-negative cancer (sky blue; ~80% of total disease). Divisions within segments reflect the rough proportions of HR (ER, PR)-positive and -negative disease, which, respectively, are 50%/50% in HER2-positive cancer and 75%/25% in HER2-negative cancer (the rough proportions in all cancers are 70% HR-positive and 30% HR-negative). Doubled blocking lines indicate settings of greater HER-targeting drug effect. B, signaling pathways involved in HER-targeting agent effects. MAPKs, mitogen-activated protein kinases; JNK, c-JUN N-terminal kinase; mTOR, mammalian target of rapamycin; S6K, p70 S6 ribosomal kinase; 4EBP1, 4E-binding protein 1; TF, tissue factor.

Figure 1

HER-family targeting for breast cancer prevention. A, potential clinical preventive applications of lapatinib (along with known applications of trastuzumab, SERMs, and AIs). The major circle segments reflect HER2-positive cancer (violet; ~20% of total disease) and HER2-negative cancer (sky blue; ~80% of total disease). Divisions within segments reflect the rough proportions of HR (ER, PR)-positive and -negative disease, which, respectively, are 50%/50% in HER2-positive cancer and 75%/25% in HER2-negative cancer (the rough proportions in all cancers are 70% HR-positive and 30% HR-negative). Doubled blocking lines indicate settings of greater HER-targeting drug effect. B, signaling pathways involved in HER-targeting agent effects. MAPKs, mitogen-activated protein kinases; JNK, c-JUN N-terminal kinase; mTOR, mammalian target of rapamycin; S6K, p70 S6 ribosomal kinase; 4EBP1, 4E-binding protein 1; TF, tissue factor.