The HER2 subtype of breast cancer, defined by amplification of the HER2 gene, represents 20% to 25% of breast cancers, and this number is relatively consistent worldwide. When the HER2 gene is amplified, the number of HER2 receptors expressed in the cell increases. As shown in the upper left-hand corner of this slide, a normal cell or a breast cancer cell without the HER2 alteration typically expresses 20,000-50,000 receptors per cell-surface membrane. However, as shown in the center of this slide, HER2 amplification in a tumor cell results in a commensurate overexpression of the receptor and the expression of 2 million or more HER2 receptors per cell in some patients. In general, there is a 2 log increase in the number of receptors displayed on tumor cells when the HER2 alteration is present, which has several phenotypic consequences. Compared with a HER2-normal cell, a HER2-overexpressing cell: Has a significantly increased growth rate (as shown in the bottom right-hand corner of this slide) Has a significantly increased ability to form tumors in experimental mice Displays an increased ability to form metastatic deposits in animal models owing to an increase in cellular motility Begins to secrete high levels of vascular endothelial growth factor (VEGF) to support metastatic growth When making therapeutic decisions, it is important to keep in mind that HER2-overexpressing cells are frequently estrogen receptor and progesterone receptor positive, like in the case patient’s tumor. Although estrogen receptor– and progesterone receptor–positive breast cancers are likely responsive to hormonal therapy, response rates decrease significantly with hormonal therapy alone when the HER2 alteration is present. 1. Rowinsky. Annu Rev Med . 2004;55:433. 2 . Slamon et al. Science . 1987;235:177. 3. Pegram et al. Cancer Treat Res . 2000;103:57.
Women with breast cancer cells harboring the HER2 amplification and the associated pathologic overexpression of the HER2 receptor have a much shorter survival. The data on this slide were among the first to show that HER2-positive tumors behave differently clinically.
EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor. This slide summarizes some of the targeted agents currently being evaluated in clinical trials for HER2-positive metastatic breast cancer. The treatment of HER2-positive breast cancer has gone from a very effective, heavily used agent to a number of agents that target HER2, as well as rational combinations of agents based on other molecular changes that occur in HER2-positive tumors that may mediate resistance. Treatment of this disease has gone from having very few treatment options to now having among the most treatment options, and outcome data will likely continue to improve with further use of these various HER2-targeting combinations, as well as anti-HER2 therapy, with therapies directed at other pathways that facilitate the growth of these tumors.
EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor. There are 2 approved HER2-targeting agents: trastuzumab, a monoclonal antibody, and lapatinib, a small-molecule tyrosine kinase inhibitor. Trastuzumab was the first to be described and the first approved. It binds to the extracellular, juxtamembrane domain of the HER2 receptor. Upon binding, trastuzumab prevents the dimerized receptor from transmitting an effective signal, thereby inhibiting or reversing some of the phenotypic consequences of HER2 overexpression previously discussed: cellular proliferation, motility, increase in VEGF levels, and issues of hormone resistance. The binding of trastuzumab to HER2 also contributes to apoptosis and potentiates the effects of chemotherapy. In addition to these intracellular effects, trastuzumab may also have an extracellular effect in mediating antibody-dependent immune recognition. However, there are no overt clinical data suggesting that this mechanism is operating, because it is difficult to demonstrate in clinical cases. Although the precise biological mechanisms of trastuzumab may still be uncertain, the clinical observations are clear: The antibody results in less aggressive behavior and a change in the biologic activity back toward a cell that is HER2 normal. A better understanding of the mechanisms of action of trastuzumab has led to rationally designed clinical trials and improved treatments that target HER2.
MBC, metastatic breast cancer. Lapatinib is a small-molecule inhibitor of the intracellular tyrosine kinase domain of the HER2 receptor, as well as the HER1 or epidermal growth factor receptor. Currently, lapatinib is indicated in combination with capecitabine for the treatment of patients with HER2-positive advanced or metastatic breast cancer only after progression on previous therapy including trastuzumab, an anthracycline, and a taxane.
In terms of the combination of lapatinib and trastuzumab and using dual targeting of the extracellular and intracellular portions of the HER2 receptor, interesting preclinical data have been presented by Konecny and colleagues. The initial study showed that lapatinib plus trastuzumab did not have additive effects in HER2-positive cells; rather, the combination was synergistic. This interaction has been confirmed by other groups, both in vitro and in vivo. These findings led to clinical trials evaluating the dual targeting combination.
Mohsin S, et al. J Clin Oncol 2005;23:2460-2468
Her2 in breast cancer, New directions in the treatment
NEW DIRECTIONS IN THE TREATMENT OF BREASTCANCERHER2 IN BREAST CANCER DR IMRANA TANVIR
What is a biomarker?Biomarkersanatomical, physiological, biochemical or molecular parametersassociated with the presence and severity of specific disease statesdetectable and measurable by a variety of methods including physicalexamination, laboratory assays and medical imaging
What is a useful biomarker?• A useful marker should meet two criteria • can be measured reproducibly by means of a reliable and widely available assay • conveys information about the disease that is meaningful to the physician and the patient
Potential uses for biomarkers inoncology Screen for disease Distinguish between Assess risk of benign versus developing malignant processes disease Biomarker including staging Monitor disease status before and after therapy Predict response to therapy Determine prognosis independent of therapy
Prognostic versus predictive: animportant distinction• Prognostic markers • indicate the likelihood of outcome (tumour recurrence or patient survival) regardless of the specific treatment the patient receives• Predictive markers • indicate the likelihood of response to a specific therapy
Molecular biomarkersGene expression microarray quantitative reverse transcription-polymerase chain reaction (RT- PCR)Gene amplification (FISH/CISH)Gene sequence DNA sequencingProtein expression Immunohistochemistry (IHC) Enzyme-linked immunosorbent assay (ELISA)IHC, FISH and ELISA are widely established in clinical pathology laboratories
HER2 testing in breast cancer• HER2-positive status has both prognostic and predictive value in breast cancer • shorter overall survival time • earlier relapse after adjuvant chemotherapy • required for response to Anti Her2 therapies
Molecular diagnostics in cancer: Current and Future 21st century (?) mRNA expression arrays 19th century 1980s 2000 Multiplex PCR ProteomicsTumour type Single-gene/protein predictors Multi-gene/protein predictorsHistologyPatient characteristics
The EGFR (erbB) family EGF NRG2 TGF-α No specific NRG3Ligands Heregulins Amphiregulin ligands Heregulins Receptor Extracellular domain Membrane Tyrosine Intracellular kinase K K K domain erbB1 erbB2 erbB3 erbB4 HER1 HER2 HER3 HER4 EGFR neu
HER2 Overexpression in Breast Cancer HER2 is overexpressed in ~ 25% of breast cancers Normal (1x) ~ 25,000-50,000 HER2 receptors Overexpressed HER2 (10-100x) up to ~ 2,000,000 HER2 receptorsPegram MD, et al. Cancer Treat Res. 2000;103:57-75.Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Excessive cellular divisionSlamon DJ, et al. Science. 1987;235:177-182.
HER2 Overexpression Shortens SurvivalHER2 oncogeneamplification HER2 oncoprotein overexpression Shortened survival Median Survival From First Diagnosis HER2 overexpressing 3 yrs HER2 normal
1.0 1.0 Herceptin + paclitaxel 0.8 Paclitaxel 0.8Probability of survival Probability of survival 0.6 0.6 0.4 0.4 0.2 0.2 40% 17.9 24.8 0 0 0 12 24 36 48 0 5 10 15 20 25 30 35 40 Months Months Simulation of effect of Herceptin in Herceptin combination pivotal trial: unscreened population overall survival (IHC 3+) MBC = metastatic breast cancer
Current assay of HER2/neu Immunohistochemistry‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive) Fluorescence in situ hybridization (FISH) HER2 gene no amplification HER2 gene amplification FISH negative FISH positive
Targeted Agents for HER2+ BreastCancer Trastuzumab Bevacizumab phase III VEGF T-DM1 phase III Sunitinib EGFR Pertuzumab phase II VEGFR HER2 phase III P P P P P P PI3-K P P Akt/PKB Lapatinib PTEN phase III Everolimus phase III mTOR Neratinib phase III 4E-BP1 S6K1 Gefitinib elF-4E phase II Protein synthesis Cell growth, proliferation, survival, metastasis, angiogenesis
Lapatinib Blocks Signaling ThroughMultiple Receptor Combinations Blocks signaling through 1+1 2+2 1+2 ErbB1 and ErbB2 homodimers and heterodimers Might also prevent signaling through heterodimers between these receptors and other ErbB family members Potentially blocks multiple ErbB signaling pathways Downstream signaling cascade Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment
Combining Lapatinib and Trastuzumab Increases Antitumor Activity 1600 Treatment with lapatinib plusTumor Volume (mm3) 1400 trastuzumab resulted in complete 1200 Control Trastuzumab tumor remission in mouse model 1000 Lapatinib 800 – Effect was durable: no tumor relapse * Trastuzumab + lapatinib 600 † observed at 8 mos after treatment * 400 †‡ † 200 § In vivo activity was consistent with in 0 13 16 19 21 23 vitro data demonstrating the Days After Injection combination as synergistic *P < .05; P < .01 vs control; ‡P < .05 vs trastuzumab; † § P < .01 vs both lapatinib and trastuzumab. Konecny and colleagues.
NEUADJUVANT THERAPY (NAT)Initially neuadjuvant therapy (NAT )was used for locally advanced tumors only. • As a result 10 yrs survival improved more than 25% • This survival rate varied with different therapies.
Currently, neoadjuvant therapy (NAT) is being used for earlier-stage operable breast carcinoma and likely to become standard of care.
Recently, a detailed review was conducted at the 2007 National Cancer Institute State of the Science meeting.“Preoperative Therapy in Invasive BreastCancer: Reviewing state of the science andexploring new research directions.”
NSABP Protocol B-18 have shown :• Neoadjuvant or adjuvant therapy gives identical results for: -loco-regional control -metastasis-free survival.
Advantages of neoadjuvant therapy• Increased eligibility for breast conservation.• The efficacy of systemic therapy can be assessed in vivo.• Tumor response provides important clinical information .• Allow more rapid assessment of new treatments.• Research linking tumor response is facilitated.
Preoperative Trastuzumab Single Agent Therapy Study Schema Tumor size Tumor size Baseline Week 3 Total patients = 35 Responses - Median decrease: 20% (0-60) H H H H - Partial response: 23% - Apoptosis: 35-47% -No change: EGFR and P-HER2 Bx Bx -Dec in p-MAPK BxBaseline Week 1 WeekMohsin S, et al. J Clin Oncol 2005;23:2460-2468
Pathological Complete Response Rates PCR (%) Eligibility HER2+ Disease Total Patients 11 Duration of Therapy 4 weeks Efficacy Percentage pCR 9 Partial Response 36 Minor Response 5Gennari R, et al. Clin Cancer Res 2004;10:5650–5
Patient Characteristics of 3 subgroups:chemotherapy alone Vs. Chemo + trastuzumab Buzdar A, et al. Clin Cancer Res. 2007;13:228-33 Age Race Stage of disease Nodal involvement Hormone receptor status Patient characteristics were similar
•NCI – Milan randomized trial NeO Adjuvant Herceptin - NOAH• ACOSOG Z1041• Robidoux A, Breast Cancer Res.Treat. 2006; 100, S147,abst. 3068
CONCLUSIONS• Her2 testing should be done for all invasive breast cancers.• Preoperative trastuzumab as single agent – significant antitumoral activity• Chemotherapy+ trastuzumab – Higher pCR rate – Favorable efficacy data (small studies) – Favorable cardiac safety