HER2/neu Gene Determination in Women Screened for Breast Carcinoma: How Screening Programs Reduce the Skyrocketing Cost of Targeted Therapy

Discussion

We conclude that: i) only 11% of screen-detected breast carcinomas displayed HER2/neu gene amplification; ii) this represents a small proportion of more advanced disease-bearing patients selected for trastuzumab targeted therapy (up to 30% cases usually detected out of screening programs); iii) no significant differences were noted between the FDA and ASCO/CAP cut-offs; iv) the cost-effectiveness of HER2 testing and trastuzumab therapy in a patient with screen-detected breast cancer is more affordable than that detected at a population level; v) breast cancer screening could be used to help reduce the cost of use of trastuzumab targeted therapy in HER2-positive breast carcinoma. This economic evaluation has to be considered when evaluating the value, cost-effectiveness, strategies and final decisions on screening.

The HER2 immunophenotypical and HER2/neu genotypical status is required for the appropriate selection of post-surgical targeted therapies (2). Compared to original incidence of HER2-positive breast carcinomas detected at a population level (not detected at screening level) and in a metastatic setting (25-30% of cases), a lower incidence of HER-2 positivity has been observed in different cohorts of early breast cancer (8, 18). The lower incidence has also been justified in different ways, i.e. the restricted ASCO/CAP 2007 criteria used in a certain period of time, different level of internal and external quality assessment, and different kits of probes used. In the present study, we detected a low rate of breast carcinomas with 3+ HER2 immunoexpression (10%) and HER2/neu gene amplification (11%) in a cohort of screen-detected breast carcinomas. These findings significantly differ from the subset (ranging from 20 to 30% HER2-positive breast carcinoma) observed at an unselected population level (1, 6, 16). Our findings highlight how screening programs can help to reduce the cost of targeted therapy based on the fact that only a minor subset of screen-detected breast carcinomas exhibit HER-2-positive expression. It is hypothesised that intensified screening for breast cancer may detect a larger proportion of slowly growing HER2-negative tumours with a longer lead-time than for other tumour types. HER2-positive tumours are under-represented in the screen-detected patient group (18), thus screening is likely to partly explain the different incidence of prognostic and predictive biological markers (19) and molecular subtype distribution of screen-detected breast cancer differs from that of carcinomas found outside of screening and accounts in part for the better outcome of screen-detected cancers. Screen-detected carcinomas are more likely to be smaller in size and well- differentiated (pT1a), with less involvement of regional lymph nodes and the survival benefit has been attributed to the stage shift. Notably, several studies have shown that screen detection remains an independent prognostic factor after adjusting for disease stage (19).

Our group recently evaluated the HER2 status in a series of consecutive ductal breast carcinomas by using the FDA and ASCO/CAP scoring systems (8). We showed that the FDA and ASCO/CAP schemes for HER2 evaluation selected patients differently for trastuzumab therapy and that the ASCO/CAP scheme has a great concordance co-efficient between strong 3+ immunohistochemical cases and cases with high-grade, granular HER-2/neu amplification. Similarly, in the series reported in our study, we recorded a good concordance between the subset of breast carcinoma characterized as 3+ by immmunohistochemical analysis and with gene amplification by fluorescence in situ hybridization analysis. At a population level, discrepancy between breast carcinoma with 3+ immunoscore and gene amplification may be observed, although rarely after ASCO/CAP criteria corrections. Moreover, we previously evaluated the intratumoural heterogeneity of ductal breast carcinomas with HER2/neu amplification scored by ASCO/CAP criteria, and 3+ immunoexpression and showed that the routine assessment of HER2/neu amplification on whole-tissue sections is not significantly confounded by intra-tumoural heterogeneity in breast cancer with high-grade amplification (14). In the screen-detected breast carcinomas reported here, heterogeneity of HER2/neu status is an infrequent event. The use of multicore tissue microarrays may be an efficient approach in the study of heterogeneity, and it has also been proposed for routine HER2 assessment (20).

Affordability of personalised healthcare is limited by the high costs of currently available targeted therapy drugs. There is a worldwide need for detecting breast cancer at its earliest stages and access to screening and diagnostic medical equipment need to be increased in order to reduce the overall cost of breast cancer management. Bleyer et al. recently reported that despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer and although they were not certain which women were affected, the imbalance suggested that there was substantial overdiagnosis, accounting for nearly a third of all newly-diagnosed breast carcinomas, and that screening is having, at best, only a small effect on the rate of death from breast cancer (21). Adjuvant trastuzumab increases life expectancy by 1.54 (1.18 discounted) quality-adjusted life-years (QALYs) (22). The cost-effectiveness of HER2 testing and the addition of one year adjuvant trastuzumab after adjuvant chemotherapy from a societal perspective have been evaluated in different settings (22-25). Liberato et al. reported that at a cost of 675€ and $767 per weekly dose in the Italian and US settings, respectively, trastuzumab achieves its clinical benefit at a cost of 14,861€ (95% confidence interval, 3,917€ to 44,028€) and $18,970 (95% CI=$6,014 to $45,621) per QALY saved (26). The incremental cost effectiveness was higher than 50,000€/QALY (or $60,000 /QALY) for time perspectives shorter than 7.8 years and for patients older than 76 years, or with a 10-year risk of relapse lower than 15%. Their results confirmed the cost effectiveness when simulating a Herceptin Adjuvant Trial (HERA)-like scenario at a multiway sensitivity analysis and concluded that from the long-term perspective, adjuvant trastuzumab is a cost-effective therapy for patients with HER2-positive, high-risk, early breast cancer (23, 25). Again, Hedden et al. evaluated the cost-effectiveness of the currently recommended 12-month adjuvant protocol of trastuzumab using a Markov modeling approach and real-world cost data (27). In the base case analysis, treatment with a 12-month adjuvant trastuzumab regimen resulted in a gain of 1.38 QUALYs or 1.17 LYG at a cost of $18,133 per patient. Thus, the cost per QALY gained for the base case is $13,095 and that per LYG was $15,492 (27). They concluded that over the long term, treatment of HER-2/neu mutation-positive breast cancer with a 12-month protocol of trastuzumab in the adjuvant setting is predicted to be cost-effective in the Canadian context. Similar findings were obtained in different cohort of patients (28-32).

Dendukuri et al. showed that the strategy with the best cost-effectiveness ratio for HER2 testing is to screen all breast cancer patients by immunohistochemistry and to confirm 2+ and 3+ scores with fluorescence in situ hybridization (33). At the technical level, in addition to improving specificity, this approach could lead to major cost savings in treatment with trastuzumab. In a screen-detected setting of breast carcinoma, the decreasing incidence of HER2-positive breast carcinoma again acquires less restriction in performing the double (immunohisotchemical and fluorescence in situ hybridization analyses) approach for 2+ and 3+ tumours. Again, the spectrum of saving money per one year's worth of trastuzumab therapy significantly decreases from 20-30% to 10-11% for patients with HER2-positive breast carcinoma (675€ and $767 per weekly dose in the Italian and US setting, respectively, per patient), when comparing the population versus the screen-detected cohorts of patients, respectively. Moreover, at the screening level, most carcinomas detected are usually of stage pT1 (around 80%) and this indicator is the determinant for the efficacy of the end-point of screening; in contrast at the population level patients affected by pT1 carcinomas are more infrequent. These aforementioned indicators and their cross-sectional representation of more pT1 cancers and fewer HER2-positive breast carcinomas, demonstrate the potential of screening detection of HER2-positive breast cancer for the dramatical reduction of the otherwise high costs of targeted therapy.

In conclusion, the evaluation of HER2 expression in a series of screen-detected breast carcinomas helped to identify a relatively small subset of patients with HER2-positive carcinoma suitable for trastuzumab therapy. This revealed a greater affordability and cost-effectiveness for the use of targeted therapies, even in light of the current high cost of such therapy.

Assessing the impact of a targeted intervention on costs and health outcomes requires explicit consideration of the method of targeting. In this study, we report on the low incidence of HER2-positive breast carcinoma detected at the screening level and highlight how the screening programs can help to reduce the cost of anti-HER2 targeted therapy with trastuzumab or anti-HER2 inhibitors.