Epidemiology
GLOBOCAN 2018 reported an annual incidence of 1,022 new cases of breast cancer in Panama (23), of which 750 were treated at the ION and 135 were HER2+. These patients were classified into three clinical stages (based on primary therapeutic data from the ION) to determine their treatment algorithm: adjuvant stage (TNM classification from 0 to IIA); neoadjuvant stage (TNM IIB to IIIC); and metastatic stage (TNM IV). It was estimated that 33%, 44% and 23% patients are adjuvant, neoadjuvant and metastatic at diagnosis, respectively; based on the authors’ experience, while two thirds of the patients diagnosed in the adjuvant stage will require dual HER2 blockade. An estimated 60% of HER2+ patients may also present overexpression of hormone receptors (HR+).
Treatment algorithm
The adjuvant treatment algorithm is described in Fig. 1. Patients in this stage initially undergo surgery to remove the tumor, followed by a 3-month course of chemotherapy based on doxorubicin and cyclophosphamide. Taxane use was divided: 80% of patients received weekly paclitaxel and 20% received docetaxel every 3 weeks (Q3W). All patients receiving chemotherapy received 1 year of trastuzumab (18 cycles). HR+ patients also received endocrine therapy, consisting of anastrozole in 75% of cases and 25% of tamoxifen. Finally, 85% of adjuvant patients received 5 weeks of radiotherapy (Fig. 1).
The treatment algorithm for neoadjuvant patients is similar to the adjuvant stage. The main difference is that chemotherapy is administered before surgery and pertuzumab is used as targeted therapy concomitantly with trastuzumab; i.e., both treatments are administered for 4 cycles before surgery and patients complete the year of treatment with trastuzumab. Endocrine and radiotherapy regimens are administered as in the adjuvant stage (Fig. 2).
Finally, in the first line of treatment, metastatic patients receive 10 cycles of trastuzumab and chemotherapy based only on taxanes: 80% of cases receive docetaxel and the remaining 20% receive paclitaxel. Trastuzumab is contraindicated in about 8% of patients, and this cohort is given 9 cycles of capecitabine instead. In total, 70% of patients progress to a second line of treatment, consisting in 90% of cases of ado-trastuzumab emtansine (T‑DM1) for 8.5 cycles during the expected 6 months of treatment, and capecitabine or gemcitabine for an average of 7.5 cycles in the remaining 10% of patients. Overall, 57% of the patients who received a second line (i.e., 40% of total patients) would receive a third line of treatment with capecitabine, and 44% of those patients (i.e., 25% of total patients) would finally progress to a fourth line with gemcitabine. Finally, only 10% of patients in this stage receive endocrine therapy with exemestane or anastrozole for 1 year.
Clinical impact of current HER2+ breast cancer management
The average 5-year OS of a patient diagnosed with HER2+ breast cancer at the ION, independently of stage, is 69%. In terms of stages, the 45 patients in adjuvant stage had a 5-year OS of 89%, the 60 patients in neoadjuvant stage had an OS of 86%, while the 30 patients with metastatic disease had an expected 5-year OS of 18%.
Economic impact of current HER2+ breast cancer management
The annual budget for HER2+ breast cancer treatment at the ION for the 135 new patients detected annually was estimated at $6m. Estimated allocated budget by stage is $2m, $3m, and $1m for adjuvant, neoadjuvant and metastatic stages, respectively. Considering total expenditure per patient, the adjuvant stage cost $40,000 per patient, while the budget for the average neoadjuvant patient was $50,000 and $40,000 for metastatic patients.
Additionally, the ION paid, on average, an estimated $640 for each 5-year OS percentage point; estimated by stage, the ION paid $445, $580, and $2,230 for each percentage point in 5-year OS in adjuvant, neoadjuvant and metastatic disease, respectively. This measurement (willingness to pay, WTP) was estimated as the ratio of the average total cost per patient compared to the average 5-year OS. We estimated this same ratio (WTP) for each of the scenarios evaluated to compare the results with the current situation in the ION.
This assessment highlights the aggressiveness of metastatic disease, in which current cost per patient is low but the cost per 5-year OS was the highest: on average 4.3 times higher than the earlier stages.
Assessment of innovative targeted therapies
The following 4 innovative targeted therapies with 5 indications not currently used at the ION were assessed: pertuzumab, trastuzumab emtansine (T-DM1), lapatinib, and neratinib. As in the assessment of current management, secondary research and FDA product labels (22) were consulted to identify either OS data or hazard ratio, which were later extrapolated to 5-year OS.
Pertuzumab in combination with trastuzumab and a taxane is indicated in all 3 disease stages and currently used at the ION in patients in the neoadjuvant stage. One of the two indications assessed was an 18-cycle adjuvant treatment in patients at high risk of recurrence, defined as lymph node- positive or hormone receptor-negative cases (25). Given the patient definition in the algorithm used to assess current management, high risk was defined as hormone receptor-negative. The other indication assessed was first-line treatment in metastatic patients, where pertuzumab is given until disease progression or unacceptable toxicity, expected to be 22 months, equivalent to 31 cycles.
T-DM1 is already used in metastatic patients who previously received trastuzumab and a taxane. The new indication assessed in this study was adjuvant treatment in patients who received neoadjuvant treatment with trastuzumab and a taxane and did not achieve pathological complete response (pCR). It was assumed from real world data (26) that 39% of patients who received neoadjuvant treatment with trastuzumab, pertuzumab and a taxane would not achieve pCR and would be considered candidates for adjuvant treatment with T-DM1 for 14 cycles. The use of T-DM1 in an adjuvant indication has shown a reduction of 51% compared to the standard neoadjuvant use of trastuzumab in distant recurrence as the first invasive disease event and a hazard ratio of 0.7 for mortality compared to standard treatment with trastuzumab; as the study was not yet sufficiently mature to report OS, this hazard ratio value was used to estimate the 5-year OS of T-DM1, yielding a 5-year OS of 95.1% of patients in this indication (28).
Lapatinib is indicated in combination with capecitabine for patients who progress on trastuzumab and was assessed as a third line of treatment, i.e. after T-DM1. Seventy 250 mg tablets were estimated to cost $840 at a daily dose of 1,250 mg over 27 weeks.
Finally, neratinib is indicated after adjuvant treatment with trastuzumab in the adjuvant stage of disease. A cost of $6,525 for 180 tablets of 40 mg was assumed along with the administration of of 240 mg daily for 1 year.
Table 2 summarizes outcomes by stage: number of patients per indication, and clinical and economic impact of each molecule in each of the assessed stages. For example, the use of T-DM1 in the adjuvant indication would include 23 neoadjuvant patients with no pCR, resulting in an increase in 5-year OS to 86.0% from 85.6%, equivalent to an increase in OS of 0.4%. The cost per patient at this stage would increase by $16,000, with an annual budget impact of $0.8 million; nevertheless, since the impact of T-DM1 alone in an adjuvant indication has a 5-year OS of 95.1%, representing a relative increase of 2.3% compared to the 5-year OS of 93.0% currently obtained in the indication, an additional investment of $42,000 would be needed per patient.
It should be clarified that the impact of pertuzumab in the adjuvant stage is less than 1% because only 26% of the patients would be candidates for this treatment. If the impact on these patients alone is compared, the absolute and relative increase in 5-year OS would be 6.8% and 7.7% respectively, requiring an additional $63,000 per patient.
Table 2 Summary comparison of molecules
Molecules
|
Indication
|
Total number of annual patients
|
5-year OS Current/ Expected
|
Absolute / relative 5-year OS impact in stage
|
Impact in cost per patient in stage, $ thousand (%)
|
Total annual budget impact, $ million
|
Pertuzumab
|
Adjuvant
Metastatic
|
12a (26%)
30
|
89% / 90%
18% / 29%
|
1% / 1%
11% / 62%
|
+17 (43%)
+145 (360%)
|
+0.8
+4.5
|
T-DM1
|
Adjuvantb
|
23c (39%)
|
85.6% / 86.0%
|
0.4% / 0.5%
|
+19 (39%)
|
+1.0
|
Lapatinib
|
Metastatic
|
20
|
18% / 20%
|
2% / 10%
|
+9 (22%)
|
+0.3
|
Neratinib
|
Adjuvant
|
45
|
89% / 90%
|
1% / 1%
|
+60 (160%)
|
+2.8
|
a Two out of 3 patients with HR- in adjuvant stage would need dual HER2 blockade
b As adjuvant treatment for patients with residual disease after neoadjuvant treatment with trastuzumab, therefore its impact is considered for the neoadjuvant stage
c Expected use in 31% of neoadjuvant patients according to pCR
Impact of innovative targeted therapies in disease management
First, the average impact on relative change in OS, total cost per patient and WTP were assessed by disease stage. Results are shown in Table 3, where it can be observed that the neoadjuvant stage has the lowest increase in WTP, while metastatic disease has the highest relative OS increase compared to current management.
Table 3. Average impact of innovative targeted therapies by stage
Indication
|
Relative impact on 5-year OS in stage
|
Relative impact on total cost per patient in stage
|
Relative impact on stage WTPa
|
Adjuvant
|
1%
|
100%
|
99%
|
Adjuvantb
|
0.5%
|
39%
|
38%
|
Metastatic
|
36%
|
190%
|
95%
|
a Total cost divided by total benefit (5-year OS) within disease stage
b As adjuvant treatment for patients with residual disease after neoadjuvant treatment with trastuzumab, therefore its impact is considered for the neoadjuvant stage
Table 3 shows that investment in the neoadjuvant stage has the best cost-benefit ratio. However, this stage already has innovative targeted therapeutic options other than trastuzumab. In absolute terms, increases in OS of +1%, +0.5%, +36% were achieved for the adjuvant, neoadjuvant, and metastatic stages, respectively. This suggests that there is an opportunity for additional investment in the metastatic stage of disease, where other innovative targeted therapies, currently used in second line only, can help delay disease progression.
The impact of potential combinations of the 5 indications was assessed, i.e., the combined use of innovative targeted therapies, each administered as indicated. Combinations of two innovative therapies for the same patient group were deemed invalid and were not assessed. As a result, 23 combinations were assessed and their clinical and economic impact were mapped on a Cartesian plane with the origin representing the clinical and economic impact of current disease management, i.e., annual budget, $6 million and expected 5-year OS, 76% (Fig. 4).
Four main quadrants were identified in this plane for analysis, labelled as optimal, savings, no-go and trade-off. An optimal quadrant represents an improvement in clinical outcomes with savings: all treatments in this quadrant improve disease management. At the other extreme, the no-go quadrant describes treatments with worse clinical outcomes and increased costs: from a resource optimization perspective, treatments in this quadrant should not be used.
Finally, the savings and trade-off quadrants for all treatments in which clinical and economic impact have the same sign, mean that better clinical outcomes have additional costs and worse clinical outcomes are offset with savings.
Decision-making variables
The main decision-making variable was change in WTP, i.e., the change in total costs versus total benefit; this variable optimizes investment as it decreases. Graphically, current WTP can be represented in the Cartesian plane of clinical and economic impact, e.g., Fig. 4, with a straight line in which total benefit increases are in constant relationship with economic increases. This helps to assess all the combinations by highlighting the combinations on the right or left side of said line, corresponding to decreases and increases in WTP accordingly. In addition, combinations that are closest to the current WTP line can be observed graphically and are deemed as optimal (Fig. 5).
By comparing the 23 combinations against WTP, we found that all combinations would increase the current cost of each percentage point in 5-year OS. It is interesting to note that the use of lapatinib would have the lowest increase in WTP, both around 3%, but with a relative clinical impact of less than 1%. The next indication with lowest impact in WTP is pertuzumab in the adjuvant indication, with a relative increase of 12%, but it also shows a relative clinical impact less than 1%. On the other hand, the indication with the highest relative clinical impact is pertuzumab in the metastatic indication, which increases 5-year OS relatively in the metastatic stage by 62%, resulting in a 5-year OS improvement in HER2+ management of 4% and increases the WTP by 69% (Fig. 5).