1. INTRODUCTION
The HER2 gene (formerly called c-erbB-2) encodes a 185-kDa transmembrane glycoprotein
with intra-cellular tyrosine kinase activity. In breast cancer, overexpression of
HER2 is seen in 20%–30% of breast cancer cases 1. Initially, the goal of HER2 status
assessment for breast cancer was to determine which patients with metastatic disease
might benefit from treatment with trastuzumab (Herceptin: Genentech, San Francisco,
CA, U.S.A.), the mono-clonal antibody to HER2, either alone or in combination with
chemotherapy. Subsequently, the HER2 status of breast tumours was shown to have a
potential role in the selection of adjuvant systemic therapy because of prognostic
relevance and a putative role in predicting resistance to specific chemotherapies
and hormonal therapies. Accordingly, some centres routinely tested for tumour HER2
status at the time of diagnosis.
At the 2005 meeting of the American Society of Clinical Oncology, early reports from
three randomized studies demonstrated a 50% improvement in disease-free survival and
a 33% improvement in overall survival with the addition of trastuzumab to standard
adjuvant chemotherapy. Thus, it is now essential that HER2 status be available at
the time of breast cancer diagnosis. Although medical oncologists will use this information
to determine the need for adjuvant trastuzumab, the extent to which HER2 status might
affect their adjuvant chemotherapy and hormonal therapy recommendations is not known.
Amplification of HER2 has been found to correlate with a worse prognosis in both node-negative
and node-positive disease 2–4. However, whether patients with such amplification would
benefit from receiving more aggressive systemic therapy than they might otherwise
receive is still unknown. Reports about the ability of HER2 overexpression to predict
response to systemic chemotherapy and hormonal therapy are conflicting. Studies have
suggested that, as compared with patients without HER2 overexpression, patients with
such overexpression benefit less from chemotherapy regimens that lack an anthracycline
5–7. It has also been suggested that patients with HER2 overexpression are resistant
to tamoxifen 8 and that alternative strategies such as aromatase inhibition or ovarian
oblation or both may be superior in these patients 9. However, other studies have
not found HER2 overexpression to adversely influence response to tamoxifen 10. Interpretation
of the data is further complicated by the fact that large discrepancies exist between
centres worldwide with respect to the method of detecting HER2 gene overexpression
11,12.
Despite the uncertainties, some authors advocated—long before the release of the promising
adjuvant trastuzumab data—that, because of its prognostic usefulness, HER2 testing
be routinely performed for all new breast cancer cases 13. In Ontario, the most populous
province in Canada, such routine testing was adopted at some centres, but not at others.
Accordingly, to better understand whether and how HER2 status affects systemic chemotherapy
and hormonal therapy recommendations by medical oncologists, we conducted a survey
of those practitioners across Ontario.
2. MATERIALS AND METHODS
An introductory letter, consent form, and questionnaire were mailed to all medical
oncologists practicing at cancer centres and teaching hospitals in Ontario, and to
all community oncologists across Ontario who were members of the Canadian Association
of Medical Oncologists at the time of mailing. Medical oncologists who did not regularly
treat breast cancer were excluded. A total of 99 packages were mailed in September
2002.
The questionnaire was divided into two sections:
Section 1 gathered demographic data, including the physician’s age, years in practice,
type of practice, and percentage of time devoted to treating oncology patients in
general and breast cancer patients in particular. The questionnaire also asked about
the availability to the physician of common prognostic and predictive factors in breast
cancer, including tumour size, tumour grade, oestrogen receptor (er) and progesterone
receptor (pr) expression, lymphovascular invasion, perineural invasion, lymph node
involvement, and HER2 overexpression.
Section 2 of the questionnaire was designed in two separate versions (version A and
version B). Both versions contained five hypothetical scenarios of newly diagnosed
breast cancer cases for which an adjuvant treatment decision was requested. Cases
with a risk of recurrence ranging from low to high were included. Each scenario supplied
patient demographic data as well as information on the primary tumour, including size,
grade, lymphovascular invasion, er/pr status, and lymph node involvement. In each
case scenario, HER2/neu overexpression was also included and listed as positive (HER2+)
or negative (HER2−). Questionnaire versions A and B differed only with respect to
the HER2 status of each case. Version A scenarios 1, 3, and 5 were marked as HER2+,
and scenarios 2 and 4 as HER2−; version B scenarios reversed the HER2 status of each
case. The medical oncologists were randomized to receive either questionnaire version
A or version B, with stratification by cancer centre.
The oncologists were blinded to the specific study hypothesis and were told in the
letter that the project was evaluating the availability and utility of prognostic
and predictive markers for decision-making in the adjuvant treatment of breast cancer.
Written informed consent was obtained from all participants.
For each case scenario, physicians were instructed to choose from a list of systemic
treatment options one or more regimens that they would recommend. The chemotherapy
regimens included were cmf, cef, ac, ac plus Taxol, caf, and mf (see Table I for a
description of these regimens—information that was included with the questionnaire).
The options of choosing no chemotherapy or an alternative regimen not listed were
also provided.
In addition to the systemic chemotherapy options, systemic hormonal therapy options
were added for the two hormone receptor–positive cases. The options included were
tamoxifen, aromatase inhibitor, ovarian ablation (surgical or medical)—either alone
or in combination—and “other therapy.” The questionnaire assumed that some form of
hormonal therapy would be offered. Table II shows one sample case scenario from the
questionnaire.
For the purpose of analysis, each case scenario was classified as showing a low, intermediate,
or high risk of recurrence, based on projected 10-year disease-free survival according
to Mayo Clinic criteria 14.
Each physician’s systemic chemotherapy recommendation for a given scenario was grouped
into one of three categories: “no chemotherapy,” “less aggressive” (cmf, ac, or mf),
and “more aggressive” (ac plus Taxol, cef, fac, or caf). If regimens from more than
one category were chosen, the selection was recorded as “less aggressive” because,
presumably, the physician would opt to treat the patient with the least toxic of the
regimens selected. If no chemotherapy was selected as one of the choices, then regardless
of other selections, “no chemotherapy” was recorded. The number of physicians specifically
recommending either or both of ac and cmf was noted. For the two case scenarios with
hormone-receptor-positive disease, endocrine therapy was coded as either “tamoxifen”
or “other.”
All results with ordered categories (that is, “no chemotherapy,” “less aggressive,”
and “more aggressive” chemotherapy) were analyzed using chi-square for trend. Variables
with two categories were analyzed using the Fisher exact test.
3. RESULTS
Of the 99 medical oncologists to whom questionnaires were mailed, 50 received version
A (group A) and 49 received version B (group B). The group A physicians returned 30
questionnaires. One questionnaire was incompletely answered; the remaining 29 were
included in the final analysis. The group B physicians returned 29 completed questionnaires.
Both groups had similar male:female ratios, mean years in practice, and type of practice
(Table III). At the time of consultation, HER2 status was routinely available in 53%
and 55% of cases in groups A and B respectively. The other prognostic and predictive
factors included in the questionnaire were almost universally routinely available
to both groups.
3.1 Scenario 1
Scenario 1 presented a 47-year-old woman with a 0.6-cm, grade 3, er/pr-negative, node-negative
infiltrating ductal carcinoma (low risk, 90% disease-free survival at 10 years 14).
We observed no significant difference in treatment recommendations between the group
A and B physicians [Figure 1(a)]. Also, among physicians recommending less aggressive
chemotherapy, the proportion of those choosing ac as compared with cmf did not differ
by HER2 status (4/13 vs. 6/17).
3.2 Scenario 2
Scenario 2 presented a 59-year-old woman with a 1.5-cm, grade 2, er/pr-positive, node-negative
infiltrating ductal carcinoma (intermediate risk, 81% disease-free survival at 10
years). Physicians who received the HER2+ version of the scenario were more likely
to select some form of adjuvant chemotherapy [21/29 vs. 10/29, p = 0.008, Figure 1(b)].
Among the physicians who selected less aggressive chemotherapy, a higher proportion
of those receiving the HER2+ version recommended ac over cmf (3/9 vs. 3/18), but the
difference was not statistically significant (p = 0.37).
For adjuvant endocrine treatment [Figure 2(a)], a tendency to favour aromatase inhibitors
over tamoxifen was seen among the oncologists who received the HER2+ version (5/29
vs. 1/29, p = 0.19).
3.3 Scenario 3
Scenario 3 presented a 65-year-old woman with a 2.2-cm, grade 2, er/pr-positive infiltrating
ductal carcinoma metastatic to 2 of 11 axillary nodes (high risk, 50% disease-free
survival at 10 years). Of the oncologists who received the HER2+ version, only 1 of
29 selected “no chemotherapy” as compared with 5 of the 29 who received the HER2−
version (p = 0.13). No statistically significant difference was seen in the aggressiveness
of the chemotherapy recommended [Figure 1(c)], nor in the choice of ac over cmf.
3.4 Scenario 4
Scenario 4 presented a 43-year-old woman with a 1.7-cm, grade 3, er/pr-negative, node-negative
infiltrating ductal carcinoma (intermediate risk, 81% disease-free survival at 10-years).
All respondents selected adjuvant chemotherapy regardless of HER2 status. Of the physicians
who received the HER2+ version of the scenario, 20 of 29 recommended aggressive chemotherapy
as compared with 14 of 29 who received the HER2− version [p = 0.18, Figure 1(d)].
Among the physicians who selected less aggressive chemotherapy, the proportion of
those choosing ac over cmf did not differ by HER2 status.
3.5 Scenario 5
Scenario 5 presented a 37-year-old woman with a 1.1-cm, er/pr-positive, grade 2 infiltrating
ductal carcinoma with 2 of 16 nodes positive for cancer (high risk, 56% disease-free
survival at 10-years). All respondents selected some form of adjuvant chemotherapy.
No difference was seen between group A and B physicians in the recommendation of less
aggressive (5/29 with HER2+, 4/29 with HER2−) versus aggressive chemotherapy [Figure
1(e)], and no significant difference was seen between the two groups in the selection
of ac over cmf.
In the group that received the HER2+ version of the questionnaire, hormonal treatments
other than tamoxifen were more frequently recommended, with 8 of 29 physicians choosing
ovarian ablation with or without an aromatase inhibitor in the HER2+ group and only
2 of 29 choosing non–tamoxifen based treatment in the HER2− group [p = 0.08, Figure
2(b)].
3.6 Additional Analyses
The data were also analyzed looking exclusively at respondents who indicated that
HER2 testing was routinely performed at diagnosis in their place of practice (32 total,
16 from group A and 16 from group B). We noted statistically significant differences
in the chemotherapy recommendations for scenarios 2 and 4, both of which were intermediate-risk
cases. In scenario 2, 14 of 16 physicians who received the HER2+ version of the question
recommended chemotherapy as compared with only 4 of 16 who received the HER2− version
(p = 0.004). In scenario 4, for which all oncologists recommended chemotherapy, 12
of 14 who received the HER2+ version of the question selected aggressive chemotherapy
as compared with just 6 of 16 who received the HER2− version (p = 0.009).
4. DISCUSSION AND CONCLUSION
The results of our survey suggest that medical oncologists in Ontario use HER2 status
to guide their adjuvant chemotherapy and hormonal therapy treatment recommendations
for breast cancer cases with an intermediate risk of recurrence.
For the low-risk case, HER2 status did not influence chemotherapy selection; however,
given that more than 60% of the oncologists recommended chemotherapy in the low-risk
scenario, it is conceivable that HER2 status might have a greater impact even on a
lower-risk case (that is, similar to the first scenario, but er-positive). Recommendations
for the two high-risk cases were not affected by HER2 status. That finding makes intuitive
clinical sense because, for cases already considered high risk based on more traditional
prognostic factors, additional information would not be needed to persuade the oncologist
to recommend aggressive treatment.
We also saw a trend toward the increased use of hormonal treatments other than tamoxifen
for HER2+ cases. It is difficult to discern from the survey whether the lack of statistical
significance of that trend is an artefact of the modest sample size or a true reflection
of varying interpretations of the literature.
The effect of HER2 status was more pronounced among oncologists for whom HER2 was
routinely available at diagnosis. Presumably, these physicians already routinely incorporated
HER2 status into their decision-making, and those who lacked routine HER2 information
did not. However, it is also conceivable that only the oncologists who felt strongly
about the importance of HER2 status for determining adjuvant treatment would have
pushed to have the test routinely performed for all newly diagnosed breast cancer
cases at their centre.
One limitation of this study is that our hypothetical cases may or may not accurately
reflect the “real world.” However, 170 consecutive charts of newly diagnosed early-stage
breast cancer patients at our centre were systematically reviewed by one of the authors
(JAM). For cases with a profile resembling any of the study scenarios, the range and
frequency of the actual treatment recommendations were similar to those among the
survey responses for the corresponding hypothetical scenario.
Although our 60% response rate is above average for most mailed physician surveys
15, it is conceivable that our results may not be easily generalized to the non-responders.
However, systematic differences between participants and non-participants with respect
to HER2 status utilization would be unlikely because all potential participants were
blinded to the study hypothesis.
More important than the question of whether HER2 status in breast cancer influences
adjuvant chemotherapy and hormonal therapy treatment decision-making is whether HER2
should influence treatment decision-making at all. The most recent version of Adjuvant!
(version 7.0), the popular computer software aid to adjuvant breast cancer therapy
decision-making, allows users to insert additional prognostic markers of their own
choosing but it does not specifically include HER2 in the initial profile 16. Sufficiently
powered prospective clinical trials in which HER2 testing methodology is standardized
are clearly necessary to clarify whether modifying adjuvant chemotherapy and hormonal
therapy according to HER2 status can favourably alter the natural history of breast
cancer. In the meantime, a formal state-of-the-art practice guideline on the use of
breast cancer HER2 status for adjuvant chemotherapy and hormonal therapy decision-making
would be extremely helpful to medical oncologists.