Discussion
In this study, we extended our previous conclusions to patients who
received NAC and BCS.
Atypical
hyperplasia at the margins also did not confer worse local ipsilateral
breast recurrence-free survival, DMFS or OS in patients underwent BCS
after NAC, and the observed IBTR rate was low (16/323, 5.0%).
Data from a Netherlands study showed higher rates of tumor-involved
margins in patients treated with NAC and BCS versus primary BCS (23 vs.
10%)2. Consistent with
this literature, we found a high re-excision rate 30.9% (100/323) in
our study. The rate of tumor at margins requiring intraoperative
re-excision was actually quite low (37 patients, 11.4%). Although 63
patients received intraoperative re-excision due to severe AH appeared
at primary resection margins, the local recurrence rate of patients with
severe AH was not higher than the patients without AH. In addition,
Coopey et al . reported that patients with ADH and severe ADH were
equally likely to develop invasive cancer and
DCIS16. This indicates
that if intraoperative frozen pathology can be accurately distinguish
severe AH from DCIS, then there is no need to further resect severe AH
at the margins. Our findings therefore lend further support for the
oncology safety of residual severe AH at the margins to minimize
unnecessary re-excisions.
AH of the breast refers to spectrum of abnormal epithelial proliferative
lesions that does not qualify as carcinoma in situ. AH is found in
approximately 10% of breast biopsies with benign lesions, and it is
classified as a high-risk precancerous lesion due to its association
with, and potential to progress to breast
cancer18. Women with AH
have an approximate four-fold increase in BC
risk6,7.
Why AH did not confer higher IBTR in the present study, the following
reasons may address to this issue. First, the conclusion that AH
contributes to higher risk of breast cancer was drawn from people with
benign diseases but not patients who have already suffered from breast
cancer. The tumor burden of breast cancer patients was significantly
different from those with only benign disease. Holland et al.reported in their study, of the 282 patients with invasive cancers that
underwent lumpectomy, 105 (37%) showed no other tumor foci in the
residual breast, but other tumor foci were found in the remaining 177
breasts, of which 20% tumor foci were present within 2 cm off the
reference tumor in the residual
breast19. Therefore, it
is clearly a negative margin that does not indicate that there is no
residual cancer in the breast, however, the residual tumor can be
controlled by radiotherapy and adjuvant treatments such as endocrine
therapy and targeted therapy. The risk of IBTR of breast conserving
therapy is about 0.5–2% per year with an increased risk during the
first few
years20,21,
and the median time to IBTR is 36
months22. Additionally,
results from NSBAPB-18 suggested that patients downstaged after NAC for
BCS may have higher local recurrence
rate23. However, the
annual incidence of breast cancer caused by AH is not significantly
higher than the risk of IBTR after BCS. Recent reports with long-term
follow-up have demonstrated that absolute risk for developing breast
cancer is in the range of 1-2% per
year7,24.
More recently, Menes and colleagues’ research which was large and
contemporary, found that the 10 years cumulative risk for developing
breast cancer in women with atypical ductal hyperplasia (ADH) is only
5.6%25. Therefore, the
effect of AH on IBTR may be offset by the breast cancer itself. Thus, it
is not surprising that AH involved at the margin does not contribute to
a higher risk of IBTR. Second, endocrine therapy can reduce IBTR. Data
from the NSABP P-1 trial showed that tamoxifen administered for 5 years
decreased the risk of invasive and non-invasive breast cancer by
approximately 50%26.
In the present study over 70% of the patients received endocrine
therapy. We postulate that this result is attributable in part to the
use of endocrine therapy. Third, the follow-up period of our study may
not be long enough to reveal the effectiveness of the difference between
groups. Page et al. reported that the interval of ADH and ALH to
breast cancer is 8.2 and 11.9
years27, but the median
follow-up period of our study was approximately 48 months.
In addition to margin status, other important determinants of overall
prognosis including the pCR rate, are being recognized. It has been
reported that different chemotherapy responses and residual tumor
burdens have different risks of cancer relapse, since patients who
achieved a pCR will have favorable DFS and
OS28,29.
In the present study, patients who
achieved a pCR had more excellent
DMFS compared with those with residual lesions after NAC in our study.
In patients undergoing NAC, the lack of an axillary pCR has been shown
to be associated with less favorable overall
survival30-32.
Consistent with these published studies, we also found that positive
lymph nodes post-NAC was associated with inferior OS.
Our study has some potential limitations due to its retrospective
design. The chemotherapy regimens given to the patients varied among
different subtypes, and this may affect the relationship between NAC
response and DFS/OS. Furthermore, the number of patients enrolled in the
study was limited. Future multi-centered studies and more patients
enrolled with a longer follow-up are needed to achieve greater
statistical power so as to address this issue more clearly.
In summary, our study did not find
a higher risk of IBTR or distant metastasis or death events in patients
with AH involved at the surgical margin who underwent BCS after NAC. In
multivariate analysis, there was no association between AH status and
IBTR, DMFS or OS. The lack of a pCR, and positive pathologic lymph nodes
post-NAC were associated with inferior outcomes. Although further
studies are needed to determine how AH status is related to IBTR in this
population, the excellent long-term
outcomes demonstrated in patients with AH at margins following NAC in
this study suggest that AH involved at the margins may be acceptable in
appropriately selected patients with breast cancer.