Residual Ductal Carcinoma In Situ Research Articles

Abstract P3-06-28: Alterations in HER2 status and outcome following neoadjuvant chemotherapy in HER2-positive breast cancer (BC)

Abstract Background: Emerging data suggest that chemotherapy and anti-HER2 agents can change HER2 status in HER2+ BC and that this may have prognostic implications. The findings suggest a role for post-treatment (tx) retesting of HER2 status in surgical specimens. However, few studies have specifically examined this phenomenon, and direct comparisons of post-tx HER2 testing modalities are lacking. Furthermore, the biologic basis for HER2 alterations remains poorly understood. The aims of this study were to systematically evaluate the effects of neoadjuvant chemotherapy (NAT) including anti-HER2 agents on HER2 protein expression (P-EXP) and gene amplification (G-AMP), and to examine the potential prognostic impact of HER2 alterations on outcomes in HER2+ BC. Design: We retrospectively identified 129 patients with HER2+ BC who received NAT at our institution. HR (ER and PR) and HER2 P-EXP were evaluated by immunohistochemistry (IHC) and HER2 G-AMP by fluorescence in situ hybridization (FISH) in pre- and post-tx samples. Pathologic tumor responses were categorized as no residual disease (RD; no invasive or in situ cancer), residual ductal carcinoma in situ (DCIS) only, and residual invasive carcinoma. Pathologic complete response (pCR) was defined as DCIS only or no RD. Association between groups was determined by Fisher exact test. For survival analysis, Kaplan Meier curves were constructed and significance in curve separation was assessed by log rank test. Results: Mean follow-up was 52.6 months (range 6-162). Eighty-four (65%) cases had residual invasive cancer, 21 (16%) residual DCIS only and 24 (19%) no RD. Post-tx HER2 status was available in 70 cases with residual invasive cancer, and 27 (39%) of these showed reduced HER2 P-EXP (staining intensity 0, 1+, 2+) by IHC. Twenty-one (78%) of 27 cases with reduced HER2 P-EXP retained HER2 G-AMP (IHC-/FISH+), and 6 (22%) were negative for both HER2 P-EXP and G-AMP (IHC-/FISH-). The subset of IHC-/FISH- patients showed 100% 5-year recurrence free survival (RFS), whereas IHC-/FISH+ and IHC+ (intensity 3+) cases demonstrated similarly decreased 5-year RFS of 67% and 71%, respectively. There was a trend towards reduced HER2 expression in HR+ versus HR- cases (46% vs 26%, p=0.19). HR-HER2+ tumors were more likely to achieve pCR than HR+HER2+ cases (48% vs 26%; p=0.014, OR=0.375). In the HR- subset, RFS was significantly better in patients with no RD compared to those with residual invasive cancer (p=0.047); this relationship was not observed in the HR+ group (p=0.693). Conclusion: A significant fraction of pre-tx HER2+ BC demonstrate reduced HER2 P-EXP following NAT. In a subset of these, post-tx decreased HER2 P-EXP is associated with retained HER2 G-AMP, suggestive of HER2 protein downregulation. In another subset, decreased HER2 P-EXP with associated lack of HER2 G-AMP indicates selection for HER2 non-amplified clones in HER2 heterogeneous tumors. Array comparative genomic hybridization studies are in progress to further elucidate these mechanisms. Lastly, our results suggest that post-tx evaluation of HER2 status by FISH in addition to IHC may have prognostic and/or predictive value in HER2+ BC. Further studies in larger prospective study populations are needed to confirm our findings. Citation Format: Dianna Ng, Gregor Krings, Christina Yau, Kristie White, Jie Hou, Anthony Chua, James P Grenert, Yunn-Yi Chen. Alterations in HER2 status and outcome following neoadjuvant chemotherapy in HER2-positive breast cancer (BC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-28.

Abstract P2-03-07: Prediction of the pathological response to neoadjuvant chemotherapy in patients with breast cancer using sonazoid-enhanced ultrasonography

Abstract Background: Altered blood flow in malignant tumors is evidenced by contrast-enhanced ultrasonography (CEUS) because of its image perfusion capabilities. This study aimed to investigate the value of CEUS in the evaluation of the response of breast cancer lesions to neoadjuvant chemotherapy (NAC). We evaluated whether the prediction of a pathological complete response (pCR) using CEUS was more precise than that using other standard evaluation methods such as magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT). Methods: Ten patients (mean age, 50.2 years) who underwent NAC for invasive breast cancer between September 2012 and April 2013 were eligible for this cohort study. Clinical tumor response was evaluated using contrast-enhanced MRI, PET/CT, and CEUS following NAC. A pCR was defined as the absence of invasive cancer in the breast and lymph nodes according to the Japanese Breast Cancer Society criteria. A clinically complete response (cCR) was defined as the absence of residual disease on MRI and PET/CT. The HI VISION ASCENDUS (Hitachi Aloka Medical Corp.) was used for ultrasonography. Tumors were observed 50 s after Sonazoid injection at a dose of 0.01 ml/kg. A time-intensity curve of tumor signal intensity was drawn. The brightness of the tumor was digitized and the curve was created on the basis of brightness changes over time. The intensity of brightness of the breast cancer lesions was calculated as the increased rate of brightness (IRB) using the following formula: maximal intensity/intensity before contrast. Results: Four (40%) of the 10 patients were diagnosed with pCR by NAC. Among 4 (40%) patients diagnosed with cCR by MRI, 1 (25%) achieved pCR. All patients were diagnosed with pCR by PET/CT. The IRB values of the 10 patients who received CEUS before surgery were 1.0, 1.1, 1.2, 1.2, 1.3, 1.6, 1.8, 1.9, 2.5, and 4.2. The IRB values of the 4 patients diagnosed with pCR were 1.0, 1.1, 1.2, and 1.2. IRB values were significantly lower in patients who achieved pCR than in those who did not (pCR vs. no pCR, 1.1 ± 0.9 vs. 2.2 ± 1.0, P < 0.05). Furthermore, among the patients who achieved pCR, the IRB values of 2 patients with no residual ductal carcinoma in situ (DCIS) were 1.0 and 1.1, whereas those of 2 patients with residual DCIS were both 1.2. In the 4 patients who achieved cCR as diagnosed by MRI and PET/CT, 3 with pathological residual disease had detectable IRB by CEUS. table 1caseageStageSub typeMRIPET-CTpathological responseIncrease rate of brightness (IRB)167T2N1 IIBLuminal HER2PRCRCR1237T2N0 IIAHER2 positivePRCRCR1.1346T3N1 IIIAHER2 positiveCRCRCR1.2446T2N3c IIICLuminal HER2PRCRCR1.2564T2N0 IIAHER-2 positiveCRCRPR1.3658T2N1 IIBLuminal BCRCRPR1.6738T2N0 IIALuminal BPRCRPR1.8857T1cN0 ILuminal HER-2PRCRPR1.9939T2N1 IIBLuminalBSDCRSD2.51050T2N1 IIBTriple negativePRCRSD4.2 Conclusions: The prediction of pCR after NAC in patients with breast cancer is more precise with Sonazoid-enhanced ultrasonography than with standard methods such as MRI and PET/CT. Furthermore, CEUS may be useful for predicting residual DCIS on the basis of brightness intensity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-03-07.

Abstract P3-14-06: The Utility of Margin Index to Predict Residual DCIS Following Breast Conserving Surgery

Abstract Background: Although breast conserving surgery (BCS) is commonly performed for ductal carcinoma in situ (DCIS), patients may require re-excision for close or positive margins to rule out residual disease. The concept of margin index (defined as margin distance/tumor size) has been found to predict residual disease in patients with invasive breast cancer, but this concept has yet to be evaluated for patients with DCIS. We sought to determine if DCIS margin index (defined as the closest margin of DCIS/extent of DCIS) was predictive of residual disease. Methods: We performed a chart review of all in situ breast cancers treated with BCS at an academic breast center in 2009. DCIS margin index was calculated as closest margin distance of DCIS (mm)/extent of DCIS (mm). Non-parametric statistical analyses were performed to evaluate the relationship between margin index and residual DCIS. Results: 177 patients with DCIS were treated with BCS in 2009. Of these, 87 (49.1%) underwent resection of additional tissue for close margins or as routine practice, and had recorded quantitative margin distances and tumor sizes such that margin index could be calculated. Of these, 18 (20.7%) had residual DCIS in the additional tissue excised. Median patient age was 60.4 years (range; 31.9–91.4). Of the 50 patients with available immunohistochemistry analysis, 42 (84%) were ER-positive and 36 (72%) were PR-positive respectively. 12 (13.8%) had low grade DCIS, 53 (60.9%) intermediate grade DCIS, and 22 (25.3%) high grade DCIS. Median tumor size was 16mm (range; 1–80 mm); and median margin distance was 2 mm (range; 0–18 mm). Median margin index was 0.125 (range; 0 to 18). Factors correlating with residual DCIS on univariate analysis were high tumor grade (33.3% vs. 23.2%, p = 0.044), PR-negativity (66.7% vs. 22.7%, p = 0.044), increasing tumor size (median 27.5 mm vs. 15.0 mm, p = 0.003), decreasing margin distance (median 1.0 mm vs. 2.1 mm, p = 0.004), and lower margin index (median 0.032 vs. 0.200, p < 0.001). Patient age and ER status were not correlated with residual DCIS. In a multivariate model controlling for grade and PR-status, margin index was no longer a significant predictor of residual disease, although a trend was noted (p = 0.076). To determine the relative strength of margin index (vs. extent of DCIS and margin distance) in predicting residual DCIS, a second multivariate model including PR-status, grade, extent of DCIS and margin distance was created. In this second model, extent of DCIS (p = 0.634) and margin distance (p = 0.152) were less predictive of residual disease than margin index was in the first model. PR-negativity remained the only predictor of residual disease in both. Conclusions: Margin index is a stronger predictor of residual DCIS than either margin distance or extent of DCIS, but loses significance when taking PR status into account. That PR-negativity is strongly associated with residual DCIS (independent of tumor size, grade and margin status) is intriguing and warrants further research. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-06.

Use of postexcision preirradiation mammography in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy

PurposePostexcision preirradiation mammography (PPM) is frequently performed in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving therapy (BCT) to evaluate for residual suspicious calcifications; but no clear evidence supports this practice. The current study was undertaken to investigate the value of PPM in the management of patients with DCIS. Methods and MaterialsWe conducted a retrospective review of patients treated for DCIS with BCT at the University of Pennsylvania. The impact of PPM on surgical management and on local recurrence was evaluated. Factors associated with the use of PPM, the results of PPM, and the likelihood of finding residual malignancy at the time of re-excision in patients with PPM were also examined. ResultsOne hundred forty-four of 281 patients (51%) underwent PPM. Of the 144 patients who received PPM, 34 (24%; 95% confidence interval, 17%-31%) had residual suspicious calcifications (a “positive PPM”). Of the 34 patients with a positive PPM, all underwent a re-excision and 19 (56%; 95% confidence interval, 35%-70%) were found to have residual malignancy. Ten of 34 patients with a positive PPM had negative margins, of which 6 had a residual malignancy. Assuming all patients with close, positive, or indeterminate surgical margins would have undergone re-excision regardless of the findings of PPM, PPM resulted in a change in surgical management in 7% (10/144) of patients and removal of residual DCIS in 4% (6/144). With a median follow-up of 9.5 years, the use of PPM was not associated with an improvement in 10-year local recurrence-free survival (94.8% vs 91.5%, P = .368). ConclusionsIn this study, PPM affected surgical management in only a small percentage of patients and had no impact on local recurrence. The routine use of PPM in women undergoing BCT for DCIS may not be warranted.

HER‐2 pulsed dendritic cell vaccine can eliminate HER‐2 expression and impact ductal carcinoma in situ

HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. A HER-2/neu dendritic cell vaccine was administered to 27 patients with HER-2/neu-overexpressing DCIS. The HER-2/neu vaccine was administered before surgical resection, and pre- and postvaccination analysis was conducted to assess clinical results. At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, whereas among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing estrogen receptor (ER)(neg) with ER(pos) DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER(neg) subjects compared with 5.9% in ER(pos) subjects. Sustained HER-2/neu expression was found in 10% of ER(neg) subjects compared with 47.1% in ER(pos) subjects (P = .04). Postvaccination phenotypes were significantly different between ER(pos) and ER(neg) subjects (P = .01), with 7 of 16 (43.8%) initially presenting with ER(pos) HER-2/neu(pos) luminal B phenotype finishing with the ER(pos) HER-2/neu(neg) luminal A phenotype, and 3 of 6 (50%) with the ER(neg) HER-2/neu(pos) phenotype changing to the ER(neg) HER-2/neu(neg) phenotype. Results suggest that vaccination against HER-2/neu is safe and well tolerated and induces decline and/or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor-associated antigens and pathways.

Magnetic resonance imaging evaluation of residual ductal carcinoma in situ following preoperative chemotherapy in breast cancer patients

To retrospectively evaluate the ability of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in helping to distinguish between lesions with and without residual ductal carcinoma in situ (DCIS) in patients showing no residual invasive cancer after preoperative chemotherapy. DCE-MR images of 46 consecutive breast cancer patients (mean age, 47 years; range, 30-69 years) with no residual invasive cancer (15 had residual DCIS and 31 had no residual DCIS) following preoperative chemotherapy and surgery were blindly reviewed and categorized by two radiologists in consensus. Thereafter, DCE-MRI findings that could be helpful in distinguishing lesions with and without residual DCIS were analyzed. When any enhancement was present, 93% (14 of 15) sensitivity and 35% (11 of 31) specificity for the detection of residual DCIS on post-chemotherapy MRI were achieved. Although 65% (20 of 31) of lesions without residual cancer had some enhancing findings, the lesion to fibroglandular signal intensity ratio showed 86.7% (13 of 15) sensitivity and 83.9% (26 of 31) specificity with an Az value of 0.854 (95% confidence interval: 0.718, 0.940) when a cut-off point of a ratio of 1.34 was used. DCE-MRI has the potential in distinguishing between lesions with and without residual DCIS in patients showing no invasive cancer after preoperative chemotherapy.

Abstract P1-15-09: Ductal Carcinoma In Situ of the Breast: Clinico-Pathological Features Predicting Residual Disease in Postlumpectomy Re-Excision Specimens

Abstract INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, which often grows discontinuously within the breast tissue. Younger age, residual mammographic microcalcifications, positive surgical margins, tumor size, nuclear grade and architectural type are consistently related to ipsilateral breast tumor recurrence in DCIS. To re-excise or not when a lumpectomy margin is close is a controversial issue for breast pathologists, surgeons and oncologists, and often no residual disease is found when a re-excision is performed. The aim of this study is to investigate the clinico-pathological features of DCIS that might predict residual disease in the re-excision specimen in patients treated by lumpectomy with either positive or close margins. METHODS: Consecutive patients with DCIS who required postlumpectomy re-excision either for positive or for close margins were selected in this retrospective analysis. Close margin was defined as less than 0.1 cm. The initial lumpectomy specimens were examined for tumor size, architectural type, nuclear grade and margin status, and patient age was considered. The subsequent re-excision specimens were analyzed for residual disease. The clinico-pathological features of original lumpectomy specimens were correlated with the presence or absence of residual DCIS in the re-excision specimens. Logistic regression statistical test was used to determine if any of these clinico-pathological features predicted the presence or absence of DCIS in the subsequent re-excision specimens. RESULTS: There were 37 cases of DCIS without accompanying invasive carcinoma that had positive or close resection margins (positive margin n=8; 21.6%, close margin n=29; 78.4%). Age of the patients ranged from 30 to 93 years. DCIS present in the original lumpectomy specimen was comedo type with necrosis n=8; 21.6% and non-comedo type n-29; 78.4%. Twenty-one lumpectomy specimens (57%) exhibited more than one type of DCIS. Four tumors were nuclear grade 1 (10.8%). 17 were nuclear grade 2 (45.9%), and 16 were nuclear grade 3 (43.2%). Residual DCIS was present in 20 out of 37 (54.1%) re-excision specimens. Six out of 8 (75%) comedo DCIS had residual disease, compared to 14 out of 29 (48.3%) non-comedo DCIS. Eleven out of 20 patients (55%) with residual disease were younger than 60 years. The correlation of patient age and type of DCIS to residual disease in the re-excision specimens was short of statistical significance due to small size of study sample (p value = 0.178 and 0.175 respectively). There was no statistically significant association between nuclear grade and distance to margin with residual disease in re-excision specimens (p value = 0.757 and 0.734 respectively). CONCLUSION: Younger age and comedo type DCIS may be important factors in predicting residual disease in the re-excision specimens. If this can be confirmed in a larger, multi-institutional data set, there could be a more tailored selection of who needs a re-excision. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-09.

Significance of lobular intraepithelial neoplasia at margins of breast conservation specimens: a report of 38 cases and literature review

BackgroundPresence of lobular intraepithelial neoplasia (LIN) is not routinely reported as part of margin assessment in breast conservation therapy (BCT) as in ductal carcinoma in situ (DCIS). With new emerging evidence of LIN as possible precursor lesion, the hypothesis is that LIN at the margin may increase the risk of local recurrence with BCT. The aim is to determine whether there is an increase incidence of recurrence when LIN is found at surgical margins on BCT.MethodsWe retrospectively reviewed a total of 1,334 BCT at a single institution in a 10 year period. Inclusion criteria are positive margin with LIN from primary BCT containing invasive and/or in situ carcinoma with comparison to the negative control group who had similar diseases with negative margin for LIN.ResultsWe identified 38 cases (2.8%) with LIN either lobular carcinoma in situ/atypical lobular hyperplasia (LCIS/ALH) at a margin on initial BCT with 36% recurrence rate. Of the 38 cases: 5 (13%) were lost to follow-up, 12 (32%) had no further procedures performed and 21 (55%) had re-excision. Out of 21 patients who had re-excisions, 12 (57%) had residual invasive carcinoma or DCIS, three (14%) had pleomorphic LCIS and 4 (19%) showed residual classic type LCIS. 71% had significant residual disease (local recurrence) and 29% had no residual disease. A negative control group consisted of 38 cases. We found two patients with bone or brain metastasis and one local recurrence. Clinical follow up periods range from 1 to 109 months.ConclusionsLIN found at a margin on BCT showed a significant recurrent ipsilateral disease. Our study supports the view that LIN seen at the margin may play a role in recurrence.

Review of Re-Excision for Narrow or Positive Margins of Invasive and Intraductal Carcinoma

The trend in breast surgery has shifted towards breast conservation. Re-excision rates for narrow or positive margins have been variable in published reports. A retrospective analysis of 3246 patients who underwent either a lumpectomy for a palpable mass or a needle localization biopsy between January 2003 and December 2007 was done. Five hundred and eighty-five patients underwent re-excision surgery for margins. The mean patient age was 59-years-old (range 25-93). Needle localization was used to guide initial excision in 372 of 585 patients (64%). Invasive carcinoma was seen in 402 (69%) patients, ductal carcinoma in situ (DCIS) alone in 183 (31%) patients, and 308 (53%) patients had both invasive carcinoma and DCIS. Well-differentiated carcinomas accounted for only 24 per cent of the re-excisions. Four hundred and sixteen patients underwent re-excision of margins, whereas 169 underwent mastectomy as the second surgery. Residual carcinoma was seen in 38 per cent of cases with involved margins, as compared with 24 per cent with <1 mm margins and only 12 per cent cases with >1 mm margins. Residual DCIS was seen in 65 per cent with involved margins, 50 per cent with <2 mm margins, and 35 per cent of cases with 2 to 5 mm margins (P < 0.001, chi2 association). Lesser re-excision was noted in well-differentiated invasive carcinomas. Only 12 per cent of patients with margins greater than 1 mm had residual tumor on re excision, which raises the possibility of nonoperative management in such cases.

Pharmacodynamic study of the biologic effects of GW572016 (lapatinib) in cellular apoptosis and signaling pathways in HER2-positive ductal carcinoma in situ (DCIS) of the breast.

e11044 Background: DCIS is a heterogeneous disease, with increasing incidence, accounting for up to 25% of screen-detected cancers. Approximately 60% of cases of DCIS overexpress HER2. Lapatinib is a tyrosine kinase inhibitor that directly inhibits HER2 receptor signaling by blocking the receptor's kinase activity. We hypothesize that Lapatinib must have substantial activity against HER2 positive DCIS; such activity will be assessed by measurement of PI3K/AKT and RAS/ERK inhibition pathways, as well as apoptosis induction. Methods: The trial was conducted among patients (pts) with DCIS diagnosed by core needle biopsy with low risk of having a hidden invasive component. All of the DCIS had to have HER2 amplification (FISH rate > 2.2). Neoadjuvant lapatinib 1,500 mg daily was administered for 4 weeks prior to surgical resection. EGFR was analyzed by FISH in the biopsy specimen. Ki67, PTEN, AKT, pAKT and nuclear pERK were evaluated by IHQ. PI3KCA mutations were screened at the exons 9 and 20 by PCR. Apoptosis was analyzed by TUNEL assay. All biological markers were measured before and after lapatinib treatment. Results: So far, 11 pts with HER2-positive DCIS have been included. Pre-lapatinib treatment evaluation: none of the pts had EGFR amplification; six pts (54%) had a Ki67 > 25%; AKT was overexpressed in 3 pts (27%); positive nuclear pERK was observed in 4 pts (36%); loss of PTEN expression was detected in 3 pts (27%). PI3KCA mutations were detected in only 1 pt (9%). Post-lapatinib treatment evaluation: 9 pts were evaluable. No change in Ki67 index was found. Only one of the three patients with loss of PTEN had no residual DCIS. A trend for inactivation of the RAF/ERK signaling pathway was observed, whereas no change was observed in the pAKT signaling pathway. In addition, 3 pts (33%) showed an increase in the apoptotic index. Conclusions: High-grade DCIS usually overexpresses/amplifies HER2. In our study, four weeks of lapatinib against HER2- positive DCIS caused a trend for inactivation of nuclear pERK as well as apoptosis induction. We expect this trend to be confirmed with the inclusion of more pts. No significant financial relationships to disclose.

Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ

BackgroundEndocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations.MethodsPatients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months.Biomarker changes were compared to a cohort of patients who had not received preoperative treatment.ResultsMedian age of the cohort was 53 years (range 38–78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery.ConclusionPreoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention.Trial RegistrationClinicalTrials.gov NCT00290745

Optimal Use of Re-Excision in Patients Diagnosed with Early-Stage Breast Cancer by Excisional Biopsy Treated with Breast-Conserving Therapy

The goal of the current study is to help refine guidelines for the need for re-excision and the appropriate amount of breast tissue to re-excise in patients with early breast cancer following excisional breast biopsy when treated with breast-conserving therapy (BCT). The study population consisted of 441 patients derived from a dataset of 607 consecutive cases of stage I and II breast cancer treated with BCT, in which patients underwent primary excisional diagnostic biopsy and subsequent re-excision prior to the initiation of radiation therapy (RT). A single pathologist reviewed all specimens. Re-excision was indicated because tumor was found close to or involving the resection margin. In 333 of the 441 cases, it was possible to measure the extension of carcinoma into the re-excision specimen. Margins were classified as negative (carcinoma>4.2 mm from the margin), near (<4.2 mm from the margin) or positive. Any carcinoma identified near the final margin was quantified by width of invasive carcinoma and number of ductal carcinoma in situ (DCIS) ducts near the margin and subdivided into three distinct groups: least, intermediate, and greatest amount. These factors were then analyzed to determine the likelihood and extent of residual carcinoma in re-excision specimens. Statistical analysis was performed using Systat version 10 (SPSS Inc., Chicago, IL). The quantity of carcinoma near the initial biopsy margin and the invasive carcinoma-to-specimen dimension ratio demonstrated a significant association with increasing amounts of residual carcinoma at re-excision. Combination of these two variables allowed for a statistically significant (P<0.001) calculation of risk index for identifying significant residual invasive carcinoma or DCIS in the adjacent breast parenchyma at re-excision, and yielded stratification into low- (6%), intermediate- (27%), and high-risk (44%) groups. In re-excision specimens, the observed distance of carcinoma extension into adjacent breast tissue was associated with a statistically significant decrease in the ratio of the initial excisional biopsy specimen dimensions and invasive carcinoma dimensions. Combining the initial margin status with the specimen-to-invasive carcinoma maximum dimension ratio yielded an accurate predictor of the maximum distance of tumor extension. Evaluation of the initial excisional biopsy margin status in correlation with the invasive carcinoma-to-specimen maximum dimension ratio may be helpful for (1) identifying patients who require re-excision prior to RT and (2) predicting the quantity of additional breast tissue to excise to ensure adequate surgical margins with BCT.

High and intermediate grade ductal carcinoma in-situ of the breast: a comparison of pathologic features in core biopsies and excisions and an evaluation of core biopsy features that may predict a close or positive margin in the excision

Low and high-grade ductal carcinoma in-situ (DCIS) are known to be highly disparate by a multitude of parameters, including progression potential, immunophenotype, gene expression profile and DNA ploidy. In this study, we analyzed a group of intermediate and high-grade DCIS cases to determine how well the core biopsy predicts the maximal pathology in the associated excisions, and to determine if there are any core biopsy morphologic features that may predict a close (≤ 0.2 cm) or positive margin in the subsequent excision. Forty-nine consecutive paired specimens [core biopsies with a maximal diagnosis of DCIS, and their corresponding excisions, which included 20 and 29 specimens from mastectomies and breast conserving surgeries respectively] were evaluated in detail. In 5 (10%) of 49 cases, no residual carcinoma was found in the excision. In another 4 cases, the changes were diagnostic only of atypical ductal hyperplasia. There were 4 and 3 respective cases of invasive and microinvasive carcinoma out of the 49 excision specimens, for an overall invasion frequency of 14%. In 28 cases where a sentinel lymph node evaluation was performed, only 1 was found to be positive. Among the 40 cases with at least residual DCIS in the excision, there were 5 cases in which comedo-pattern DCIS was present in the excision but not in the core biopsy, attributed to the lower maximal nuclear grade in the biopsy proliferation in 4 cases and the absence of central necrosis in the 5th. For the other main histologic patterns, in 8 (20%) of 40 cases, there were more patterns identified in the core biopsy than in the corresponding excision. For the other 32 cases, 100%, 66%, 50%, 33% and 25% of the number of histologic patterns in the excisions were captured in 35%, 5%, 17.5%, 15% and 7.5% of the preceding core biopsies respectively. Therefore, the core biopsy reflected at least half of the non-comedo histologic patterns in 77.5% of cases. In 6(15%) of the 40 cases, the maximum nuclear grade of the excision (grade 3) was higher than that seen in the core biopsy (grade 2). Overall, however, the maximum nuclear grade in the excision was significantly predicted by maximum nuclear grade in the core biopsy (p = 0.028), with a Phi of 0.347, indicating a moderately strong association. At a size threshold of 2.7 cm, there was no significant association between lesional size and core biopsy features. Furthermore, the clear margin width of the cases with lesional size ≤ 2.7 cm (mean 0.69 cm) was not significantly different (p = 0.4) from the cases with lesional size > 2.7 cm (mean 0.56 cm). Finally, among a variety of core biopsy features that were evaluated, including maximum nuclear grade, necrosis, cancerization of lobules, number of tissue cores with DCIS, number of DCIS ducts per tissue core, total DCIS ducts, or comedo-pattern, only necrosis was significantly associated with a positive or close (≤ 0.2 cm) margin on multivariate analysis (Phi of 0.350). It is concluded that a significant change [to invasive disease (14%) or to no residual disease (10%)] is seen in approximately 24% of excisions that follow a core biopsy diagnosis of intermediate or high-grade DCIS. Core biopsy features are of limited value in predicting a close or positive margin in these lesions.

Does the receptor expression pattern in ductal carcinoma in situ predict recurrence?

22189 Background: Ductal carcinoma in situ (DCIS) of breast is a heterogeneous disease, and the treatment strategy is based on tumor size and pathologic features. We evaluated the value of estrogen, progesterone and Her-2/neu receptors expression in DCIS for predicting recurrence. Methods: This retrospective study included 50 patients with DCIS treated at Barretos Cancer Hospital between January 2000 and December 2002. DCIS with microinvasion was not included. Results: Fifty patients were included and the median age and tumor size was 56.5 years and 17 mm, respectively. Thirty five patients (70%) had wide excision with final margins of > or = 10 mm or a re-excision without residual DCIS and only two patients had margin < 1mm. Twenty four DCIS were comedo-type DCIS and 15 were classified as high-grade DCIS. The ER, PR, HER-2 receptors were assessed in 27 patients and we found positive expression of ER, PR, and HER-2 in 85.2%, 74.0% and 26.9%, respectively. Median follow-up was 65.3 months. Four patients de...

Residual Ductal Carcinoma In Situ in Patients With Complete Eradication of Invasive Breast Cancer After Neoadjuvant Chemotherapy Does Not Adversely Affect Patient Outcome

To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with histologically defined complete eradication of invasive cancer. Retrospective analysis of a database including 2,302 breast cancer patients treated with neoadjuvant chemotherapy at The University of Texas M.D. Anderson Cancer Center between 1980 and 2004 was performed. The overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were compared for patients with no residual invasive or in situ cancer (pathologic complete response [pCR]) and patients with no residual invasive cancer but persistent in situ disease (pCR+DCIS). The mean follow-up time was 250 months. Of the 2,302 treated patients, 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2,025 (88%) had residual invasive cancer. For patients with pCR and pCR+DCIS, the 5-year DFS rates (87.1% in both groups) and 10-year DFS rates (81.3% v 81.7%, respectively) were similar; the 5-year OS rates (91.9% v 92.5%, respectively) and 10-year OS rates (91.8% v 92.5%, respectively) were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%; P < .001). The 5-year locoregional recurrence-free survival rates were also not different between patients with pCR (92.8%; 95% CI, 86.1% to 96.4%) and patients with pCR+DCIS (90.9%; 95% CI, 77.3% to 96.5%; P = .63). Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of patients with residual DCIS in the definition of pCR is justified when this outcome is used as an early surrogate for long-term survival.

Effect on patient outcome of residual DCIS in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy

530 Background: To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with hiostologically defined complete eradication of invasive cancer. Methods: Retrospective analysis of a database including 2,302 breast cancer patients treated prospectively with neoadjuvant chemotherapy at the UT MD Anderson Cancer Center between 1980 and 2004 was performed. The overall, disease-free and local recurrence-free survivals were compared for patients with no residual invasive or in situ cancer (pCR) and those with no residual invasive cancer but persistent in situ disease (pCR+DCIS). Results: The mean follow-up was 250 months. Of the 2,302 treated patients 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2025 (88%) had residual invasive cancer. The 5-year (87.1% in both) and 10-year (81.3% vs 81.7%) disease-free survival rates were similar for cases with pCR and pCR+DCIS. The 5-year (91.9% vs. 92.5%) and 10-year (91.8% vs. 92.5%) overall survival rates were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%, p&lt;0.001). The 5-year local-regional recurrence-free survival rates were also not different for patients with pCR (92.8%, 95% CI: 86.1%-96.4%) and those with pCR+DCIS (90.9%, 95% CI: 77.3%- 96.5%), p=0.63. Conclusions: Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of cases with residual DCIS in the definition of pathologic complete response is justified when this outcome is used as early surrogate for long term-survival. No significant financial relationships to disclose.

Targeting HER-2/neuin Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.

Prospective Study of Wide Excision Alone for Ductal Carcinoma in Situ of the Breast

It has been hypothesized that wide excision alone with margins > or = 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial. Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of < or = 2.5 cm treated with wide excision with final margins of > or = 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients. In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease. Despite margins of > or = 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.

Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma

Patients who have no residual invasive cancer following neoadjuvant chemotherapy for breast carcinoma have a better overall survival than those with residual disease. Many classification systems assessing pathological response to neoadjuvant chemotherapy include residual ductal carcinoma in situ (DCIS) only in the definition of pathological complete response. The purpose of this study was to investigate whether patients with residual DCIS only have the same prognosis as those with no residual invasive or in situ disease. A retrospective analysis of a prospectively maintained database identified 435 patients, who received neoadjuvant chemotherapy for operable breast cancer between February 1985 and February 2003. Of these, 30 (7%; 95% CI 5–9%) had no residual invasive disease or DCIS and 20 (5%; CI 3–7%) had residual DCIS only. With a median follow-up of 61 months, there was no statistical difference in disease-free survival, 80% (95% CI 60–90%) in those with no residual invasive or in situ disease and 61% (95% CI 35–80%) in those with DCIS only (P=0.4). No significant difference in 5-year overall survival was observed, 93% (95% CI 75–98%) in those with no residual invasive or in situ disease and 82% (95% CI 52–94%) in those with DCIS only (P=0.3). Due to the small number of patients and limited number of events in each group, it is not possible to draw definitive conclusions from this study. Further analyses of other databases are required to confirm our finding of no difference in disease-free and overall survival between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer.

Predictors of Residual Disease in Repeat Excisions for Lumpectomies with Margins Less Than 0.1 cm

Purpose This study sought to identify factors that would predict the presence of residual disease (RD) in repeat-excision specimens following an initial breast-sparing excision procedure in which the margins of resection were free of tumor but in which tumor was very close to ≥ 1 margins. Patients and Methods Ninety-one lumpectomies with close but not transected margins and their subsequent repeat-excision specimens were analyzed for tumor type near margin in the primary excision, presence of RD, type of RD, stage of infiltrating carcinoma (IC) in the primary excision, extent of ductal carcinoma in situ (DCIS), and grade of IC and/or DCIS. Results Nineteen of 91 patients had DCIS only; 15 had IC only; and 57 had IC with DCIS in their primary excisions. Thirty-five cases (38%) contained RD in their subsequent repeat-excision specimens. Residual DCIS and/or IC was present in 58% of patients whose primary tumors were DCIS only or invasive carcinoma < 6 mm (T1a), whereas invasive carcinomas ≥ 6 mm had RD in only 28%. Twenty-three patients (64%) with extensive DCIS had RD, whereas 12 patients (22%) with no DCIS or minor DCIS (< 10 mm) had RD (χ 2 = 16.27; P < 0.001). Ductal carcinoma in situ was within 0.1 cm of the margin in 52 patients, and RD was present in 26 (50%), whereas 18 of 56 patients (32%) with IC close to the margin had RD ( P < 0.05). Grade of DCIS and IC was not related to presence of RD. Residual carcinoma was present in 38% of repeat-excision specimens with close but not transected margins in this study. Conclusion The extent of DCIS in the primary specimen, DCIS near ≥ 1 margins, and size of infiltrating tumor were related to the presence of RD.