bluuebunny/crossref_metadata_2025 huggingface dataset:
P2-06-04: Phosphatidylinositol-3-Kinase Pathway Mutations Are Common in Breast Columnar Cell Lesions.
Authors: Troxell ML , Brunner AL , Montgomery K , Zhu SX , Neff T , Warrick A , Beadling C , Corless CL , West RB
Published: June 2012

The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated in invasive breast carcinoma, with PIK3CA mutations present in ∼25% of invasive carcinomas, and AKT1 mutations identified in up to 5%. Several studies have demonstrated the same complement of mutations in ductal carcinoma in-situ (DCIS), as well as benign papillomas. We sought to investigate whether PIK3CA mutations occur in breast columnar cell lesions (CCL).

Twenty-five breast resection specimens containing CCL (including columnar cell change, columnar cell hyperplasia, and flat epithelial atypia) were identified from the files of Stanford University Pathology; 15 of these had associated invasive carcinoma (IDC) or carcinoma in situ. DNA was prepared from punches of formalin-fixed paraffin-embedded tissue blocks using standard methods. DNA extracts were screened for a panel of point mutations using a multiplex PCR panel with a mass-spectroscopy readout (Sequenom MassARRAY). The panel covers 321 mutations in 30 genes, including ABL, AKT1/2/3, BRAF, CDK4, CTNNB1, EGFR1, ERBB2, FBX4, FBXW7, FGFR1/2/3, FLT3, GNAQ, HRAS, JAK2, KIT, KRAS, MAPK2K1/2, MET, NRAS, PDGFRA, PIK3CA, PTPN11, RET, SOS1, and TP53. The majority of mutations were confirmed by Sanger sequencing. PIK3CA mutations were identified in 12/25 CCL (48%); paired normal breast tissue was tested in 21 cases and was negative for mutations in all but one case. In associated DCIS, 4/8 (50%) harbored PIK3CA mutations, while 3/9 IDC had mutations (33%, 2 PIK3CA, 1 AKT1). The mutation status of CCL and carcinomas was frequently discordant. Of 15 cases, only 6 demonstrated the same genotype in matched samples of CCL and carcinoma (5 wildtype, 1 PIK3CA H1047R). Interestingly, 5 patients had mutations in CCL with wildtype DCIS or IDC; 2 patients had different point mutations in CCL and carcinoma, including one patient with discordant mutant DCIS and wildtype IDC. Only 3 cases had wildtype CCL and mutated carcinoma.

The nearly 50% PIK3CA mutation prevalence in CCL is greater than reported in most studies of invasive breast cancer. Further, CCL and carcinoma were frequently discordant for PIK3CA/AKT1 mutation status; most commonly the CCL harbored a PIK3CA mutation, while the associated carcinoma was wildtype. Although these findings need validation in a larger study, they raise interesting questions as to the role of PIK3CA/AKT pathway in breast carcinogenesis, and as to the biologic/precursor potential of CCL.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-04.
P2-09-11: Role of 18FDG-PET/CT in the Staging of Large Primary Operable Breast Cancer.
Authors: Groheux D , Giacchetti S , Hamy A-S , Vercellino L , Delord M , Berenger N , Toubert M-E , Misset J-L , Hindié E , Espié M
Published: June 2012

Background: Prospective evaluation of the role of 18FDG-PET/CT in patients with large primary operable breast cancer.

Material and Methods: During 56 months, consecutive patients with large (>2cm) breast cancer and clinical stage IIA/IIB/IIIA (based on clinical examination, mammography, breast MRI and ultrasonography) underwent 18FDG-PET/CT. The nuclear physician was blind to the results of any other procedure (bone scan, chest X-ray, liver ultrasound, or thoraco-abdominal CT scan). Results: Out of the 131 examined patients, 36 had clinical stage IIA (34 T2 N0, 2 T1 N1), 48 stage IIB (20 T3 N0, 28 T2 N1), and 47 stage IIIA (29 T3 N1, 9 T2 N2, 9 T3 N2). 18FDG-PET/CT modified staging for 5.6% of stage IIA patients, for 14.6% of stage IIB patients, and for 27.6% of stage IIIA patients. However, within stage IIIA, the yield was specifically high among the 18 patients with N2 disease (56% stage modification). When considering stage IIB and primary operable IIIA (T3 N1) together, the yield of 18FDG-PET/CT was 13% (10/77); extra-axillary regional lymph nodes were detected in 5 and distant metastases in 7 patients. In this series, 18FDG-PET/CT outperformed bone scan with only 1 misclassification versus 8 for bone scan (p=0.036).

Discussion: 18FDG-PET/CT provided useful information in 13% of patients with T3 N0 / T2 N1 / T3 N1 disease. The yield was more modest in patients with T2 N0 disease. The very high yield in the case of lymph nodes classified N2 demonstrates that stage IIIA comprises two quite distinct groups of patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-11.
P2-11-05: Stromal Matrix Metalloproteinase-14 Expression Correlates with the Grade and Biological Behavior of Mammary Phyllodes Tumors.
Authors: Lee JS , Park MH , Yoon JH
Published: June 2012

Phyllodes tumors (PTs) of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. Matrix metalloproteases (MMPs) and their tissue inhibitors of metalloproteases (TIMPs) are involved in several key aspects of tumoral growth, invasion and metastasis, but little is known of their expression in PTs. The objective of this study was to assess the expression of MMPs and TIMPs in PTs and to determine their association with grade and clinical behavior of PTs. Eighty-two PTs (50 benign, 22 borderline, and 10 malignant) were studied. Automated immunohistochemical staining for MMP-1, -2, -7, -9, -11, -13, and -14 and TIMP-1, -2, and -3 was performed using tissue microarray blocks and the expression of MMPs and TIMPs was assessed in both the stromal components. There were no significant differences in the expression of stromal MMPs and TIMPs in the three groups of PTs, except for MMP-14. There was a significant increase in stromal MMP-14 expression with increasing PT grade (P < 0.01). The stromal MMP-14 expression in the borderline and malignant PTs was higher than that in benign PTs (P < 0.05 and P < 0.05, respectively). Furthermore, the expression of stromal MMP-14 was associated with a higher rate of recurrence (P < 0.05). Our results show for the first time that stromal MMP-14 expression is associated with the grade and clinical behavior of PTs of the breast.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-05.
P2-11-10: Low Toll-Like Receptor 9 Expression Is Required for the Aggressive Behavior of Triple Negative Breast Cancer Cells in Hypoxia.
Authors: Selander KS , Tuomela J , Sandholm J , Karihtala P , Pressey C , Ilvesaro J , Vuopala K , Kauppila JH , Kauppila S , Harris KW , Graves D , Jukkola-Vuorinen A
Published: June 2012

Toll-like receptor-9 (TLR9) is a cellular DNA-receptor and a member of the innate immune system which is widely expressed in breast cancers. Although synthetic TLR9-ligands stimulate breast cancer cell invasion in vitro, through down-regulation of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), the role of this protein in breast or other cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with a significantly shortened breast cancer specific survival among patients with triple negative tumors, but not among those with ER+ tumors. We further discovered that hypoxia induces TLR9 expression in breast cancer cells in vitro and in vivo. Although the triple negative TLR9 siRNA MDA-MB-231 breast cancer cells (with lower TLR9 expression) were less invasive than control siRNA cells in normoxia, these cells became highly aggressive in hypoxia and they formed significantly larger tumors than corresponding control cells in an orthotopic model in vivo. Further in vitro experiments revealed that the removal of TLR9 expression through siRNA significantly potentiated the hypoxia-induced invasive capacity of the triple negative MDA-MB-231 cells, but not that of the ER+ T47-D cells. Low TLR9 expression in hypoxia resulted also in complete disappearance of TIMP-3 in the MDA-MB-231 cells, but not in the ER+ T47-D cells. Taken together, these studies suggest that low TLR9 expression has different effects on the behavior of triple negative and ER+ breast cancer cells in hypoxia; triple negative cells become more invasive under these conditions, possibly through loss of endogenous invasion inhibitors, such as TIMP-3. Furthermore, these studies suggest that low TLR9 expression in triple negative breast cancers may serve as a novel prognostic factor and help characterize the group of patients that are at a high risk of relapse. Finally, our results suggest that any treatments or factors that lower TLR9 expression or induce hypoxia in residual or metastatic triple negative breast cancer cells, might actually induce their spread.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-10.
P2-12-11: Clinical Relevance of a IL-8/B-Cell Gene Signature Identified from Triple Negative Breast Cancer (TNBC) in Intrinsic Breast Cancer Subtypes.
Authors: Rody A , Holtrich U , Ruckhaeberle E , Radosa J , Juhasz-Boess I , Solomayer EF , Kaufmann M , Karn T
Published: June 2012

Background: As presented recently (SABCS 2010, #S5-5) a ratio of high B-cell and low IL-8 metagenes using gene expression analysis identified 32 % of triple negative breast cancers with good prognosis and was the only significant predictor in multivariate analysis including routine clinicopathological variables.

However, the clinical relevance of this signature within the intrinsic breast cancer subtypes still remains unclear and is analyzed here.

Methods: Affymetrix gene expression data from n=2417 breast cancer patients have been assembled. We performed an unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC (SABCS 2010, #S5-5). A high expression of B- cell metagenes was associated with good and high expression of IL-8-related metagenes were associated with poor prognosis.

To identify intrinsic subtypes we used the method previously described by Hu et al. (2006) and the prognostic value within those subtypes was assessed by analyzing the event free survival of patients as function of high and low B-cell/IL-8 metagene ratio.

Results: Comparing ER positive with ER negative patients the B-ceh7LL-8 ratio showed only in ER negative breast cancer a significant prognostic value (log rank p-value <.0001).

Within the entire cohort 37.8 % of patients could be assigend to luminal A, 35.2 % to luminal B, 7,4 % to erbB2 and 19.6 % to basal-like subtypes. Event free survival of patients with good or poor B-cell/IL-8 ratio showed only in basal-like breast cancer patients a statistical significant difference (p<.0001). However, we could not observe any difference in prognosis in luminal A and B, as well as erbB2 tumors. No difference in the expression of the proliferation metagene was observed when samples of the intrinsic subtypes were stratified according to the prognostic predictor based on high expression of the B-Cell metagene and low expression of the IL-8 metagene.

Conclusion: The B-cell/IL-8 ratio is highly prognostic in basal-like/TNBC and shows no association with proliferation status.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-11.
P2-12-18: A Prognostic Model Based on Node Status, Cathpesin-D and Ki-67 Predict the Outcome of Patients Failing To Achieve Pathological Complete Response after Anthracycline-Based Neoadjuvant Chemotherapy for Breast Cancer.
Authors: Chen S , Chen C , Yu K , Shao Z
Published: June 2012

Background

Aim of this study was to evaluate factors which could possibly affect the outcome of patients failing to achieve pathological complete response (pCR) after anthracycline-based neoadjuvant chemotherapy (NCT) for breast cancer, and built a prognostic model to predict disease free survival (DFS) and overall survival (OS).

Material and Methods: We retrospectively collected data of 199 stage II-III breast cancer patients who had failed to achieve pathological complete response after neoadjuvant chemotherapy in Shanghai Cancer Hospital. The NCT regimens were NE (navelbine 25mg/m2, day 1, 8 and epirubicin 60mg/m2, day 1; every three weeks) or CEF (cyclophosphamide 600 mg/m2, day 1; epirubicin 60 mg/m2, day 1 and 5-fluorouracil 600 mg/m2, day 1; every three weeks) for a median treatment course of 3 cycles. To develop the prognostic model, variables at baseline(age, menopausal status, tumor size, node status, ER, PR, and HER-2) and at surgery(tumor size, grade, histotype, node status, vascular invasion, ER, PR, HER-2, Cathpesin-D, P53, Topo-IIα, Nm-23, Bcl-2, BAX, MDR, GSTn, PS2, P27, Cyclin D1 and Ki-67) were investigated. Multivariate Cox regression model and Kaplan-Meier method was used to build the model, and show the discrimination of DFS and OS in different risk groups.

Results: By multivariate analysis, ≥4 lymph node metastasis (HR=1.9, P=0.009), Cath-D positive (HR=2.5, P=0.006), and Ki-67 index≥20% (HR=1.9, P=0.001) at surgery were independent predictors for lower DFS and OS rate among non-pCR responders. We built a prognostic scoring model on the basis of these variables, in which ≥4+ nodes, Cath-D + or Ki-67 index≥20% would contribute 1 point separately to the risk score. The 5-year DFS rates in low(0 point), intermediate-low(1 point), intermediate-high(2 points) and high risk groups(3 points) were 94%, 65%, 43%, and 28%, respectively (Log-rank teat p<0.001). The 5-year OS rates in these four groups were 94%, 84%, 66% and 34%, respectively (Log-rank test p<0.001).

Conclusion: Post-NCT node status, Cathpesin-D and Ki-67 were used to develop a prognostic model which could simply discriminate patients with poor prognosis among non-pCR responders after anthracycline-based neoadjuvant chemotherapy, and might help to tailor further individualized treatment strategies.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-18.
P2-12-20: Adjuvant! Online Is Overoptimistic in Predicting Survival of Asian Breast Cancer Patients.
Authors: Bhoo Pathy N , Yip CH , Hartman M , Saxena N , Taib NA , Bulgiba AM , van der Graaf Y , Verkooijen HM
Published: June 2012

Background

Adjuvant! Online is a free web-based tool which predicts 10-year breast cancer outcomes and efficacy of adjuvant therapy in patients with breast cancer. As its prognostic performance has only been validated in high income Caucasian populations, the model was validated in a middle income Asian setting.

Material and Methods: Within the University Malaya Hospital-Based Breast Cancer Registry, all 631 women receiving standard surgery for invasive non-metastatic breast cancer between 1993 and 2000 were identified. Calibration of Adjuvant! Online was evaluated by comparing the predicted 10-year overall survival with observed 10-year survival. Discrimination of the model was tested by receiver operating characteristic (ROC) analysis.

Results: For the entire cohort, Adjuvant! Online predicted 10 year survival (70.3%) was significantly higher than the observed 10 years survival (63.6 %) by a difference of 6.7% (95%CI: 3.0%- 10.4%). The model was especially overoptimistic in women under 40 years and in women of Malay ethnicity, where survival was overestimated by approximately 20% (95%CI: 9.8- 29.8%) and 15% (95%CI: 5.3−24.5%) respectively.

Adjuvant! Online performed fairly in terms of discrimination, with an area under ROC curve of 0.73 (95%CI: 0.69−0.77).

Conclusion: Even though Adjuvant! Online is capable of discriminating between good and poor survivors, it systematically overestimates survival. These findings suggest that the model requires adaptation prior to use in Asian settings.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-20.
P2-14-02: NCIC CTG MA.27: Clinical Tolerability and Overall Survival of Racial and Ethnic Minority Women on Aromatase Inhibitor Therapy.
Authors: Moy B , Shepherd LE , Chapman J-AW , Le Maitre A , Gelmon KA , Elliott C , Ingle JN , Goss PE
Published: June 2012

Background

Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. We previously reported that racial/ethnic minority women receiving an AI in NCIC CTG MA.17 experienced fewer hot flashes, fatigue, and arthralgias than Caucasians (Moy B et al. Ann Oncol 2006;17:1637). Here we examined whether race affected clinical outcomes in the MA.27 AI trial comparing exemestane (E) with anastrozole (A).

Methods: Fisher's exact test was used to compare observed side effects (0 vs grades 1–5) between minority and Caucasian women. Adverse events (AE), including menopausal symptoms, were assessed according to the Common Terminology Criteria of the National Cancer Institute (version 3.0). ITT univariate test of race effects on overall survival (OS) was determined with a stratified log-rank test, while multivariate testing was with stratified Cox regression.

Results: Among 7312 for whom race was known, distribution was: Caucasian (n=6939; 95%); black (n=235; 3%); Asian/Native Hawaiian/Pacific Islander (n=93); 1%; American Indian (n=39; 1%); and mixed race (n=6). Among women treated with E, minorities reported a significantly lower incidence of hot flashes (45% vs. 56%; p=0.003) and fatigue (34% vs. 46%; p=0.001) compared to Caucasians. Similarly with A, minority women reported significantly fewer hot flashes (47% vs. 58%; p=0.002) and lower cholesterol (12% vs. 18%; p=0.01); however, they reported more headaches than Caucasians (16% vs. 10%; p=0.01). Caucasian women were more likely to discontinue therapy due to AE or side effects (32% vs. 24%). There was a significant OS interaction (p=0.02) between race and treatment with minority women on E having fewer deaths than those on A. Caucasian women had HR of E to A of 0.98 (95% CI 0.81−1.20), p=0.85, while minorities had HR of E to A of 0.72 (95% CI 0.33−1.58), p=0.41.

Conclusions: Minority women tolerated AIs better and were also more compliant than Caucasians, supporting our previous findings. A significant interaction between race and type of AI therapy for OS was seen, favoring exemestane in minority women. Replication of these findings in larger cohorts is necessary. Since race/ethnicity may serve as a surrogate for genetic differences, our findings suggest pharmacogenomic differences which require further research.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-02.
P2-15-04: Clinical Significance of Resection with Curative Intent for Isolated Pulmonary Metastases from Breast Cancer. Multi-Institutional Study in Japan.
Authors: Sato N , Ohsumi S , Iwase T , Inaji H , Mizutani M , Nishimura R , Mukai H
Published: June 2012

OBJECTIVE: Although resection of isolated pulmonary metastases is a common treatment in other primaries such as colon cancer, the role of lung metastasectomy of breast cancer is still unclear. The objective of the present study was to investigate the clinical outcome of our operated patients with isolated pulmonary breast cancer metastases and discuss the clinical implication of resection with curative intent for them.

METHODS: We retrospectively analyzed 86 female patients with histologically proven isolated pulmonary metastases from breast cancer who were treated with surgery of curative intent between January 1980 and September 2010 at 7 Japanese hospitals. The mean age of them was 50 years, the median disease free interval (DFI) from the definitive surgery for the primary breast cancer was 4.6 years (range: 0.5−20.4 years) and the median follow-up after lung metastasectomy was 4.1 years (range: 0.3−30.9 years).

RESULTS: Lung metastasectomy was performed by thoracotomy in 22 patients and by video-assisted thoracoscopic surgical resection in 64 patients. The number of metastatic foci resected was one for 79 patients, two for 6, and unknown for 1. Lymph node resection was performed for 12 patients, was not done for 69, and unknown for 5. Five-year survival rates after lung metastasectomy were 68% in the patients. The main prognostic factor was the DFI. Five-year survival rates for patients with DFI of longer than 2 years (n = 72) and those with DFI of shorter than 2 years (n=14) were 74.5% and 33.8%, respectively (p = 0.0006). Five-year survival rates after lung metastasectomy were 68% in patients without macroscopic residual pulmonary tumor after lung metastasectomy (n = 69) and 34% in those with macroscopic residual tumor (n = 12) (p = 0.023). Five-year disease free survival after lung metastasectomy for patients without macroscopic residual tumor was 51 %. Five-year survival rates were 78% in patient with endocrine hormonal therapy following lung metastasectomy (n = 51) and 53% in those without endocrine hormonal therapy (n = 35) (p = 0.045). No prognostic influence could be demonstrated for age, number of initial axillary node metastases, primary tumor size.

CONCLUSION: The prognosis of the breast cancer patients with isolated pulmonary metastases who underwent metastasectomy with curative intent was good. It was affected by the biological aspects of the primary tumor, “curativity” of the resection, and systemic treatments after lung resection. It may be expected that some of those patients will be cured by surgery with curative intent.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-04.
P2-15-08: New Trends for Surgical Treatment of Large Breast Tumors.
Authors: Zucca Matthes AG , Vieira RAC , Kerr LM , Matthes ACS , Folgueira MAAK , Uemura G
Published: June 2012

Introduction: The locally advanced breast cancer is still common in developing countries. The neoadjuvant chemotherapy (NC) allows converting large tumor into operable one. Oncoplastic surgery (OS) adds new techniques to breast conservative treatment(BCT). The association between NC and OS provides the resection of large amount of breast tissue, including skin, with satisfactory aesthetic results.

Objective: Evaluate the possibilities to indicate oncoplastic techniques to determine BCT after NC for large breast tumors.

Material and Methods: A prospective clinical trial (www.clinicaltrials.gov; NCT00820690) study with women breast cancer patients, clinical stage III, no extense skin involvement, submitted to NC, based on four cycles of doxorubicin 60mg/m2 + cyclophosphamide 600 mg/m2 and 4 cycles of paclitaxel 175mg/m2. Preoperative tattoo was realized for all patients to determine the clinical dimensions of the tumor. Tumor size was controlled by physical and radiological exams. The oncoplastic surgeries were offered in accordance to clinical-imaging previous to NC, final response to chemotherapy, tumor localization, tumor size, breast size, oncologic security, patient comorbidities and experience of the surgeon. The skin-sparing mastectomy with immediate breast reconstruction was also considered an oncoplastic technique. The surgical planning has involved the whole area previously marked by the tattoo regardless of tumor response. A detailed analysis of the pathological specimen was provided to confirm the oncologic safety of the treatment. All patients were followed by radiotherapy after surgery.

Results: 50 patients were enrolled. PE tumor median measurement was 6.5 cm (3.0 to 14.0 cm) and pathologic median tumor was 4.0 cm (0 to 14.5cm). Pathologic response was rated as stable disease, progressive disease, partial response and complete response in 18%, 10%, 68% and 4% of the cases, respectively. Pathologic responses were diverse and included tumor micro-fragmentation and macrofragmentation. PE tumor size before chemotherapy correlated best with MRI (ricc 0.588, p < 0.001), as well as pathologic tumor size measured after chemotherapy correlated best with MRI (ricc 0.738, p <0.001). The surgical approach allowed BCT in 34% (17) of patients. Skin involvement was presented in 38% of pathologic specimen regardless previous clinical exam noticed.

Conclusion: Oncoplastic techniques increase the rates of BCT for selected patients in spite of large locally advanced tumors. The surgical planning is fundamental to this approach. This study recommends the full resection of the tumoral area previous to NC, including marked skin, regardless the response to neoadjuvant treatment. Follow-up of these patients will be important for additional information in the future.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-08.
P2-15-13: Oncologic and Cosmetic Outcome in Breast Cancer Patients Who Underwent “Moving Window” Operation.
Authors: Ohno Y , Noguchi M , Nakano Y , Noguchi M , Kosaka T
Published: June 2012

Background: An inappropriate skin incision on the breast reduces the cosmetic benefit of breast-conserving surgery (BCS).

Methods: To improve the cosmetic outcome, we have performed “Moving window” operation in which BCS can be performed via a periareolar incision (periareolar approach) and/or axillary incision (axillary approach) under direct visualization. Axillary lymph node dissection is also performed via an axillary incision.

Results: Periareolar approach was performed in 65 patients and axillary approach in 43 patients. Average operation time was 130 minutes in periareolar approach and 131 minutes in axillary approach. Average blood loss was 37 mL and 50 mL, respectively. Postoperatively, the surgical margin of breast tissue was histologically confirmed to be negative in 107 (99%) of 108 patients, while two patients underwent reoperation because of positive surgical margin. Fifty-two patients (85%) in periareolar approach and 37 patients (86%) in axillary approach had excellent or good cosmetic results.

With a mean follow-up of 36 months, one patient with DCIS developed in-breast recurrence, while 3 patients who had neoadjuvant chemotherapy developed in-breast recurrence.

Conclusion: The moving window operation can improve a cosmetic outcome of the conserved breast without compromising the oncological safety.

Moreover, it can reduce operating time and blood loss when compared with the endoscope-assisted BCS.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-13.
P2-16-05: Delay of Adjuvant Chemotherapy after Elective Mastectomy and Immediate Reconstruction in Breast Conservation Candidates: A Matched-Pair Analysis.
Authors: Barry PN , Riley EC , Pan J , Crew JB , Lee K , Jain D , Kruse B , Quillo AR , Rai S , Dragun AE
Published: June 2012

Background: To analyze factors that influence the timing of adjuvant chemotherapy in patients who are candidates for breast conservation therapy (BCT) but elect mastectomy with immediate reconstruction (M-IR).

Methods: Using data from the University of Louisville Cancer Registry, we identified 35 consecutively-treated patients with stage I or II breast cancer between 2004 and 2009 who underwent M-IR and adjuvant chemotherapy. These were matched for age and AJCC stage to 35 controls who underwent BCT and adjuvant chemotherapy. We examined the timing of initiation of chemotherapy from the date of surgery and assessed the probability of therapeutic delay using univariate logistic regression and McNemar's test for matched pairs. Results: For the 70 patients included in this study, the median age was 46y (range: 30–65y), and the distribution for stage I, IIA and IIB was 22.9%, 65.7% and 11.4%, respectively. The two groups were well balanced in terms of race, rural/urban status, smoking, diabetes, insurance coverage, and histology. The median time to initiation of adjuvant chemotherapy was 38 days (range: 25–103 days) for BCT and 55 days (range: 30–165 days) for M-IR. Patients undergoing M-IR were more likely to experience any delay (> 45 days; 74.3% vs. 25.7%, p < 0.001) and/or significant delay (>90 days; 20.0% vs. 2.9%, p < 0.001) than those choosing BCT. On univariate logistic regression analysis, the extent of surgery had a major impact on the likelihood of any delay in chemotherapy (OR= 8.35, 95% C.I. = 2.86−24.3, p <0.001). None of the other aforementioned factors predicted for delay. Conclusion: The use of elective mastectomy with immediate reconstruction in breast conservation candidates independently predicts for delay in initiation of adjuvant chemotherapy. Further study is needed to qualify the underlying causes of and ultimate clinical significance of these delays.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-16-05.
P2-16-06: A Systematic Review of Standardised Clinical Outcomes and Patient Reported Outcome Measures (PROMS) in Breast Reconstruction.
Authors: Winters ZE , Chaudhry A , Benson JR
Published: June 2012

Introduction: Failure to prospectively define and report surgical complications across a range of study designs is a confounding factor that fundamentally compromises the interpretation of data on health-related quality of life (HRQL) and PROMS. The UK National Mastectomy and Breast Reconstruction audit on 5000 breast reconstruction patients found higher than expected levels of complications (including rates of reoperation and levels of infection). We aimed to analyze the reporting of complications in a systematic review of all studies evaluating PROMS in breast reconstruction since 19781.

Methods: Efficace criteria for HRQL methodology were used to assess the inclusion eligibility for each study1. Two out of 34 eligible studies were excluded due to overlapping patient datasets and small numbers (n<5) of breast reconstruction cases. Two reviewers examined the reporting of complications. The study designs comprised: 2 randomised controlled trials (RCT); 10 prospective longitudinal studies (PLS) and 20 retrospective studies (RS). RCTs and PLS were evaluated for predefined complications, their grading according to Clavien-Dindo2 and their integration into the evaluation of PROMS results. RS were evaluated for the reporting of complications and their statistical methodology.

Results: A total of 3213 patients were included in the 32 studies. The type of reconstruction was only recorded in 71% of patients. The majority of patients in these studies underwent abdominal flap reconstruction, compared to implant only techniques (32%), and less than 10% comprising Latissimus dorsi flaps. Only 19% of studies recorded complications with the majority (81%) failing to report any complications. Only 3 studies provided details of the numbers and level of complications amongst a total of 44 patients (1.4% of the total number of patients). Reported complications were graded and classified either as major (requiring surgical intervention) or minor comprising 55% and 45%, respectively. None of the RCT or PLS studies defined either the type or level of complications a priori, nor stratified complications based on risk factors such as age, body mass index, smoking and diabetes.

Conclusion: There is a significant under estimation of the contribution of complications to HRQL and PROMS reporting. This fact diminishes the current evidence on the effects of breast reconstruction on PROMS. There should be collective efforts to improve the standards of documentation for clinical outcomes in breast reconstruction. This together with standardized reporting of PROMS will consolidate clinical evidence upon which decision-making and provision of patient information can be confidently based.

1. Winters ZE, Benson JR, Pusic AL. Annals of Surgery 2010;252(6):929–42

2. Dindo D et al. Annals of Surgery 2004;240(2):205–213

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-16-06.
P2-16-09: Nipple-Areolar Sparing Mastectomy: Utility of the Lateral Inframammary Incision in Immediate Implant-Based Reconstructions.
Authors: Guth AA , Blechman K , Levovitz C , Small K , Axelrod D , Karp N , Choi M
Published: June 2012

Purpose: Nipple and/or areola-sparing mastectomy as a therapeutic or prophylactic procedure for breast cancer is rapidly gaining popularity as the literature continues to support it safety. The lateral inframammary fold (IMF) approach provides adequate exposure and eliminates visible scars on the anterior surface of the breast, making this incision cosmetically superior to radial or periareolar approaches.

Methods: We reviewed 58 consecutive nipple and/or areola-sparing mastectomies performed through a lateral IMF incision with immediate implant-based reconstruction, with or without tissue expansion, between June 2008 and February 2011. Prior to incision, breasts were lightly tumesced with dilute anesthetic solution with epinephrine. Sharp dissection, rather than electrocautery, was used as much as possible to minimize thermal injury to the mastectomy flap. When indicated, acellular dermal matrix was placed as an inferolateral sling. Subsequent fat grafting to correct contour deformities was performed in select patients. Three-dimensional (3D) photographs assessed changes in volume, antero-posterior projection, and ptosis. Retroareolar/nipple tissue underwent routine intraoperative frozen section analysis in cancer cases.

Results: Mean patient age was 44 years, and mean follow-up time was 14 months. Depending upon the judgment of the oncologic surgeon, 44 (76%) mastectomies were nipple/areola-sparing, and 14 (24%) were areola-sparing. Thirteen mastectomies (22%) were therapeutic, the remaining 45 mastectomies (78%) were prophylactic. Five of the nine sentinel lymph node biopsies (56%) were performed through the lateral IMF incision without the need for a counter-incision. Acellular dermal matrix was used in 44 (76%) breasts. Average permanent implant volume was 313 cc (range 170 to 750 cc), and average fat grafting volume was 90 cc (range 36 to 177 cc). Mastectomy flap necrosis, requiring operative debridement, occurred in three breasts (5%). One of these breasts required a salvage latissimus dorsi myocutaneous flap to complete the reconstruction. Of the 44 nipple/areola sparing mastectomies, three (7%) required operative debridement and reconstruction for partial nipple necrosis. No statistically significant differences existed between therapeutic and prophylactic mastectomies for developing partial skin or nipple necrosis (p = 0.65). Morphologic outcomes using 3D scan measurements showed reconstructed breasts were larger, more projected, and less ptotic (196 vs. 248 cc, 80 vs. 90 mm, 146 vs. 134 mm, p < 0.01 for each parameter).

Conclusion: Excellent results can be achieved with immediate implant-based reconstruction of nipple and/or areola-sparing mastectomy through a lateral IMF incision. NAC survival is reliable, and complication rates are low.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-16-09.
P2-16-10: Practice Variations in Post-Mastectomy Breast Reconstruction: What Are the Roles of Clinical Factors, Access Barriers, and Delayed Reconstruction?
Authors: Cox D , Milucky J , Dominik R , Lee C
Published: June 2012

Background: Breast reconstruction rates vary widely by race, income, and location. Proposed explanations have included clinical contraindications to reconstruction, access barriers, and patient or surgeon preference for delayed reconstruction. We sought to determine whether clinical contraindications (planned radiation, comorbidities) or access barriers (distance to care, surgeon) were associated with reconstruction and to estimate the frequency of delayed reconstruction over time.

Methods: A retrospective cohort study was conducted among women treated with mastectomy for Stage 0-IIIa breast cancer between 2002 and 2007 at one institution. Demographics, stage, comorbidities, adjuvant therapy plans, and treatments were obtained from the medical record. Multivariable modified Poisson regression analyses were performed, with immediate and any reconstruction (immediate or delayed) as outcomes. Interaction terms were added to examine surgeon effects. Kaplan-Meier survival analysis was performed. Results: Among 539 women, 18.9% had a plan for chemotherapy; 13.7% had a plan for radiation. Comorbidities were: obesity 17.1%, diabetes 11.9%, smoking 16.3%, heart disease 5.6%, immunodeficiency 2.2%. Most patients (59.8%) lived within 50 miles of the hospital. 33.8% had immediate reconstruction; 5.6% had delayed. Patients who had a plan for adjuvant therapy or comorbidity were less likely to have reconstruction. Patients who lived farther from the hospital were slightly more likely to have reconstruction, but this was not statistically significant (p<0.08). None of the associations varied significantly by surgeon. Few patients had reconstruction more than 2 years after mastectomy.

Conclusion: Clinical contraindications may explain some breast reconstruction practice variations. Few patients who defer immediate reconstruction, however, ever have delayed reconstruction.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-16-10.
P2-19-01: Impact of Zoledronic Acid on Fractures, Bone Mineral Density and Bone Remodeling in the AZURE Trial (BIG 01–04).
Authors: Coleman R , Woodward E , Turner L , Marshall H , Collinson M , Dodwell D , Davies C , Bell R , Cameron D , Brown J
Published: June 2012

Background: The AZURE trial was designed to determine whether the addition of zoledronic acid (ZOL) to standard adjuvant therapy improves disease free survival (DFS) in patients (pts) with stage II/III breast cancer. Although in a recent analysis after 752 events and a median follow-up of 59 months no difference in overall DFS was seen between ZOL and control pts, significant benefits were seen in women >5years post menopause. Here, we report the impact of ZOL on fractures in the main study, and on bone mineral density (BMD) and bone remodeling evaluated within a sub-study.

Materials and methods: 3360 pts were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy with (n=1681) or without (n=1678) up to 19 doses of ZOL 4mg over 5 years. Pts with osteoporosis and those using bisphosphonates, either at baseline or in the previous year, were excluded from study entry. BMD was assessed in 228 patients within a sub-study; 40 of these also underwent quantitative bone scanning (QBS), a novel imaging technique that yields values for 99mTc-MDP/HMDP whole skeleton plasma clearance (Kbone) as a surrogate for the rate of bone remodeling and enables assessment of specific regions of interest within the skeleton.

Results: Fractures occurred in 152 (4.5%) pts; 60 (3.6%) ZOL pts compared with 92 (5.5%) control (CTRL) pts (difference −1.9%; 95%CI −3.3%, −0.5%). The difference in fracture incidence appeared early and persisted throughout the follow-up period. Fifty-six (86.2%) of the fractures in the ZOL group and 68 (61.8%) in the CTRL group occurred in the absence of, or prior to a DFS event. The fracture rates before disease recurrence were similar at 3.0% (51 pts) in the ZOL group and 3.4% (57 pts) in the CTRL group (difference −0.4%; 95%CI −1.6%, 0.8%). In contrast, 2.1% (8 ZOL pts) and 9.1% (34 CTRL pts) experienced a fracture after a DFS event (difference −6.9%; 95% CI −10.2%, −3.7%). For pts with a DFS event, the majority of fractures occurred after a skeletal recurrence; 87.5% (7 of 8) ZOL and 88.2% (30 of 34) CTRL pts. BMD Z-scores at completion of protocol treatment were higher in patients treated with ZOL. Kbone was lower in ZOL patients (26.5 vs 29.8 ml min−1 using 99mTc-MDP and 34.3 vs 39.3 ml min−1 with 99mTc-HMDP). Expressed as a percentage of whole skeleton clearance, regional values in the mandible were similar 1.15% (ZOL) vs. 1.22% (CTRL).

Conclusions: Adjuvant ZOL given in the schedule studied in AZURE reduced the fracture rate in patients who developed recurrence of breast cancer. BMD was higher and the rate of bone remodeling less in patients treated with ZOL. Further follow-up will determine the duration and clinical relevance of these effects on bone health.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-01.
P2-19-03: Influence of Zoledronic Acid on BMD in Premenopausal Women with Breast Cancer and Neoadjuvant or Adjuvant Chemotherapy and/or Endocrine Treatment – The ProBone Studies.
Authors: Hadji P , Kauka A , Bauer T , Kalder M , Albert U , Birkholz K , Baier M , Muth M , Ziller M
Published: June 2012

Background: Based on baseline bone mineral density (BMD), adjuvant chemotherapy or endocrine therapy for early breast cancer patients can lead to substantially increased fracture risk. A significant decrease of BMD >10% after 2 years of chemotherapy (CT) and/or endocrine therapy (ET) has been reported. In recent studies, zoledronic acid (ZOL) produced an increase in BMD in premenopausal and postmenopausal patients with breast cancer (ABCSG-12, Z-FAST, ZO-FAST, etc). In addition, a significant increase in disease-free survival (DFS) with ZOL vs no ZOL was observed in most of these studies.

Methods: The aim of 2 single-center, placebo-controlled, randomized studies—Probone I and Probone II—was to investigate the effect of adjuvant treatment with ZOL on BMD in premenopausal women with early breast cancer treated with CT and/or ET. Patients with hormone-receptor-negative (HR−) breast cancer (Probone I) were treated with (neo)adjuvant CT; patients with hormone-receptor-positive (HR+) breast cancer (Probone II) were treated with ET alone or in combination with (neo)adjuvant CT. Randomized patients received ZOL 4 mg or placebo IV every 3 months for 24 months. The primary objective was the change in BMD at the lumbar spine between baseline and month 24 (measured by dual-energy X-ray absorptiometry [DXA]). Secondary objectives included DFS; BMD at total hip, femur, and os calcis; quantitative ultrasonometry (QUS) at os calcis and phalanges; markers of bone turnover (C-telopeptide of type I collagen [CTX] and N-terminal propeptide of type I procollagen [P1NP]); endocrine hormones (follicle-stimulating hormone [FSH], estradiol, testosterone, sex hormone-binding globulin [SHBG], parathyroid hormone [PTH], vitamin D, anti-Müllerian hormone [AMH], inhibin A/B, etc); pathologic fractures; and safety and tolerability.

Results: 70 HR+ and 11 HR− breast cancer patients have been enrolled into the studies. The last patient will have been treated for 24 months by the end of June 2011.

Conclusions: The effects of ZOL on lumbar spine BMD at 24 months and secondary endpoints will be presented at the meeting.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-03.
P3-01-03: The Hominoid-Specific Gene SHON Is Oncogenic in Human Mammary Carcinoma.
Authors: Jung Y , Shastri BG , Kong X-J , Zhu T , Perry JK , Lobie PE , Liu D-X
Published: June 2012

Breast cancer is still the most common malignancy and the leading cause of cancer deaths in both developed and under developed countries. Molecular targeted therapy, in particular monoclonal antibody-based treatment, has emerged as a promising approach to treat this disease because of its high specificity and reduced toxicity. As a consequence, identification of novel molecular therapeutic targets is of crucial importance. In an effort to discover new targets for monoclonal antibody-based targeted therapy, we have identified a novel and secreted hominoid-specific molecule, SHON (secreted hominoid-specific oncogene), in the human mammary carcinoma cell line, MCF-7. Like other hominoid-specific genes, SHON has no known orthologs outside of the primate lineage. It is highly expressed in all cancer cell lines tested so far including breast, lung, liver, stomach, colon and prostate cancer as determined at the mRNA level by RT-PCR and at the protein level by western blotting. Forced expression of SHON in MCF-7 cells significantly increased cell proliferation and survival as demonstrated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and Annexin V/propidium iodide apoptosis assays, respectively. Forced expression of SHON also promoted MCF-7 cell anchorage independent growth in soft agar and enhanced cell migration and invasion. Moreover, forced expression of SHON in MCF-7 cells increased tumour volume in a xenograft model of human breast cancer in immunodeficient mice. Furthermore, depletion of endogenous SHON expression using small interfering RNAs, or functional inhibition using an inhibitory rabbit anti-SHON polyclonal antibody, decreased MCF-7 cell proliferation and survival, and reduced MCF-7 oncogenicity and invasiveness. Therefore, SHON is a novel oncogene for mammary carcinoma cells which may be useful as a therapeutic target for the treatment of breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-03.
P3-05-05: Cyclin D1 Gene Amplification Is Rarely Heterogeneous in Breast Cancer.
Authors: Burandt E , Grünert M , Choschzick M , Müller V , Bokemeyer C , Simon R , Sauter G , Lebeau A , Jänicke F , Wilczak W
Published: June 2012

Background: Amplification of Cyclin D1 (CCND1) occurs in about 10–20% of breast cancers and has been suggested to predict resistance to anti-hormonal therapy. As the diagnostic accuracy of predictive biomarkers can be substantially limited by regional expression differences within tumors, heterogeneity of CCND1 amplification was assessed in this study. To assess heterogeneity, a novel tissue microarray based analysis platform was developed.

Material and Methods: To comprehensively asses the three-dimensional molecular composition of breast cancers, a “heterogeneity TMA” was constructed containing 8 different tissue cylinders from as many different cancer containing tumor blocks as possible (at least 4) from 147 primary breast cancers. Additional tissue samples were taken from 1–4 corresponding nodal metastases from 35 of these patients. Dual labeling fluorescence in situ hybridization (FISH) with probes for CCND1 and centromere 11 was applied.

Results: The analysis revealed amplification in 29 of 133 (21.8%) patients with interpretable FISH data. CCND1 amplification was more frequently seen in ductal (22 of 87; 25.29%) than in lobular type (5 of 32; 15.63%) (p=0.251). CCND1 amplification was also associated with high tumor grade with amplification rates of 1 of 18 (5.56%) in grade 1, 15 of 72 (20.83%) in grade 2 and 12 of 40 (30%) in grade 3 carcinoma (p=0.075). CCND1 amplification was more frequently seen in ER positive cases (27 of 110; 24.55%) than in ER negative cases (1 of 17; 5.88%) (p=0.052). No association could be found between CCND1 amplification and tumor stage (p=0.445) and CCND1 amplification and PR status (p=0.752). Heterogeneous amplification status was detected in 9 of 29 (31.0%) amplified tumors, i.e. in 6.8% of all informative cases. Heterogeneity was successfully validated on large sections in all 4 heterogeneous cases with high level amplification. In the remaining 5 “heterogeneous cases” discordant results were due to variable interpretation of borderline amplification results with CCND1/centromer 11 ratios between 1.7 and 2.3. There were no discrepancies seen between primary tumors and matched lymph node metastases.

Discussion: The high degree of homogeneity seen for CCND1 amplification suggests that this alteration represents an early event in tumor development/progression in a subset of breast cancers. CCND1 status determined in a small biopsy will be highly representative of the entire tumor and will thus be appropriate for predicting treatment outcome.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-05.