Primary Breast Cancer Lesions Research Articles

Alterations in three biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor 2) and the Ki67 index between primary and metastatic breast cancer lesions.

In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast cancer may benefit a patient by allowing for a novel personalized treatment strategy.

Correlation of Molecular Subtypes of Invasive Ductal Carcinoma of Breast with Glucose Metabolism in FDG PET/CT: Based on the Recommendations of the St. Gallen Consensus Meeting 2013.

This study aimed to investigate the relationship between the SUVmax of primary breast cancer lesions and the molecular subtypes based on the recommendations of the St. Gallen consensus meeting 2013. Clinical records of patients who underwent F-18 FDG PET/CT for initial staging of invasive ductal carcinoma (IDC) of the breast were reviewed. A total of 183 patients were included. SUVmax was correlated with the molecular subtypes defined by the St. Gallen Consensus Meeting 2013, i.e., luminal A-like (LA), luminal B-like HER2 negative (LBHER2-), luminal B-like HER2 positive (LBHER2+), HER2 positive (HER2+), and triple negative (TN), and with the clinicohistopathologic characteristics. The molecular subtype was LA in 38 patients, LBHER2- in 72, LBHER2+ in 21, HER2+ in 30, and TN in 22. The mean SUVmax in the LA, LBHER2-, LBHER2+, HER2+, and TN groups were 4.5 ± 2.3, 7.2 ± 4.9, 7.2 ± 4.3, 10.2 ± 5.5, and 8.8 ± 7.1, respectively. Although SUVmax differed significantly among these subtypes (p < 0.001), the values showed a wide overlap. Optimal cut-off SUVmax to differentiate LA from LBHER2-, LBHER2+, HER2+ and TN were 5.9, 5.8, 7.5, and 10.2 respectively, with area under curve (AUC) of 0.648, 0.709, 0.833, and 0.697 respectively. The cut-off value of 5.9 yielded the highest accuracy for differentiation between the LA and non-LA subtypes, with sensitivity, specificity, and AUC of 79.4%, 57.9%, and 0.704 respectively. The SUVmax showed a significant correlation with the molecular subtype. Although SUVmax measurements could be used along with immunohistochemical analysis for differentiating between molecular subtypes, its application to individual patients may be limited due to the wide overlaps in SUVmax.

Abstract 729: Novel role of CB2R in tuning breast tumor microenvironment, EGF/EGFR and IGF-I/IGF-IR pathways

Abstract Cannabinoid receptor-2 (CB2R) is an integral part of the endocannabinoid system. It is upregulated in the primary breast cancer lesions and in different types of immune cells however; its functional role in breast tumorigenesis is not well understood. The present study was aimed at evaluating the mechanistic anti-tumor role of CB2R activation on breast cancer cells and immune cells within the breast tumor microenvironment. First, we analyzed the anti-tumorigenic mechanisms of CB2R activation in ERá- and ERá+ breast cancer cells. Our studies showed that CB2R specific agonist (JWH-015) inhibits EGF and IGF-I-induced migration and invasion of ERá+ and ERá- breast cancer cells. At the molecular level, JWH-015 inhibits EGFR and IGF-IR activation and their downstream targets STAT3, AKT, ERK, NF-kB and MMP-9/MMP-2. Interestingly, We found that JWH-015 significantly reduces breast cancer growth in vivo and the tumors that were derived from CB2R agonist treatment showed reduced activation of EGFR and IGF-IR and their downstream targets compared to control group. Since CB2R is overexpressed in immune cells, we assessed for the role of CB2R activation on modulation of immune cells present in tumor stroma. We observed increased tumor weight, more myeloid derived suppressor cells (MDSCs) (CD11b+/Gr-1+) and less CD3+/CD8+ cells in orthotopically injected CB2R knock out mice compared to wild type mice. Furthermore, we found that JWH-015-treated wild type mice have reduced tumor growth and metastasis, more CD3+/CD8+ cells and less MDSCs within the tumor stroma. For the first time, we show that CB2R activation might suppress breast tumor growth and metastasis through novel mechanisms of inhibiting EGFR and IGF-IR signaling axes on tumor cells and modulating the immune cells’ compositions within the breast tumor microenvironment. Citation Format: Mohamad Elbaz, Mohd Nasser, Janani Ravi, Dinesh Ahirwar, Ramesh Ganju. Novel role of CB2R in tuning breast tumor microenvironment, EGF/EGFR and IGF-I/IGF-IR pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 729.

Patients with Concordant Triple-Negative Phenotype between Primary Breast Cancers and Corresponding Metastases Have Poor Prognosis

PurposeWe investigated the prognostic impact of discordance between the receptor status of primary breast cancers and corresponding metastases.MethodsA total 144 patients with breast cancer and distant metastasis were investigated. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status of primary tumor and corresponding metastases were assessed. Tumor phenotype according to receptor status was classified as triple-negative phenotype (TNP) or non-TNP. Concordance and discordance was determined by whether there was a change in receptor status or phenotype between primary and metastatic lesions.ResultsThe rates of discordance between primary breast cancer and metastatic lesions were 18.1%, 25.0%, and 10.3% for ER, PR, and HER2, respectively. The rates of concordant non-TNP, concordant TNP and discordant TNP were 65.9%, 20.9%, and 13.2%, respectively. Patients with concordant ER/PR-negative status had worse postrecurrence survival (PRS) than patients with concordant ER/PR-positive and discordant ER/PR status (p=0.001 and p=0.021, respectively). Patients who converted from HER2-positive to negative after distant metastasis had worst PRS (p=0.040). Multivariate analysis showed that concordant TNP was statistically significant factor for worse PRS (p<0.001).ConclusionDiscordance in receptor status and tumor phenotype between primary breast cancer and corresponding metastatic lesions was observed. Patients with concordant TNP had worse long-term outcomes than patients with concordant non-TNP and discordant TNP between primary and metastatic breast cancer. Identifying the receptor status of metastatic lesions may lead to improvements in patient management and survival.

Association between semiquantitative PET parameters and molecular subtypes of breast invasive ductal carcinoma.

Molecular subtypes of breast cancer have been proposed since 2012. The correlation between various baseline [18F]fluorodeoxyglucose ([18F]FDG) uptake parameters, including total lesion glycolysis (TLG), and molecular subtypes of primary breast cancer lesions in patients with invasive ductal cancer will be investigated. Staging [18F]FDG PET/CT for breast invasive ductal carcinoma were retrospectively evaluated. Breast lesions were examined for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation index (Ki-67). Breast tumors were classified into five molecular subtypes: Luminal A, Luminal B-HER2(-), Luminal B-HER2(+), HER2(+) and Basal or Triple Negative cancers. The correlations between tumor characteristics and PET semiquantitative data of primary breast lesion (SUVmean, SUVmax, Mean tumor volume (MTV), TLG) were assessed. Specific Breast Uptake Ratio (SBUR) is used as a new quantification method of breast uptake to correct for physiological background activity. Fifty-eight patients were included. TLG was significantly higher in triple negative group when compared with luminal A (P<0.01). Significantly higher uptake was found in triple negative lesions when compared with luminal B-HER2(-) and luminal B-HER2(+) categories using SUVmax, SUVmean and TLG (all P<0.05). Conversely, no statistically significant difference for [18F]FDG uptake was observed between all other molecular subtypes. No value of SBUR in terms of correlation with histopathological parameters was demonstrated. TLG was superior to SUVmax and SUVmean in differentiating between triple negative breast cancer lesions and all other molecular subtypes. SBUR was not different statistically between various molecular subtypes.

Abstract P5-03-04: The role of lung biopsy in the management of lung nodules in breast cancer patients

Abstract Background: A biopsy of lung nodules in patients, who had received previous surgery for breast cancer, can be performed with three aims: to confirm that the lesion is lung metastasis, to confirm the diagnosis of other diseases including primary lung cancer, and to reassess tumor’s characteristics. Discordance in estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status between primary breast cancer and metastatic lesions has been reported. The aim of this study was to assess the role of lung biopsy in the diagnosis and to determine the changes in hormonal receptor and HER2 status of the metastatic lesions. Methods: A total of 38 consecutive patients who underwent surgery in 31 or transbronchial lung biopsy (TBLB) in 7 for lung nodules between 1997 and 2014 after curative operation for breast cancer were reviewed. Results: Eighteen patients (47%) had a solitary lung nodule. The pathologic diagnoses of lung nodules were lung metastases of breast cancer in 20 patients, primary lung tumor in 14 (Adenocarcinoma in 10; Large cell carcinoma in 2; Small cell carcinoma and Carcinoid tumor in 1 each), and other diagnoses in 4 (Inflammation and organizing pneumonia in 2 each). Median follow up duration were 118.8 months in metastatic breast cancer patients and 105.3 months in other histology patients (p=0.392). The average disease-free interval from the surgery for primary breast cancer were 68.6 months in metastatic breast cancer patients and 66.3 months in other histology patients (p=0.897). The 10-year survival rate after the surgery for primary breast cancer was significantly longer in other histology patients (92.3%), including primary lung cancer patients than in metastatic breast cancer patients (55.1%) (p=0.0308). In 20 cases of metastatic breast cancer, rates of discordance were 5%, 10% and 10% for ER gain, PgR gain and HER2 loss, respectively. Sixteen of patients maintained the same tumor phenotype, whereas 4 changed during progression. Especially, 2 cases of ER, PgR gain could receive endocrine therapy instead of chemotherapy. Conclusion: As lung nodules that appear in breast cancer patients are not always lung metastases, the pathologic diagnosis should be confirmed, and surgery is an option for the pathologic confirmation. Furthermore, discordance in biomarker status between primary breast cancer and the lung metastasis occurred in 20% of cases. It is necessary for clinicians to check biomarker status in recurrent breast cancer patients as it may assist a shift in the treatment plan. Citation Format: Kazuo Matsuura, Takayuki Kadoya, Norio Masumoto, Hideo Shigematsu, Akiko Emi, Keiko Kajitani, Morihito Okada, Tsuyoshi Kataoka, Rumi Haruta, Koji Arihiro, Midori Noma, Toshiyuki Itamoto. The role of lung biopsy in the management of lung nodules in breast cancer patients [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 P5-03-04.

Abstract P5-01-14: Visualisation of histologic proven breast cancer on the MAMMI-PET: A dedicated PET for hanging breast imaging

Abstract Aim: The MAMMI–PET, a high–resolution full–ring system for dedicated hanging breast imaging was originally developed in the context of a EU–founded project to improve the detection of breast cancer. The aim of the present study was to evaluate the performance of the MAMMI–PET device in patients with at least one histologic confirmed primary breast cancer lesion (or index lesion), scanned in two European centres. All patients were included in the study after being scheduled to receive pre–operative chemotherapy (NAC) or radiotherapy. Material and methods: From March 2011 to March 2014, we included 234 female patients (mean age 52 y, range 24–82y) with histologically confirmed breast cancer. All patients were scanned with the MAMMI–PET (Oncovision, Valencia, Spain) after giving informed consent. Scans were acquired 110 min after a dose of a mean dose of 197.12 MBq18F–FDG. In both centers the acquisitions, the reconstruction of the images and the data collection were performed using similar standardized methods. We tested the relation between visualization of the primary tumor and possible additional lesions on the MAMMI–PET as well as the influence of various variables; including age, weight, breast cancer subtypes and receptor status, breast length, maximal tumor diameter and affected breast quadrants. Results: A total of 236 breasts were imaged and 211 (98.4%) of the index lesions (diameter 5–170 mm, mean 32 mm) were located within the MAMMI–PET scanning range. Of all index lesions within the scanning range 1.4% was not FDG avid on the MAMMI–PET images. Lesions that were FDG-avid were either clearly (86.3%) or moderately (12.3%) visible. The overall MAMMI–PET sensitivity increased from 88.6% to 98.6% after exclusion of lesions outside the scanning range. No significant differences in lesion visibility were found due to breast cancer subtypes or breast quadrant location. Of the 35 index lesions touching the pectoral muscle 62.9% reached into the scanning range. A total of 41 additional FDG-avid lesions were detected, not categorized as an index tumor. Conclusions: The MAMMI–PET missed only a small percentage of malignant lesions located within the scanning range of the device. Lesions near the pectoral muscle were the subgroup less often visualized. No significant influence on the visualization of the FDG avid lesions was seen due to tumor subgroups, hormone receptor status, and breast quadrant location or tumor size. Citation Format: Suzana C Teixeira, José Ferrer Rebolleda, Bas B Koolen, Raúl Sánches Jurado, Marcel P Stokkel, María del Puig Cózar Santiago, Emiel J Th Rutgers, Renato A Valdés-Olmos. Visualisation of histologic proven breast cancer on the MAMMI-PET: A dedicated PET for hanging breast imaging [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 P5-01-14.

Receptor Expression Discrepancy between Primary and Metastatic Breast Cancer Lesions

SummaryBackground: Recent studies have shown that the expression status of hormone receptors and human epidermal growth factor receptor 2 (HER2) in breast cancer may change during disease progression. The aim of this study was to determine and compare the estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status in primary breast cancer and metastatic lesions. Methods: 58 patients with registered biopsy reports or available samples of the primary tumor and distant metastases were included in the final analysis. Biopsy samples were re-stained using immunohistochemical methods to determine receptor status (if not already recorded in previous reports) and re-examined by 2 independent pathologists. Results: Discordance rates for receptor expression status of the primary tumor and distant metastases for ER, PR, and HER2 were 17.4, 45.4, and 13.3%, respectively. No statistically significant difference in overall survival due to receptor expression discordance between the primary tumor and metastatic sites (p > 0.05) was found, although a tendency toward worse survival time was observed in patients with HER2 expression discrepancies. Conclusion: This study showed receptor discordance rates between primary and metastatic breast cancer sites for ER, PR, and HER2 of 17.8, 45.4, and 13.3%, respectively. Re-biopsy and IHC evaluation of metastatic sites for receptor status may change treatment decisions in patients with relapsed/progressed BC.

The importance of biopsy in clinically diagnosed metastatic lesions in patients with breast cancer.

BackgroundReceptor status discordance, such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status between primary breast cancer and metastatic lesions has been reported. The aim of this study was to evaluate the biopsy of clinically diagnosed metastatic lesions and to determine the changes in hormonal receptor and HER2 status of the metastatic lesions.MethodsSixty-three patients with clinically diagnosed metastatic breast cancer underwent an excisional biopsy or core needle aspiration guided by computed tomography/ultrasound. ER, PR and HER2 were assessed by immunohistochemistry (IHC).ResultsA total of 48 metastases (76.2%) and nine second primary malignancies (14.3%, seven primary lung cancers and two primary pancreatic cancers) were found. The discrepancies between ER, PR and HER2 status between the primary breast cancer and metastatic lesions were 14.6%, 16.7% and 8.3%, respectively. Six lesions (9.5%) were proved benign upon biopsy.ConclusionsThe biopsy of clinically suspicious metastatic lesions could histologically confirm the diagnosis of metastasis, evaluate discrepancies between ER, PR and HER2 status and exclude secondary malignancy, which might change the therapeutic strategy for breast cancer patients.

Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer

Bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration. On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. Cyclophosphamide, Adriamycin®, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient’s entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual compression, the patient required blood transfusion for the massive blood loss. She eventually succumbed to respiratory failure. This case report demonstrates that primary breast cancer lesions with skin involvement have the potential to cause massive hemorrhage after bevacizumab-based treatment.

Molecular subtyping of breast cancer using dedicated breast PET-CT.

e22090 Background: Recently dedicated breast 18FDG breast PET-CT has emerged as an additional imaging tool for assessment and staging of primary breast cancer. Expression of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and HER2 status, has direct prognostic and therapeutic implications in patient management. This study aimed to determine whether correlations exist between 18FDG up-take of the primary breast cancer lesions and these predictive and prognostic factors. Methods: Before undergoing surgery 114 patients with primary breast cancer underwent 18FDG breast PET-CT. The maximum standardized uptake value (SUVmax) of the primary breast cancer was measured in each patient and standard immunohistochemistry was performed on a surgical specimen to characterize the receptor state of tumor cells. Appropriate statistical tests were used to test for any association that may exist among ER, PR, and HER2. Results: A significant association was found between a triple negative status and the SUVmax (p &lt; 0.001) of breast tumors. ER-negative tumors (mean SUVmax, 10.4) demonstrated a significantly higher SUVmax than did ER-positive tumors (median SUV, 5.1) (p= 0.045). No statistical significant difference was found for SUVmax of PR-negative vs. PR-positive lesions with a mean SUVmax of 8.6 and 4.9 (p=0.15) respectively. No statistical significant difference was found for SUVmax of HER2-negative vs. HER2-positive lesions with mean SUVmax of 6.4 and 5.3 respectively (p=0.55). If either ER or PR was positive, then the other tended to be positive as well (chi2 = 84%, P &lt; 0.01). No such significant relationship was detected between PR or ER and HER2 (P &gt; 0.05). Conclusions: ER-negative breast cancer tumors display higher 18FDG uptake than ER-positive tumors. Triple-negative breast tumors are associated with increased 18FDG uptake commensurate with their aggressive biology. The data suggest that SUVmax measurements of 18FDG breast PET-CT can provide valuable information about the state of ER, PR, and HER2 and the associated glucose metabolism of the primary breast cancer lesions. Such an association may be of importance to treatment planning and outcome in these patients.

The discordance between primary breast cancer lesions and pulmonary metastatic lesions in expression of aldehyde dehydrogenase 1-positive cancer cells

We evaluated the expression of aldehyde dehydrogenase 1 (ALDH1) between primary breast lesions and pulmonary metastatic (PM) lesions in breast cancer patients. We retrospectively analyzed the clinicopathological features and the expression statuses of ER, PR, HER2, Ki-67 and ALDH-1 in both primary and metastatic breast cancer lesions and evaluated the discordance rates in the expressions of these markers between the primary and metastatic lesions, and also the prognostic value of these factors. None of the PM patients had metastases at any other sites, and all had undergone curative breast cancer surgery. The pulmonary operation was partial resection in 15 (88 %) patients and lobectomy in 2 (12 %) patients. The median overall survival (OS) after resection of the PNs (OS) was 48 months. The discordance rates in the expressions of ER, PR, HER2, Ki67 and ALDH-1 between the primary and metastatic lesions were 0, 29, 21, 43 and 50 %, respectively. There was significant discordance in the biomarkers between the primary tumors and the metastatic lesions.

Metastatic lobular carcinoma of the breast masquerading as a primary rectal cancer

BackgroundColorectal metastasis of lobular carcinoma of the breast is a diagnostic challenge. It may macroscopically simulate primary colon cancer or inflammatory bowel disease. In some cases, the interval between the primary breast cancer and metastatic colorectal lesions is so long that the critical records for diagnosis including history might be lost or missed.Case presentationReported herein is a case of metastatic lobular carcinoma of the breast masquerading as a primary rectal cancer developed in a 62-year-old Japanese woman. The case initially presented as a circumferential rectal lesion, and information on the patient’s history of breast cancer was not noted. As the result of endoscopic biopsy, diagnosis of poorly differentiated rectal adenocarcinoma was made. The lesion was surgically resected after chemo-radiotherapy. Histopathological examination of the resected specimen with hematoxylin and eosin (HE) stain revealed a single-file arrangement of the tumor cells, reminiscent of lobular carcinoma of the breast. Immunohistochemical analysis revealed an immunophenotype consistent with lobular carcinoma of the breast. Because further review of the patient’s history revealed an occurrence of ‘poorly differentiated adenocarcinoma of the breast’, which she had experienced 24 years earlier, the final diagnosis of the lesion was made as rectal metastasis from lobular breast carcinoma.ConclusionsPoorly differentiated adenocarcinoma of the colorectum is rarer than that of the stomach. Linitis plastica-type cancer of the colorectum is also rarer than that of the stomach. A lesson from the present case is that before we conclude a linitis plastica-type cancer of poorly differentiated type as a primary colorectal cancer, it is critical to exclude a possibility of metastatic colorectal cancer.

Effects of DNA Ploidy and S-Phase Fraction on Fluorine-18 FDG Uptake of Primary Breast Cancer Lesions

BackgroundFlow cytometry (FCM) evaluating DNA content is emerging as the tool to monitor cell proliferation and malignant potential in several cancers such as stomach, lung, and salivary gland tumor. The purpose of this study was to correlate 18F-FDG uptake of dual–time-point (DTP) positron emission tomography (PET) imaging with DNA ploidy and S-phase fraction (SPF) in primary breast cancer lesions. Patients and MethodsSeventy-two consecutive female patients (mean age ± SD, 52.7 ± 11.1 years; range, 28-81 years) had undergone 18F-FDG DTP PET/computed tomography (CT) imaging for staging of breast malignancy in our institution during a 5-month period. FCM was performed on fresh-frozen samples of specimens obtained from surgery. 18F-FDG uptake was then compared with DNA content. ResultsForty-four malignant lesions were included in this study. On FCM, DNA aneuploidy was detected in 14 lesions (31.8%). The maximum standardized uptake values (SUVmax1 and SUVmax2) (SUVmax1, 6.8 ± 4.6 vs. 3.4 ± 2.4; P = .017), (SUVmax2, 7.9 ± 5.7 vs. 3.6 ± 2.7; P = .015) and retention index (RI) (12.8 ± 11.6 vs. 2.4 ± 10.8; P = .010) were significantly higher in DNA aneuploidy cancer than in DNA diploidy cancer. The value of RI (11.3 ± 11.5 vs. 2.6 ± 11.2; P = .022) was significantly higher in high SPF (> 15%) breast cancer than in low SPF (≤ 15%) breast cancer. ConclusionsHigh 18F-FDG uptake in breast cancer might be an indicator of DNA aneuploidy and high SPF. We propose that 18F-FDG PET/CT imaging may be a noninvasive and useful tool for predicting the DNA content in breast cancer.

FDG-PET/CT for the early prediction of histopathological complete response to neoadjuvant chemotherapy in breast cancer patients: initial results

Up to about one-quarter of patients treated with neoadjuvant chemotherapy do not adequately respond to the given treatment. By a differentiation between responders and non-responders ineffective toxic therapies can be prevented. To retrospectively test if FDG-PET/CT is able to early differentiate between breast cancer lesions with pathological complete response (pCR) and lesions without pathological complete response (npCR) after two cycles of neoadjuvant chemotherapy (NACT). In this retrospective study 26 breast cancer patients (mean age, 46.9 years ± 9.9 years) underwent a pre-therapeutic FDG-PET/CT scan and a subsequent FDG-PET/CT after the second cycle of NACT. Histopathology of resected specimen served as the reference standard. Maximum standardized uptake values (SUVmax) of cancer lesions before and after the second cycle of NACT were measured. Two evaluation algorithms were used: (a) pCR: Sinn Score 3 and 4, npCR: Sinn Score 0-2; (b) pCR: Sinn Score 4, npCR: Sinn Score 0-3. The absolute and relative decline of the SUVmax (ΔSUVmax, ΔSUVmax(%))was calculated. Differences of the SUVmax as well as of the SUVmax decline between pCR lesions and npCR lesions were tested for statistical significance P < 0.05. To identify the optimal cut-off value of ΔSUVmax(%) to differentiate between pCR lesions and npCR lesions a receiver-operating curve (ROC) analysis was performed. Using evaluation algorithm A the ΔSUVmax was 13.5 (pCR group) and 3.9 (npCR group) (P = 0.006); the ΔSUVmax(%) was 79% and 47%, respectively (P = 0.001). On ROC analysis an optimal cut-off ΔSUVmax(%) of 66% was found. Using evaluation algorithm B the ΔSUVmax was 17.5 (pCR group) and 4.9 (npCR group) (P = 0.013); the ΔSUVmax(%) was 89% and 51%, respectively (P = 0.003). On ROC analysis an optimal cut-off ΔSUVmax(%) of 88% was found. FDG-PET/CT may be able to early differentiate between pCR and npCR of primary breast cancer lesions after two cycles of NACT.

Abstract 683: Evaluation of PTEN and PIK3CA status in breast cancer for patient selection: Cross-validation between institutions

Abstract PTEN and PIK3CA status are potential predictors of response to PI3K-pathway inhibitors. Therefore, we searched the most reliable platform to assess both PTEN expression and PIK3CA mutations in primary and metastatic breast cancer (BC). Cross-validation across platforms at SU2C sites was performed using three different sample sets: 18 formalin-fixed paraffin-embedded (FFPE) primary triple negative breast cancer (pTNBC) samples from VHUH/VHIO, 12 FFPE pTNBC samples from Columbia University and 21 FFPE all-comers BC from VHUH/VHIO. Moreover, we evaluated the transitions occurring between early and disseminated disease in 14 paired FFPE samples from VHUH/VHIO. PTEN alterations were genotyped in 18 triple pTNBCs by OncoscanTM platform (Affymetrix) and were correlated to immunohistochemistry (IHC, 138G6 CST antibody). PTEN loss of heterozygosity (LOH, n=4) or frameshift mutation (n=1) was concordant to PTEN protein loss (H-Score&amp;lt;50) by IHC in 4 samples; with the discordant LOH having an H-Score of 60. In the other two non-concordant samples (total of 3/18, 17% discordance), presence of non-tumor DNA, as assessed by genomic heterogeneity, impeded an accurate DNA copy number variation determination by OncoscanTM. PTEN protein loss by IHC was also cross-validated between two institutions (Columbia and VHIO). In a cohort of 12 pTNBCs containing eight PTEN low samples, only two samples were discordant (2/12, 17% discordance). Paired primary versus metastatic tumors were identified to transit either way, in the PTEN assessment by IHC (2/8 paired samples, 25% transition). PTEN IHC failed in most (3/5) metastatic bone samples due to Bouin's fixative required for handling of this tissue. PIK3CA mutations by OncoscanTM were concordant to MassARRAY (Sequenom) in 4 out of 5 mutated samples within the panel of 18 pTNBCs. The discrepancy (1/18, 6%) was most likely due to differences in the sensitivity of the two assays. In another cohort of 21 BC samples, PIK3CA mutational status was cross-validated by MassARRAY at two institutions (MDACC and VHIO). Using identical, customized panels we found that only two samples were discordant because of mutant allele frequency close to the sensitivity of the assay (10%). Manual review of the individual assays increased the concordance to 100%. Among 14 paired primary vs metastatic breast cancers we detected two transitions from wild type (WT) to H1047R mutation and one transition from E545K to WT (3/14, 21% transition), underscoring the need to determine PIK3CA status in metastatic lesions. The divergence evaluating both PTEN and PIK3CA status between institutions was due to cut-off and sensitivity of the assays respectively. For patient pre-screening purposes, MassARRAY and IHC can be performed at each SU2C site both in primary and metastatic breast cancer lesions. OncoscanTM is a valid, centralized platform for evaluation of PTEN and PIK3CA genomic alterations in BC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 683. doi:1538-7445.AM2012-683

To Biopsy or Not to Biopsy: Is That the Only Question?

The clinical effects of discordance in receptor status between primary and metastatic breast cancer lesions are discussed in relation to the study of Macfarlane et al. published in this issue of The Oncologist.

CYP3A4 expression to predict treatment response to docetaxel for metastasis and recurrence of primary breast cancer

Tumors expressing high levels of CYP3A4 are likely to have a poor treatment response to docetaxel (DOC), which is metabolized by CYP3A4. Tissue samples of recurrent breast cancer are sometimes hard to obtain just before treatment because the tumor is often difficult to access. Using immunohistochemistry, we measured CYP3A4 expression in primary lesions and compared their treatment responses to DOC with those of recurrent breast cancer lesions. The subjects of this study were 42 patients who had undergone surgery for breast cancer, and had metastasis or recurrence treated by DOC (60 mg/m(2) every 3 weeks). Tumor samples resected at surgery were immunostained for CYP3A4 and its expression levels were compared with the response rate to ongoing DOC treatment. Patients with CYP3A4-negative tumors (n = 19) showed a significantly higher response rate (63.2%) to DOC treatment than did those with CYP3A4-positive tumors (n = 23) (26.1%). The predictive value, negative predictive value, and diagnostic accuracy of CYP3A4 expression in the prediction response to DOC were 63.2%, 73.9%, and 68.6%, respectively. Measuring CYP3A4 expression immunohistochemically in the primary breast cancer lesion was useful for predicting the treatment response to DOC of tumors that recurred after a long interval.

Abstract P5-14-20: Clinical Features of Surgical Resection for Solitary Pulmonary Metastasis and the Discrepancy in Immunopathological Features between Primary and Metastatic Breast Cancer Lesions

Abstract Background: The treatment for metastatic breast cancer (MBC) is usually systemic therapy decided by the hormone and HER2 status of primary breast cancer lesion. There are some reports about the discrepancy in hormone and HER2 status between primary and metastatic lesion in these days. We have reported previously that the expression of ALDH-1 which considered the pathological markers of breast cancer stem cell in axillary lymph node matastases is a significant predictor of poor outcome in primary breast cancer patients (Figure 1). We evaluated the role of surgery in the diagnosis and treatment of a solitary pulmonary nodule (SPN) in breast cancer patients and demonstrated the significance of analyzing the immunopathological features in metastatic breast cancer lesion. Methods: Between 1990 and 2006, 17 patients (PM) with SPN which were diagnosed breast cancer metastases underwent complete pulmonary resection and 36 MBC patients (AP) underwent autopsy after breast cancer related death in our hospitals. We retrospectively analyzed clinicopathological features and the expression of ER, HER2, Ki-67 and ALDH-1 in both primary and metastatic breast cancer lesions. Results: The median age of PM patients was 53 (range 30-80). All PM patients had not other metastases and had undergone curative breast cancer operation. The pulmonary operation were partial pulmonary resection in 15(88%) and lobectomy in 2 (12%) patients. The median disease free survival (DFS) was 63 months (range 9-175). Median overall survival (OS) was 181 months and the median OS after pulmonary operation was 48 months. The median DFS and OS of AP patients were 21 and 43 months. All AP patients had multiple visceral metastases. We compared the immunohistlogical status between primary and metastatic lesion and evaluated the colletation with these status in metastatic lesion and prognosis in all patients. Conclusion: Pulmonary resection was effective to diagnose and the OS after resection was relatively long in PM patients. We report the value of the expression of ER, HER2, Ki67 and ALDH-1 in distant metastatic lesions. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-20.

Hypermetabolic Axillary Mass on (18)F FDG PET/CT: Breast Cancer Arising from Accessory Breast Tissue.

Differential diagnosis among several causes of axillary malignant mass is important. The most common cause of palpable malignant axillary mass is metastatic lymphadenopathy. Although carcinoma arising from ectopic breast tissue is rare, the diagnosis should be kept in mind when evaluating malignant axillary mass. In this report we present a case with carcinoma arising from ectopic breast tissue. (18)F FDG PET/CT was performed for the purpose of localizing primary breast cancer lesion and systemic evaluation. PET/CT showed hypermetabolic lesions only in the right axilla. There is no evidence of malignancy in both breasts. When nuclear physicians encounter a hypermetabolic axillary mass indicating malignant lesion without evidence of primary breast malignant lesion, carcinoma arising from ectopic breast tissue should be included in the differential diagnosis.