Cases Of Metastatic Breast Cancer Research Articles

Abstract P6-08-40: Survival of metastatic hormone receptor (HR) positive/HER2 negative; HER2+; and triple negative (TN) breast cancer based on initial presentation

Abstract Introduction: Median overall survival (OS) for patients (pts) with metastatic breast cancer (MBC) is described as 2-3 years, but few reports compare OS for de novo versus relapsed disease. The recognized clinical subtypes of breast cancer (HR positive[+] /HER2 negative; HER2+; TN) are known to have variable OS clinically, but this has not been systematically documented. We hypothesized that pts relapsing from a non MBC stage (relapsed) might have different OS than those presenting initially with metastases (de novo), and that OS would differ for the three clinical biomarker subgroups. Methods: Using the Breast Cancer Outcomes Unit database, we identified all women diagnosed with MBC, de novo or relapsed, in British Columbia between 01/2001 and 12/2009 and referred to the BC Cancer Agency. Review of medical records confirmed ER, PR and HER2 status. Survival from MBC diagnosis was calculated for relapsed vs de novo in the three biomarker subgroups. Results: After excluding pts with a synchronous or prior contralateral disease, we identified 3645 women with known ER. Median follow up was 91 months. HER2 known (n=3010) and unknown (n=635, 17%) cases had the same median OS (17 months [m]) and HR status (72% ER+). Trastuzumab (T) was standard in MBC during this era, but fewer than 10% had adjuvant T (introduced mid 2005) which explains the high number of HER2+ MBC cases. We previously reported longer OS for HER2+ disease relapsing after adjuvant therapy without T (older cohort) than after adjuvant T (SABCS 2013 Lohrisch). HER2 unknown pts were excluded from further survival analyses. Three percent of cases with known PR were ER negative/PR +. Therefore ER was used as the main determinant of HR status. For the entire cohort and all biomarker groups, OS was longer for denovo than for relapsed MBC. Overall Survival - relapsed vs de novo MBC for each biomarker subtype Relapsed MBCDe novo MBC SubgroupsN dead/totalMedian OS, mN dead/totalMedian OS, mP-valueAll cases with known ER2124/231115593/69926<.0001HR+/ HER2 negAll821/91224290/36434<.0001PR known414/47720251/31934<.0001PR unknown407/4352839/45330.1315TNBCAll368/3919110/126150.0001HER2+All935/100811193/209170.0061ER neg268/278758/609.50.2191ER+667/73015135/149250.0088 OS was longest for denovo HR+/HER2 negative (34m) and shortest for HER2+/ER negative (7m) and TN (9m) relapsers. The difference in OS for relapsed vs denovo HER2+ disease was significant for HR+ but not HR negative cases, likely due to small numbers in the latter subset. Conclusion: Relapsers experience shorter OS than their denovo biomarker counterparts, possibly due to the selective pressure of adjuvant therapy on disease biology. When restricted to pts who received systemic therapy for MBC, OS figures may be higher. Novel therapies may decrease the total number of relapsers, and improve OS in MBC for all, but are unlikely to narrow the OS gap between relapsed and denovo groups. Trials exploring therapies for MBC of all biomarker types should therefore stratify by stage at initial diagnosis. Citation Format: Wendie-Lou D den Brok, Caroline Speers, Gondara Lovedeep, Emily Baxter, Scott Tyldesley, Lohrisch Caroline. Survival of metastatic hormone receptor (HR) positive/HER2 negative; HER2+; and triple negative (TN) breast cancer based on initial presentation [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 P6-08-40.

Abstract P3-07-26: Characteristics of de novo metastatic breast cancer in California, 2005-2011

Abstract BACKGROUND: Breast cancer (BC) that is metastatic at initial diagnosis (i.e. de novo metastatic or stage IV) has not been well described, especially in the general population. OBJECTIVE: To describe demographics, tumor characteristics and survival in a population-based cohort of patients with de novo metastatic BC (MBC). METHODS: We studied all 6268 de novo MBC cases diagnosed in California women between 1/1/2005 and 12/31/2011, as reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, based on estrogen and progesterone receptor) status. Median overall survival (OS) was calculated by Kaplan-Meier methods. Cox proportional hazards regression was used to assess independent predictors of OS. RESULTS: 5% of all newly diagnosed BC were metastatic, representing 6% of all newly diagnosed HR+/HER2+, 8% of all HR-/HER2+, 4% of all HR+/HER2- and 6% of all triple negative BC (TNBC). Compared to patients with early BC, MBC patients were of similar age (mean age at diagnosis, (interquartile range): 61,(51-71) vs. 60, (50-70) years)). They were slightly more likely to be black (10% vs. 6%) or Hispanic (19% vs. 17%) but substantially more likely to be unmarried (56% vs. 40%), to live in neighborhoods of the lowest socioeconomic quintiles (39% vs. 29%), and to have public (e.g., Medicaid) or no insurance (39% vs. 21%). Most MBC patients presented with large tumors; however, 13% of patients had tumor sizes 2 cm or less, compared with 60% of patients with early BC (of TNBC: 15% MBC vs. 44% early BC were ≤2 cm). A minority of patients with de novo MBC received breast surgery (39%), with 24% receiving full or partial mastectomy, 9% lumpectomy, 3% bilateral mastectomy and 3% other/unknown surgery . 64% of de novo MBC patients received chemotherapy and 33% received radiation. Median survival after MBC diagnosis was 27 months (mos), but varied substantially by patient characteristics including age (<40: 40 mos, 85+: 8 mos), race/ethnicity (Asian: 34 mos, black: 16 mos), and neighborhood socioeconomic quintile (lowest: 20 mos, highest 34 mos) and molecular subtype (HR+/HER2+: 45 mos, TNBC: 12 mos). In a multivariate Cox model including all available variables, TNBC was the most important predictor of death (Hazard Ratio 2.8, 95% CI: 2.4-3.3 vs. HR+/HER2+). Other significant and important predictors included HR-/HER2+ subtype (Hazard Ratio 1.6, 95% CI: 1.3-18 vs. HR+/HER2+), being unmarried, living in low socioeconomic status neighborhoods, and high tumor grade status. CONCLUSIONS: In this large diverse population, de novo MBC was more likely to be diagnosed for certain breast cancer subtypes, and among minority and underserved women (black or Hispanic race, low socioeconomic neighborhood, no or public health insurance) that may have contributed to the detection of their tumor only after it had metastasized. A high proportion of patients with MBC are not treated surgically, but most receive chemotherapy. Median survival remains poor, with worse survival strongly associated with tumor biology (triple negative and HR-/HER2+ molecular subtypes) and patient characteristics indicative of low socioeconomic status. Citation Format: Christina A Clarke, Laura Chu, Li Tao, Lisa Wang, Lisa Moy, Melissa Brammer, Chunyan Song, Marjorie Green, Scarlett Lin Gomez. Characteristics of de novo metastatic breast cancer in California, 2005-2011 [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 P3-07-26.

The preliminary report of intercalary diaphyseal endoprosthetic reconstruction for the proximal femur malignant bone tumor

Objective To evaluate the clinical effectiveness of the treatment for the proximal femur malignant bone tumor by conducting intercalary diaphyseal endoprosthetic reconstruction. Methods Form June 2011 to July 2014, 7 patients who had proximal femur malignant bone tumor were treated with intercalary diaphyseal endoprosthetic reconstruction. There were 3 males and 4 females, 61.8 years old on the average (ranging from 28 to 76 years). The tumors involved: 4 case of the limbs primary malignant tumor, 1 case of osteosarcoma, 1 case of juxtacortical osteosarcoma, 1 case of malignant lymphoma with pathological fracture, and 1 case of malignant fibrous histiocytoma with pathological fracture, as well as 3 cases of the Metastatic breast cancer of the proximal femur. All patients were evaluated by plain radiography, CT and MRI before operation. After these 7 patients were examined with MRI and the level of osteotomy was determined, prosthesis fitting is ready. The exposures of all the tumors were via the femur lateralis surgical approach. According to the general principles of tumor surgery, expose the tumor segment and soft tissue tumors. The segment of involved bone was then removed, with a surrounding cuff of normal tissue overlying the tumor. The level of osteotomy was determined as the result of preoperative imaging measurement. The proximal and distal femur intramedullary canals are reamed. The prosthesis is assembled and installed after the cement used. Results The duration of surgery was from 45 min to 120 min (90 min on average). The blood loss was from 200 ml to 800 ml (400 ml on average). All patients were followed-up for 6 months to 2 years (14 months on average). 1 case with osteosarcoma died due to pulmonary metastases 18 months after surgery. The remaining 3 cases with the primary malignant bone tumors did not recur or transfer during the follow-up period. 1 case with the metastases was comprehensive treated in another hospital, and survival with tumors. The remaining 2 cases with the metastases did not recur or transfer during the follow-up period. Conclusion The clinical results demonstrated that the intercalary diaphyseal endoprosthetic reconstruction was an ideal treatment for the proximal femur malignant bone tumor. Key words: Femur; Neoplasms; Prostheses and implants

Site-specific metabolic phenotypes in metastatic breast cancer.

BackgroundThe purpose of this study was to examine the expression of metabolism-related proteins according to metastatic site in metastatic breast cancer and to assess the implication of site-specific differential expression.MethodsA tissue microarray containing 162 cases of metastatic breast cancer (52 lung metastasis, 47 bone metastasis, 39 brain metastasis, and 24 liver metastasis) was constructed. It was subject to immunohistochemical staining of the following proteins: Glycolysis-related: Glut-1, hexolinase II, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; glutaminolysis-related: glutaminase (GLS) 1, glutamate dehydrogenase (GDH), and amino acid transporter (ASCT) 2; mitochondrial metabolism-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB; and serine/glycine metabolism related: phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), phosphoserine phosphatase (PSPH), glycine decarboxylase (GLDC), and serine hydroxymethyltransferase (SHMT).ResultsThe expression levels of glycolysis-related-proteins (Glut-1, hexokinase II, CAIX, and MCT4) differed according to metastatic site, with higher expression seen in the brain and lower expression in the bone and liver (p < 0.001, 0.001, 0.009, and <0.001, respectively). Differences in metabolic phenotype were analyzed according to metastasis site. Glycolysis type was most frequently encountered in the brain and lung (p < 0.001). In univariate analysis, the factors associated with shorter overall survival were CAIX positivity (p = 0.044), PSPH positivity (p = 0.045), and SHMT1 positivity (p = 0.002), as well as serine/glycine type (p = 0.041).ConclusionsDifferences in metabolic features according to metastatic site were seen in metastatic breast cancer, with the glycolysis phenotype found predominantly in the brain and lung and the non-glycolysis phenotype in the bone and liver.

The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway.

The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway.

Detection of circulating tumor cells and its clinical value for different stages and various subtypes of breast cancer

To explore the prognostic value of applying a semi-automated detection system for detecting circulating tumor cells (CTC) for different stages and various subtypes of breast cancer. Immunomagnetic separation and immunofluorescent staining were employed to detect the expressions of CTC and CTC HER-2. Chi-square test, univariate and multivariate analyses were used to examine the correlations between CTC and clinical characteristics. CTC was detected in 57.5% (138/240) of metastatic breast cancer (MBC). CTC enumeration, HER-2 status, number of metastasis and bone metastasis were relevant (P < 0.05). CTC was detected in 23.1% (6/26) of early-stage breast cancer (EBC). CTC enumeration, pathological type, estrogen receptor (ER), progesterone receptor (PR), Ki-67, tumor size and lymph node metastasis were irrelevant (P > 0.05). HER-2-positive MBC detected less CTC than HER-2-negative (χ(2) = 12.296, P < 0.001) . CTC HER-2 expression was different between HER-2-positive and negative patients in 99 MBC cases (χ(2) = 8.082, P = 0.004). CTC enumeration is different for various stages and different subtypes of breast cancer. CTC enumeration and bone metastasis are relevant. CTC detection in EBC may predict tumor relapse. And CTC HER-2 expression is different between HER-2-positive and negative MBC patients.

Association of CA 15-3 and CEA with clinicopathological parameters in patients with metastatic breast cancer.

The objective of this study was to investigate the association of serum cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) levels with clinicopathological parameters in patients diagnosed with metastatic breast cancer (MBC). We retrospectively evaluated the medical records of 284 patients diagnosed with MBC between January, 2007 and December, 2012 who fulfilled the specified criteria and the association between the levels of the two tumor marker and clinicopathological parameters was analyzed. Of the 284 patients, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were identified in 163 (57.4%) and 97 (34.2%) patients, respectively. Elevated CA 15-3 and CEA levels were significantly associated with breast cancer molecular subtypes (P<0.001 and P=0.032, respectively). Cases with luminal subtypes exhibited a higher percentage of elevated CA 15-3 and CEA levels compared to non-luminal subtypes. Elevated CA 15-3 level was correlated with bone metastasis (P=0.017). However, elevation of CEA was observed regardless of the site of metastasis. Elevation of CA 15-3 was significantly more common in MBC with multiple metastatic sites compared to MBC with a single metastasis (P=0.001). However, the incidence of elevated CEA levels did not differ between patients with a single and those with multiple metastatic sites. In conclusion, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were found to be associated with breast cancer molecular subtypes, whereas an elevated CA 15-3 level was significantly correlated with bone metastasis and an elevated CEA level was observed regardless of metastatic site. The proportion of MBC cases with elevated CA 15-3 levels differed according to the number of metastatic sites.

MAGE-specific T cells detected directly ex-vivo correlate with complete remission in metastatic breast cancer patients after sequential immune-endocrine therapy.

Studies suggest that conventional cancer therapies given after immunotherapy (IT) can boost antitumor immunity and possibly improve response rates and progression-free survival. We report two cases of metastatic breast cancer with durable complete responses (CRs) after sequential IT and endocrine therapy. Immune analyses of these long-term disease-free breast cancer patients previously treated with imiquimod (IMQ) suggest in-situ vaccination is achieved by topical application of the TLR-7 agonist directly onto tumors. Furthermore, IT-induced antigen-specific T cells were expanded by subsequent endocrine therapy and correlated with response, persisting > 2 years. Our findings therefore suggest that the induction/boosting of polyfunctional tumor antigen-specific T in response to sequential immune endocrine therapy and detected directly ex-vivo can serve as a peripheral blood biomarker for true clinical benefit.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-014-0032-2) contains supplementary material, which is available to authorized users.

Maintenance treatment of trastuzumab for patients with advanced breast cancer to achieve long term survival: two case reports and literature review.

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. The epidermal growth factor receptor (HER2) overexpressing breast cancers are designated as HER2-postive (HER2+) breast cancer and carry a particularly unfavorable prognosis. We present two cases of HER2-postive metastatic breast cancer (MBC) who are found to be a challenge to treat, especially due to the occurrence of brain metastasis. Trastuzumab-based therapy improves clinical outcomes, even if the patient has undergone multi-line treatment. These case reports also emphasize the importance of retesting HER2 status because it can be discordance in receptor status between primary and recurrent breast cancer.

Plasma DNA integrity as a biomarker for primary and metastatic breast cancer and potential marker for early diagnosis.

Circulating or cell-free DNA (cfDNA) has been evaluated as a biomarker in many cancers including breast cancer. In particular, integrity of cfDNA has been shown to be altered in cancers. We have estimated the biomarker potential of cfDNA in primary (PBC) and metastatic breast cancer (MBC). cfDNA integrity (cfDI) and concentrationwere determined in plasma of 383 individuals, including 82 PBC and 201 MBC cases, as well as 100 healthy controls, by measuring ALU and LINE1 repetitive DNA elements using quantitative PCR. The MBC patient group was further sub-divided into patients with detectable circulating tumour cells (CTCpos-MBC, n=100) and those without (CTCneg-MBC, n=101). A hierarchical decrease in cfDI and increase in cfDNA concentration from healthy controls to PBC and further onto MBC patients were observed. Investigation of cfDNA in media of cell lines was in concordance with these results. Combination of cfDI and cfDNA concentration could differentiate PBC cases from controls (area under the curve, AUC=0.75), MBC cases from controls (AUC=0.81 for CTCneg-MBC, AUC=0.93 for CTCpos-MBC), and CTCneg-MBC from CTCpos-MBC cases (AUC=0.83). cfDI additionally demonstrated a positive correlation to progression-free (HR of 0.46 for ALU, P=0.0025) and overall survival (HR of 0.15 for ALU and 0.20 for LINE1, P<0.0001) in MBC, and had lower prediction error than CTC status. Our findings show that reduced cfDI and increased cfDNA concentration can serve as diagnostic markers for PBC and MBC, and cfDI as a prognostic marker for MBC, thereby making them attractive candidates for blood-based multi-marker assays.

Luminal Subtypes Predict Improved Survival Following Central Nervous System Metastasis in Patients With Surgically Managed Metastatic Breast Carcinoma

Metastatic breast cancer to the central nervous system (CNS) is second only to lung cancer metastasis to the CNS in frequency. Patients with triple-negative primary breast cancer and those with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer are at an increased risk for metastasis. Very little is known about predictive or prognostic variables once patients develop CNS metastases. Currently, therapeutic options are limited, with surgery generally offered primarily to those with solitary lesions. To determine the influence of molecular subtypes of metastatic breast cancer on survival from the time of CNS metastasis and to aid in the prognostic stratification of these patients. We identified 59 cases of metastatic breast cancer to the CNS and analyzed them for various demographic and clinicopathologic parameters. Tumors were categorized into molecular subtypes using immunohistochemical methods: luminal A [estrogen receptor (ER⁺)/Ki67low], luminal B (ER⁺/Ki67 high), intrinsic HER2 (ER⁻/HER2⁺), and triple-negative. Survival after CNS metastasis for each group was plotted using a Kaplan-Meier curve, and multivariate analysis was performed. Patients with metastases from luminal tumors had a statistically significant survival advantage when compared with those of the triple-negative phenotype. Importantly, survival among patients with luminal A and luminal B tumors was not significantly different. Similarly, patient's age, histologic grade, and number of lesions did not contribute to determining outcomes. Estrogen receptor positivity (ie, luminal phenotype) of tumors appears to determine outcomes after development of metastases. In contrast, proliferation rate had little or no effect on the long-term survival. Understanding the biology of metastases can help stratify patients into prognostically meaningful categories and tailor treatment regimens for individual patients.

癌性胸水・腹水に対してS-1+CPT-11併用療法が奏効した乳癌の4例

癌性胸水・腹水に対してS-1+CPT-11併用療法が奏効した乳癌の4例

Abstract P5-01-05: Personalized peptide vaccines in combination with conventional chemo- or endocrine therapy for metastatic breast cancer: A single-arm phase II study

Abstract Background: Immunotherapy using multiple personalized peptide vaccines (PPV) has been reported to be effective for boosting anticancer immunity in patients (pts) with advanced prostate cancer and glioblastoma. The PPVs binding HLA-A2, A24, A3 family and A26 molecules were selected from 31 candidate peptides derived from various tumor associated antigens. Currently, we performed a phase II trial to evaluate the benefit of the PPVs in combination with conventional chemo-or endocrine therapy for pretreated metastatic breast cancer (MBC). Methods: Seventy-one pretreated pts had histologically confirmed measurable MBC and their HLA A molecules matched each of HLA-A2, A24, A26 and A3 family. Pre-vaccination plasma was measured for their IgG levels reactive to each of 31 peptides followed by administration subcutaneously of the four peptides at maximum showing higher levels of IgG in order with schedule of every 1-2 week. The concurrent conventional chemotherapy or endocrine therapy was available for the combination of PPVs. The primary endpoint was anti-tumor immunologic effect and safety, and the secondary endpoints were clinical responses and survival. Levels of IgG reactive to each of the 31 peptides in the pre- and post-treatment plasma at every 6 times of vaccination were measured using LUMNEX system. The CTL responses were simultaneously evaluated using ELISPOT method. Clinical response was evaluated by RECIST criteria. Results: Between May 2009 and December 2012, a total of 71 pts (Luminal-Her2- cases: 39; Her2+cases: 18; Triple negative(TN) cases:14) were enrolled in this study. The median duration of follow-up was 20.7 months. Concurrent chemotherapies (capecitabine, gemcitabine, eribulin, vinorelbine etc.) and endocrine therapies (aromatase inhibitor, toremifen or fulvestrant) were administered to 36 and 24 pts, respectively. Trastuzumab, Laptinib or Bevacizumab was simultaneously used for 13 pts. After 6th vaccination, the IgG reaction and CTL response were identified in 53 of 71 (74.6%) pts and 33 of 63 (52.3%) pts. There were no significant differences between TN cases and the other cases of MBC with regard to immunological humoral and/or cellular responses. No vaccine-related severe adverse events were observed. Clinical response rate of assessable 61 pts was 14.8% (CR 3, PR 6, SD 24, PD 28). The median PFS and OS were 7.6 m and 20.7 m, respectively. In contrast, the PFS and OS of luminal type, Her2 type or TN type were 12, 4.6 or 8.3 m and 24, 15 or 12 m. Conclusions: The phase II PPVs study for MBC demonstrated the promising response and safety, and further studies are essential to identify the clinical benefits of this novel therapy. Clinical trial information: UMIN000001482. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-01-05.

The observation of single-agent gemcitabine maintenance therapy in patients with metastatic breast cancer

Objective The aim of the study was to evaluate the efficacy and tolerability of single-agent gemcitabine in the maintenance treatment of histologically confirmed metastatic breast cancer cases.

Efficacy of exemestane and everolimus in HR positive (including HER2-neu positive) heavily pretreated cases of metastatic breast cancer in north India.

e11546 Background: M-Tor pathway is deregulated in significant percentage of patients with breast cancer. This pathway is responsible for tumor growth and metastasis especially in hormone receptor (HR) positive cases. Thus dual blockade of estrogen and M-Tor pathway has shown efficacy in this setting. Methods: Twenty patients with hormone receptor positive metatstatic breast cancer were treated with combination of everolimus 5 mg and exemestane 25 mg daily since November 2011. The median age was 53 years (age range- 32 to 75 years). All patients had two more sites of metastasis. 14 cases had 3 or more sites of metastasis. Liver- 10, lungs – 15, bones – 12, skin -3, lymph nodes – 10, and CNS – 5. Six of twenty cases were Her2 neu positive and were pretreated with Herceptin and lapatinib. All except 2 patients were treated with chemotherapy, 13 with minimum three lines of chemotherapy. All patients were ER and or PR positive and preteated with tamoxifen (5) and or aromatase inhibitors (anastrozole 9 and letrozole 11). The time gap between starting exemestane and everolimus and onset of metastatic disease was 2.5 years. Results: 7 out of 20 patients achieved disease control (either partial response-6 or stable disease -1). Out of 6 cases who were her2 neu positive, two achieved partial response. 5 out of 20 cases survive beyond nine months. Only two patients could go on to 10 mg daily everolimus. The dose limiting toxicity was development of oral ulcers. One patient had fever. No case of pneumonitis was noted with this dose. Conclusions: Combination of everolimus and exemestane is effective in HR positive cases and also in Her2 neu positive cases. 5 mg everolimus is well tolerated by most women. There is a need to further study the efficacy of this combinantion in Her2 neu positive cases.

Receptor Conversion between Primary Tumors and Distant Metastases in 121 Cases of Metastatic Breast Cancer

The article published in Vol.4 No.2 102-107, 2013 has been withdrawn by the authors for further revision. This paper will be re-submitted to IJCM after the authors revise it.

Clinical research of the combination of vinorelbine and ifosfamide in the treatment of advanced breast cancer resistant to anthracycline and taxane

Objective To observe and compare efficacy and safety of vinorelbine (NVB) plus ifosfamide (IFO) (NI regimen) and NVB plus cisplatin(DDP) (NP regimen) in treatment of metastatic breast cancer.Methods 82 cases of recurrent and metastatic breast cancer after the failure of treatment with anthracyclines and taxanes,40 cases were treated with NI regimen (NVB 25 mg/m2,day 1,day 8,IFO 1.2 g/m2,day 1,day 2,day 3),and the other 42 cases received NP regimen (NVB 25 mg/m2,day 1,day 8,DDP 25 mg/m2,day 1,day 2,day 3).Both groups were constituted of 21 days one cycle.After 2 cycles of chemotherapy,the response rate and side effects were evaluated.Results All 82 cases were evaluated for objective response.The total response rate of NI group and NP group were 52.50 ％ (21/40) and 57.14 ％ (24/42).There was no significiant difference (P ＞ 0.05).By analysis of the correlative factors,the total response rate in treatment of triple-negative breast cancer of NI group was 43.75 ％ (7/16),and that of NP group was 44.44 ％ (8/18).The two rates were also approximative (P ＞ 0.05).Main side effects were both bonemarrow suppression and gastrointestinal reaction.Bonemarrow suppression rate at grade Ⅲ-Ⅳ of NI group [57.5 ％ (23/40)] had no significant difference compared with that of NP group[57.14 ％ (24/42)] (P ＞ 0.05).But grade Ⅲ-Ⅳ gastrointestinal rate of NI group [7.50 ％ (3/40)] was significantly lower than that of NP group [26.19％(11/42)](P ＜ 0.05).Conclusion NI regimen in treatment of advanced breast cancer is effective,and it shows a similar response rate compared with NP regimen.Also it is effective for triple negeative breast cancers.The toxicity can be tolerated,and the gastrointestinal reaction rate of NI regimen is lower.NI regimen is a good choose in treatment of advanced breast cancer. Key words: Breast neoplasms; Drug therapy, combination; Advanced stage

Abstract P2-10-31: Correlation of quantitative p95HER2 and total HER2 levels with clinical outcomes in a combined analysis of two cohorts of trastuzumab-treated metastatic breast cancer patients

Abstract Background: Expression of p95HER2 (p95), a truncated form of HER2 also known as p110 or M611-CTF, is a possible trastuzumab resistance mechanism and has been associated with poor prognosis in trastuzumab-treated HER2-positive metastatic breast cancer (MBC). Previously we reported on optimal clinical cutoffs for quantitative p95 (Clin Cancer Res, 16:4226, 2010) and quantitative HER2 protein expression (H2T) by HERmark® (Cancer, 116:5168, 2010) that defined patient subsets with different progression-free survival (PFS). These cutoffs were confirmed in an independent trastuzumab-treated MBC cohort (ASCO 2011, #586). Here, using individual patient data, we performed an analysis on the combined data set of 243 cases from the discovery and validation cohorts to derive optimal cutoffs for quantitative p95 and H2T. Methods: Both quantitative H2T (HERmark, Monogram Biosciences) and p95 assays employed the VeraTag® method to quantify protein expression in formalin-fixed, paraffin-embedded tumor samples from two cohorts of 101 and 142 cases of trastuzumab-treated MBC with 7.4 and 9.2 months median PFS, respectively. All analyses were stratified by hormone receptor status, tumor grade (3 vs. 1+2) and cohort. H2T measurements were compared to pre-specified cutoffs for HERmark negative (H2T&amp;lt;10.5 Relative Fluorescence/mm2 tumor [RF/mm2]) and HERmark positive (H2T&amp;gt;17.8 RF/mm2), derived from the &amp;lt;5th percentile of centrally determined HER2-positives and the &amp;gt;95th percentile of centrally determined HER2-negatives, respectively, within a reference database of 1,090 breast cancer patient samples. Results: Patients classified as HERmark-positive had longer PFS than those classified as HERmark-negative (HR = 0.52; p = 0.0006; medians 10.0 and 5.9 months). The previously determined optimal H2T cutoff of 13.8 RF/mm2 in the center of the HERmark-equivocal zone, gave a similar result (HR = 0.54; p = 0.0005). This was close to the optimal cutoff of 12.75 RF/mm2 (HR = 0.48; p &amp;lt; 0.0001, unadjusted) for the combined data set. The PFS for the small group of patients in the HERmark-equivocal zone (n = 20) was more similar to the HERmark-negatives (equivocal vs. negative: HR=0.98; p = 0.9) than the HERmark-positives (positive vs. equivocal: HR=0.57; p = 0.057). The pre-specified p95 cutoff at 2.8 RF/mm2 separated the 174 HERmark-positive cases into two groups of longer (p95&amp;lt;2.8 RF/mm2) vs. shorter PFS (HR = 1.9; p = 0.0014; medians 13.1 and 7.4 months). Increasing continuous p95 also correlated with shorter PFS (HR = 1.9/log; p = 0.022) in the HERmark-positive subset. An optimal p95 cutoff was identified at 2.7 RF/mm2 (HR = 2.0; p = 0.0009, unadjusted), although a slightly higher local HR maximum was found at 1.55 RF/mm2 (HR = 2.3; p = 0.0004, unadjusted). Conclusions: HERmark positive and negative categories, defined by analytical comparison with centrally determined HER2 status, were confirmed to have significantly different PFS in trastuzumab-treated MBC patients. The optimal H2T clinical cutoff for this combined analysis was centered in the HERmark analytical equivocal zone. An optimal p95 clinical cutoff of 2.7 RF/mm2 derived from this combined analysis was nearly identical to the previously established cutoff of 2.8 RF/mm2. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-31.

Circulating miRNAs as Surrogate Markers for Circulating Tumor Cells and Prognostic Markers in Metastatic Breast Cancer

The use of circulating tumor cells (CTC) as a prognostic marker in metastatic breast cancer (MBC) has been well established. However, their efficacy and accuracy are still under scrutiny mainly because of methods of their enrichment and identification. We hypothesized that circulating miRNAs can predict the CTC status of patients with MBC, and tested for the same. Furthermore, we aimed at establishing a panel of circulating miRNAs capable of differentiating MBC cases from healthy controls. Circulating miRNAs from plasma of CTC-positive and CTC-negative patients with MBC, and healthy controls, were profiled by TaqMan Human MicroRNA arrays. Candidates from the initial screen were validated in an extended cohort of 269 individuals (61 CTC-positive, 72 CTC-negative, 60 CTC-low MBC cases, and 76 controls). CTC-positive had significantly higher levels of miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-375, and miR-801 than CTC-negative MBC and controls (P < 0.00001), whereas miR-768-3p was present in lower amounts in MBC cases (P < 0.05). miR-200b was singled out as the best marker for distinguishing CTC-positive from CTC-negative patients (AUC 0.88). We identified combinations of miRNAs for differentiating MBC cases from controls (AUC 0.95 for CTC-positive; AUC 0.78 for CTC-negative). Combinations of miRNAs and miR-200b alone were found to be promising prognostic marker for progression-free and overall survival. This is the first study to document the capacity of circulating miRNAs to indicate CTC status and their potential as prognostic markers in patients with MBC.

The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines.

Poly [ADP-ribose] polymerase-1 (PARP-1) localizes rapidly to sites of DNA damage and has been associated with various repair mechanisms including base excision repair (BER) and homologous recombination/non-homologous end joining (HRR/NHEJ). PARP-1 acts by adding poly-ADP ribose side chains to target proteins (PARylation) altering molecular interactions and functions. Recently small molecule inhibitors of PARP-1 have been shown to have significant clinical potential and third generation PARP inhibitors are currently being investigated in clinical trials. These drugs alone or in combination with radio/chemotherapy have resulted in meaningful patient responses and an increase in survival in metastatic breast cancer cases bearing BRCA-deficient or triple negative tumors and BRCA-deficient ovarian cancer patients. ABT-888, a potent PARP-1 inhibitor, sensitizes many cancer cells in-vitro and in-vivo to temozolomide. As such, we hypothesized that colon cancers would be sensitized to the DNA damaging chemotherapeutic agents, oxaliplatin and irinotecan, by ABT-888. Using colon cancer cell lines significant synergy was observed between ABT-888 and irinotecan at concentrations of ABT-888 as low as 0.125 μM. The level of synergy observed correlated with the degree of PARP1 inhibition as measured biochemically in cell lysates. ABT-888 at concentrations of 0.5-4 μM resulted in synergy with oxaliplatin. Furthermore, 24 h post treatment combinations of ABT-888/irinotecan generally resulted in increased G2/M cell cycle arrest and increased levels of DNA damage, followed by increased levels of apoptosis 48 h post treatment. In conclusion this study suggests that ABT-888 may be a clinically effective adjuvant to current colon cancer therapies that include the use of irinotecan and/or oxaliplatin.