bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-13-01: An innovative risk-reducing approach to post-mastectomy radiation delivery following autologous breast reconstruction
Authors: Piper ML , Evangelista M , Amara D , Daar DA , Foster RD , Fowble B , Sbitany H
Published: May 2016

Introduction:

There is no consensus among radiation oncologists regarding delivery of post-mastectomy radiation therapy (PMRT) after immediate autologous breast reconstruction, and plastic surgeons rarely participate in this decision-making process. However, radiation-induced changes markedly influence flap outcomes and affect the flap permanently. We present an innovative approach for PMRT delivery, through the use of custom bolus. This technique provides individualized, targeted PMRT to the reconstructed breast to minimize flap-related complications.

Methods:

All patients who underwent mastectomy with immediate autologous reconstruction between 2005 and 2014 at our institution were identified. Radiation was delivered to the reconstructed autologous breast in 29 patients. Post-irradiation complications and reconstruction outcomes were compared for patients treated with custom bolus, standard PMRT, and historical controls.

Results:

Over the past 10 years, 157 patients (226 breasts) underwent immediate autologous tissue breast reconstruction following mastectomy. Of the 29 patients who received PMRT, 10 were treated with custom bolus. The custom bolus uses perforated Aquaplast and a nearly tissue-equivalent wax to form a cast which conforms to the irregular contours of the chest wall, allowing for easy application through the duration of treatment. Pre-irradiation computed tomography was used to optimize dose distribution, evaluate the internal mammary vessels, and target the deeper tissues adjacent to the chest wall (minimizing dose inhomogeneity to the skin). Custom bolus resulted in fewer radiation-induced skin changes and less skin tethering/fibrosis than standard bolus (0% vs 10% and 20% vs 35%, respectively), and less volume loss and contour deformities compared with historical controls (10% vs 22.8% and 10% vs 30.7%, respectively).

Conclusion:

The use of custom bolus tailors radiation delivery to the internal mammary vessels, anastomoses, and skin; uniformly doses the surgical incision; and provides the necessary radiation dose to prevent recurrence, thus not compromising oncologic safety. It is easily fabricated, cost-effective and placement is straightforward and reproducible. Because radiation has negative effects on autologous breast reconstruction and often results in vascular intimal fibrosis and fat necrosis, plastic surgeons should participate in radiation planning. Our custom bolus PMRT technique reduces the incidence of these radiation effects.

Citation Format: Piper ML, Evangelista M, Amara D, Daar DA, Foster RD, Fowble B, Sbitany H. An innovative risk-reducing approach to post-mastectomy radiation delivery following autologous breast reconstruction. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-13-01.
Abstract P3-01-03: Optimal concentration of indocyanine green in near-infrared fluorescence guided sentinel lymph node biopsy in breast cancer
Authors: Paik H-J , Yi HW , Park S , Ryu JM , Nam SJ , Lee JE , Kil WH , Lee SK , Bae SY , Kim SW
Published: May 2016

Background: Near-infrared (NIR) fluorescence-guided sentinel lymph node biopsy (SLNB) using indocyanine green (ICG) has been successfully applied in various kinds of cancers, especially in breast cancer. Optimizing the concentration of ICG without using human serum albumin in natural lymphatic system is still required.

Methods: 25mg of ICG was diluted with distilled water (DW) or normal saline (NS). Dilution concentrations used for measurement were 0.25μg/mL, 0.5μg/mL, 2.5μg/mL, 5.0μg/mL, 25μg/mL, and 250μg/mL. The brightness of fluorescence was measured by an image system called Visual Navigator (SH System, Korea). We used graphic software (GIMP, version 2.8.14, The GIMP Team) to measure the brightness. We assumed that drained serous lymphatics from a breast cancer patient can reflect a natural lymphatic condition injected with ICG in the operation field. Drained lymphatics were mixed to reduce the concentration of ICG by half that was diluted with DW or NS. We also measured the brightness of fluorescence diluted with DW or NS that was mixed with drained lymphatics. After this screening test, we subdivided the range which brightness was measured as 100 and adjusted the intensity of illumination for more specific results.

Results: Highest brightness values were measured as 100 between 2.5μg/mL and 25μg/mL concentration of ICG with DW dilution in screening settings, and the values of brightness were measured as 100 between 2.5μg/mL and 5.0μg/mL concentration of ICG with NS dilution. When drained lymphatics were mixed together, the values of brightness were measured as 100 between 2.5μg/mL and 25μg/mL concentration of ICG with DW or NS dilution. After subdividing the ICG concentration to 2.5μg/mL, 3.13μg/mL, 5.0μg/mL, 6.25μg/mL, 12.5μg/mL and 25μg/mL with adjusting the intensity of illumination, the highest brightness value was measured as 76 in 5.0μg/mL concentration of ICG with DW dilution. When diluting with NS, the highest brightness value was measured as 61 in 5.0μg/mL ICG concentration. After mixing with drained lymphatics, the highest brightness value was both 79 in 5.0μg/mL concentration of ICG with DW and NS dilution.

Conclusions: This study showed a practically optimal ICG concentration range in fluorescence guided SLNB. The optimal range of ICG concentration is from 3.13μg/mL to 6.25μg/mL with DW or NS dilution. Although 5.0μg/mL met the best result, adjustment for individual settings may be considered.

Citation Format: Paik H-J, Yi HW, Park S, Ryu JM, Nam SJ, Lee JE, Kil WH, Lee SK, Bae SY, Kim SW. Optimal concentration of indocyanine green in near-infrared fluorescence guided sentinel lymph node biopsy in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-03.
Abstract P3-01-08: Sentinel lymph node biopsy alone after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer
Authors: Park S , Ryu JM , Paik H-J , Yi HW , Bae SY , Lee SK , Kil WH , Kim SW , Lee JE , Nam SJ
Published: May 2016

Background

The purpose of this study was to identify the feasibility and accuracy of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) in patients with axillary lymph node (ALN) metastasis at diagnosis.

Methods

This is a retrospective study of 332 patients who were diagnosed with invasive breast cancer and ALN metastasis and treated with NAC followed by curative surgery at Samsung Medical Center between January 2007 and December 2013. Patients were classified into five groups according to surgical procedure for the ALNs and pathologic results; group 1, patients with negative SLN status and no further dissection was performed; group 2, patients with negative SLN status undergoing further axillary lymph node dissection (ALND); group 3, patients with positive or undetected SLNs undergoing further ALND; group 4, patients without residual axillary metastasis undergoing complete ALND; and group 5, patients with pathologic nodal positive disease undergoing ALND.

Results

Sentinel lymph nodes identification rate after NAC was 99.1% and false negative rate was 24.1%. The median number of retrieved SLNs was 4 (range, 1–10). There was no difference in the overall survival among the groups (p=0.06). There was no significant difference in the disease-free survival rate between the SLNB only and complete ALN dissection groups who revealed a pathologic complete node response (79.6% versus 80.5%) and the rate of axillary recurrence demonstrated no significant differences among the groups. (p=0.225) There was a statistical difference of recurrence between group 1 versus 2, and group 1 versus 4 in hormone receptor-negative patients. (p=0.027)

Conclusion

SLNB after NAC in breast cancer patients with initial ALN metastasis may help identify downstaging to negative nodal status and thereby reduce the surgical morbidity by avoiding standard ALN dissection.

Citation Format: Park S, Ryu JM, Paik H-J, Yi HW, Bae SY, Lee SK, Kil WH, Kim SW, Lee JE, Nam SJ. Sentinel lymph node biopsy alone after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-08.
Abstract P3-01-10: Sentinel lymph node biopsy after neoadjuvant chemotherapy for patients with clinically node-positive breast cancer: A single institution retrospective evaluation
Authors: Gallant E , Ewing C , Wong J , Esserman L , Alvarado M
Published: May 2016

Background: In patients with clinically node-negative breast cancer sentinel lymph node biopsy (SLNB) offers accurate staging information with considerably less morbidity than a full axillary lymph node dissection (ALND). However, for clinically node-positive (cN1) patients who undergo neoadjuvant chemotherapy SLNB is thought to have a high false-negative rate and not suitable for this population. We sought to evaluate the false-negative rate (FNR) of SLNB following chemotherapy in patients initially presenting with cN1 breast cancer at a single institution.

Methods: Patients undergoing neoadjuvant chemotherapy diagnosed with cN1 breast cancer between October 2004 and February 2014 were identified from the University of California, San Francisco cancer registry. All patients underwent single agent mapping with Tc99 and SLNB followed by completion axillary lymph node dissection (ALND). Pathologic complete response, number of sentinel nodes removed and FNR were calculated.

Results: Of the 80 patients who underwent SLNB and ALND, 43 had residual metastatic disease in the nodes producing a nodal pCR of 46.25% (95%CI. 35.0%-57.8%). In 14 patients, cancer was not identified in the SLNs but was discovered in the lymph nodes retrieved by ALND, resulting in an overall FNR of 32.6% (95% CI, 19.1%-48.5%). 49 patients had only 1 SLN removed. Of the patients with only 1 SLN removed, a false-negative SLN was identified in 9 of the 21 patients with a positive node for a FNR of 42.9% (95% CI, 21.8%-66.0%). Of the patient with more than 1 SLN removed, 5 of 18 patients with a positive node had a false-negative SLN yielding a FNR of 27.8% (95% CI, 9.7%-53.5%). Only 14 patients had more than two SLNs excised.

Conclusion: Recent studies including the French GANEA 2 and ACOSOG Z1071 trials demonstrated a significant decrease in FNR when more than 1 SLN was excised. In this retrospective study however a single SLN was sampled from most patients. The FNR from this study was more than three times the generally accepted threshold of 10%. This substantial FNR further supports the need to remove more than 1 SLN during surgery in order to accurately assess nodal disease. Furthermore the implementation of a dual mapping technique would likely facilitate this process.

Citation Format: Gallant E, Ewing C, Wong J, Esserman L, Alvarado M. Sentinel lymph node biopsy after neoadjuvant chemotherapy for patients with clinically node-positive breast cancer: A single institution retrospective evaluation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-10.
Abstract P3-01-13: Risk factors of non-sentinel lymph node metastasis in breast cancer patients with metastatic sentinel lymph node
Authors: Huang J , Chen X , Shen K , Li Y , Chen W , He J , Zhu L , Huang O , Zong Y , Fei X , Jin X
Published: May 2016

Objective To study the factors influencing the non-sentinel lymph node(NSLN) status and to assess Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram performance in predicting SLN metastases in a sentinel lymph node(SLN) positive Chinese breast cancer population. Methods Data were collected from breast cancer patients who were diagnosed with pathological positive sentinel lymph node and received further axillary lymph node dissection(ALND) in Shanghai Ruijin Hospital from January 2011 to August 2014. Use MSKCC nomogram to calculate each patient's NSLN metastasis risk score. The receiver operator characteristic curve(ROC curve)and the area under the ROC curve(AUC)was used to assess the predictive accuracy of the model. Results Among the 1147 patients who received sentinel biopsy in our center, 150 SLN positive patients who received ALND were enrolled in this study. By univariate analysis, multifocal breast cancer (P = 0.017), SLN+/SLN ratio (P = 0.010) and axillary lymphadenopathy displayed by ultrasound(P = 0.005) are the influencing factors of NSLN metastases. By multivariate analysis, multifocal breast cancer (OR 7.25, 95% CI 1.73∼30.43, P = 0.007), SLN+/SLN ratio≥0.5 (OR 2.564, 95% CI 1.22∼5.39, P = 0.013) and axillary lymphadenopathy displayed by ultrasound (OR 2.471, 95% CI 1.18∼5.19, P = 0.017) are the independent influencing factors of NSLN metastases. The AUC of MSKCC nomogram in this population is 0.677. Conclusion For breast cancer patients with positive sentinel lymph node, multifocality, SLN+/SLN ratio and axillary lymphadenopathy displayed by ultrasound is related to NSLN metastasis. MSKCC has low accuracy in predicting NSLN status of this population.

Citation Format: Huang J, Chen X, Shen K, Li Y, Chen W, He J, Zhu L, Huang O, Zong Y, Fei X, Jin X. Risk factors of non-sentinel lymph node metastasis in breast cancer patients with metastatic sentinel lymph node. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-13.
Abstract P3-01-22: Sentinel lymph node metastases in breast cancer: A contributor to distant metastases?
Authors: Pereira ER , Kedrin D , Jones D , Beech E , Taghian A , Padera TP
Published: May 2016

Breast cancer metastasis remains a major cause of mortality in patients. Although significant progress has been made in understanding the mechanisms of this complex process, the findings have yet to be translated into improved survival rates in patients with metastatic disease. The presence of lymph node metastasis in most breast cancer patients is associated with tumor aggressiveness, poorer prognosis and often results in the need for systemic therapy. However, whether tumor cells in the lymph node exit and contribute to distant metastases remains controversial. To track the fate of tumor cells that metastasized to the lymph node, we engineered breast tumor cell lines to express Dendra2, a photo-convertible protein that fluoresces green in the native state and on light activation converts to red fluorescence. Using a novel chronic lymph node window that allows time-lapse imaging over a period of 10 days, we were able to track the movement of cancer cells in the dynamic microenvironment using high- resolution multi-photon microscopy. Our studies show that tumor cells entering the lymph node through the afferent lymphatic vessel proliferate in the sub-capsular sinus and later begin to invade the lymph node parenchyma. Importantly, by photo-conversion of tumor cells in the lymph node, we are able to track the tumor cells that escaped the lymph node and entered the blood circulation. The circulating tumor cells that transited through the lymph node were viable and proliferated in vitro. Our data indicate that metastatic breast cancer cells can exit the node and potentially colonize distant organs.

Citation Format: Pereira ER, Kedrin D, Jones D, Beech E, Taghian A, Padera TP. Sentinel lymph node metastases in breast cancer: A contributor to distant metastases?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-22.
Abstract P3-04-03: Investigating the therapeutic use of estrogen receptor β agonists in breast cancer
Authors: Samayoa C , Krishnegowda NK , Vadlamudi R , Tekmal RR
Published: May 2016

In breast cancer, estrogen receptor status reflects the biology of the tumor and is used to determine the likelihood of responding to endocrine therapy. 70% of all breast cancers express Estrogen Receptor α, which is indicative of estrogen dependence for growth. Current therapies aim to lower estrogen levels, or inhibit estrogen receptor signaling to ultimately prevent recurrence. However, only two-thirds of ERα-positive respond to endocrine therapy. The Estrogen Receptors are ligand-activated transcription factors with similar structures that slightly differ in their DNA binding sites and ligand binding domains. Estrogen Receptor α has been shown to induce the proliferation of mammary gland cells, whereas Estrogen Receptor β exhibits tumor suppressive properties. The objective of this study was to investigate the utility of selective ERβ agonists as a treatment for breast cancer. Using different breast cancer models, we investigated the effects of ERβ agonist treatment on growth, migration, apoptosis, cell cycle distribution and gene expression. In this study, we demonstrate that treatment with ERβ agonist results in inhibition of cell growth and migration. Additionally, treatment also impacts cell cycle distribution and affects key proteins involved in cell cycle regulation. We also demonstrate an increase in ERβ mRNA and protein levels upon treatment. This shift in the ERβ to ERα ratio, represents a viable targeting strategy in the treatment of breast cancer. To determine if our finding translate in-vivo, we employed xenograft and syngeneic mouse models. Our in-vivo studies demonstrated reduced tumor volumes in mice treated with ERβ agonists in combination with conventional therapy, confirming the growth inhibitory activity of ERβ agonists. Selective activation of ERβ, through the use of ERβ agonists has enabled us to exploit its tumor suppressive function and investigate the utility as a treatment for breast cancer. This study suggest that activation of ERβ signaling is a valuable strategy to inhibit breast cancer growth and progression.

Citation Format: Samayoa C, Krishnegowda NK, Vadlamudi R, Tekmal RR. Investigating the therapeutic use of estrogen receptor β agonists in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-04-03.
Abstract P3-04-04: Estrogen receptor β5 increases aggressiveness of the triple negative breast cancer cell line SUM159
Authors: Faria M , Tin-U C , Dey P , Gustafsson J-A , Strom AM
Published: May 2016

Recent clinical studies are indicating that the estrogen receptor β variant β5 (ERβ5) expression correlates to worse prognosis. We wanted to know if expression of ERβ5 is changing the growth behavior of the triple negative cell line SUM159. Estrogen receptor β5 is highly similar to estrogen receptor β1 except for a truncated C-terminus making the remaining ligand binding domain incapable of binding to estrogen. In addition a 4 amino acid unique peptide is added to the C-terminal end. Stably expressing ERβ5 using a transposon integrated tetracycline regulated expression system we find that expression of ERβ5 increases proliferation of the triple negative SUM159 cells especially in reduced serum condition compared to control cells. Since SUM159 have been shown to depend on autocrine stimulation for growth we are suggesting that expression of ERβ5 is affecting the production of autocrine growth factors.

Citation Format: Faria M, Tin-U C, Dey P, Gustafsson J-A, Strom AM. Estrogen receptor β5 increases aggressiveness of the triple negative breast cancer cell line SUM159. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-04-04.
Abstract P3-06-10: t-Darpp enhances protein kinase A signaling through direct effects on PKA holoenzyme and indirectly influences cell metabolism, proliferation and apoptosis
Authors: Lenz G , Theile D , Kane SE
Published: May 2016

Trastuzumab has dramatically improved the adjuvant therapy of Her2-positive breast cancer. However, acquired resistance to trastuzumab frequently occurs. Breast cancer cells in vitro selected for trastuzumab resistance exhibit over-expression of t-Darpp, a truncated form of the 32 kDa dopamine and cAMP-regulated phosphoprotein (Darpp-32). t-Darpp over-expression has previously been demonstrated to confer trastuzumab resistance and to result in increased protein kinase A (PKA) activity and signaling. Phosphorylation of Darpp-32 at threonine 75 has been shown to promote inhibition (not activation) of PKA by a yet unknown mechanism. T75 phosphorylation on t-Darpp is required for its trastuzumab resistance activity but the role of T75 phosphorylation in PKA activation by t-Darpp is not known and the molecular mechanism by which t-Darpp enhances PKA activity has not been reported. We used cells stably over-expressing either wild type t-Darpp or a T75A mutant of t-Darpp. Using proximity ligation assays, we found that t-Darpp binds directly to the RI regulatory subunit of PKA leading to 75% less RI subunit bound to the catalytic subunit of PKA (PKAc), compared to parental cells. In contrast, the t-Darpp-T75A mutant does not bind RI and those cells have only 34% less RI bound to PKAc compared to parental. These results suggest a direct effect of t-Darpp on PKA activation by binding the regulatory subunit RI and thereby preventing RI from inhibiting PKAc. The T75 phosphorylation site appears to be required for this activity. Using enzymatic and caspase activity assays, we also show that cells over-expressing t-Darpp, but not t-Darpp-T75A, have increased proliferation, up to 4-fold more cellular ATP, and diminished apoptotic response to etoposide, relative to parental cell controls. So far, this data suggests a dual mode of t-Darpp action: modulation of cell metabolism (possibly via effects on ATP production) and direct effects on PKA holoenzyme. Ultimately, pro-apoptotic response is diminished. Further studies will determine whether PKA activation by t-Darpp is responsible for, or separately influenced by, the metabolic effects of t-Darpp.

Citation Format: Lenz G, Theile D, Kane SE. t-Darpp enhances protein kinase A signaling through direct effects on PKA holoenzyme and indirectly influences cell metabolism, proliferation and apoptosis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-10.
Abstract P3-06-11: Understanding resistance mechanisms of PIK3a inhibition in breast cancer
Authors: Le X , Luo F , Treacy D , Wulf G , Garraway L
Published: May 2016

Breast cancer is the most common non-cutaneous cancer in women worldwide. PIK3CA is the most frequently mutated oncogene in all invasive breast cancers, with about one third of cases harboring activating mutations. Small molecule therapeutics targeting PI3K pathway has been developed and investigated for a decade. Everolimus (an mTOR inhibitor) is now successfully used in conjunction with hormonal therapy in patients with metastatic hormone-receptor positive breast cancers. Inhibitors of PI3Kα have shown promise as a single agent as well as in combination with hormonal therapies. The high rate of primary and acquired resistance; however, limits clinical usage of this class of drugs. There is an urgent need to understand the resistance mechanisms of PI3K inhibition and develop strategies to overcome the resistance in breast cancer. We took a genome-scale functional screening approach to identify resistance mechanisms to PI3K inhibition in breast cancer. We performed a whole-genome lentiviral open-reading frame (ORF) overexpression screen in a breast cancer cell line (T47D) in the presence of a PI3Kα inhibitor. We screened a total of 15,590 ORFs and identified 75 genes whose overexpression confers resistance to PI3K inhibition. Once we validate the hits, we plan to determine the mechanisms by which the genes confer resistance. We also plan to perform RNA-sequencing in patient samples with PI3Ka resistance to evaluate the clinical relevance of these genes and pathways.

Citation Format: Le X, Luo F, Treacy D, Wulf G, Garraway L. Understanding resistance mechanisms of PIK3a inhibition in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-11.
Abstract P3-07-10: The association between the expression of progesterone receptor and clinical benefit of adjuvant trastuzumab in estrogen receptor-positive and HER2-positive breast cancer patients
Authors: Lee HW , Ahn SG , Park JT , Yang BS , Park S , Jeong J , Kim SI
Published: May 2016

Background: Previous studies have shown that progesterone receptor (PR) status has a prognostic value in hormone receptor-positive breast cancer. In this study, we evaluated the clinical significance of PR status in estrogen receptor (ER)-positive and HER2-positive breast cancer.

Methods: We retrospectively analyzed the data of ER+ and HER2+ breast cancer patients who underwent surgery at Gangnam Severance hospital and Severance hospital from 2002 to 2012. We excluded patients who had a history of previous cancer, received neoadjuvant chemotherapy, did not received adjuvant chemotherapy, and had contralateral breast cancer or metastasis at diagnosis. A total of 346 patients were identified. Among them, 155 patients (44.8%) received adjuvant trastuzumab.

Results: At a median follow-up of 59 months, median disease-free survival (DFS) and overall survival (OS) were 56 and 59 months, respectively. The DFS and OS showed no difference according to PR status in overall patients. Then, these patients were categorized into two groups: ER+/HER2+/PR+ and ER+/HER2+/PR-. In ER+/HER2+PR+ patient, there was no difference of DFS or OS according to trastuzumab use. In ER+/HER2+/PR- patients, DFS was significantly better in patients who received adjuvant trastuzumab treatment compared to those who did not (p=0.009). We also analyzed influence of PR status on treatment outcome between patients who received adjuvant trastuzumab and those who did not. In patients who received adjuvant trastuzumab, there was no difference of DFS or OS according to PR status. However, in patients who did not receive adjuvant trastuzumab, ER+/HER2+/PR- patients showed worse DFS than ER+/HER2+/PR+ patients (p=0.006).

Conclusions: In patients with ER+/HER2+ breast cancer, we found that a prognostic value of PR only retained in those who did not receive adjuvant trastuzumab. Our findings suggest that the use of adjuvant trastuzumab may offer less clinical benefit for the patients with ER+/HER2+/PR+ breast cancer.

Citation Format: Lee HW, Ahn SG, Park JT, Yang BS, Park S, Jeong J, Kim SI. The association between the expression of progesterone receptor and clinical benefit of adjuvant trastuzumab in estrogen receptor-positive and HER2-positive breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-10.
Abstract P3-07-43: DNA methylation patterns correlating with outcome in patients treated with first-line bevacizumab for metastatic breast cancer
Authors: Gampenrieder SP , Rinnerthaler G , Weinhäusel A , Pulverer W , Hugnagl C , Hackl H , Romeder F , Monzo Fuentes C , Hauser-Kronberger C , Mlineritsch B , Greil R
Published: May 2016

Background: Biomarkers predicting response to bevacizumab containing therapy in breast cancer are of urgent need for a personalized treatment approach. DNA methylation is involved in regulation of angiogenesis and development of treatment resistance and could therefore provide predictive information for bevacizumab efficacy.

Patients and methods: A genome-wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in FFPE specimen of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (discovery set). Twenty-eight (78%) samples came from primary tumor and 8 (22%) from metastasis (2 lung mets., 1 pleural met., 1 liver met., 2 soft tissue mets., 1 ovarial met, 1 bone marrow infiltration). Based on progression-free survival (PFS) and breast cancer subtype (ER+ vs. triple-negative) patients were divided in responder (R) and non-responder (NR). By biostatistical methods differences in the methylation pattern between R and NR were detected. The 48 most interesting genes (e.g. because of there involvement in angiogenesis or carcinogenesis) showing a differential methylation status between R and NR are currently validated in two further metastatic breast cancer cohorts treated with (main set) and without bevacizumab (validation set), respectively. These validated results will be presented at the meeting.

Citation Format: Gampenrieder SP, Rinnerthaler G, Weinhäusel A, Pulverer W, Hugnagl C, Hackl H, Romeder F, Monzo Fuentes C, Hauser-Kronberger C, Mlineritsch B, Greil R. DNA methylation patterns correlating with outcome in patients treated with first-line bevacizumab for metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-43.
Abstract P3-07-68: Population-based validation study of Adjuvant! for primary breast cancer patients in the Netherlands
Authors: Siesling S , van Kleef JJ , Bretveld R , Groothuis-Oudshoorn CGM , van der Palen J , Jobsen JJ , Struikmans H
Published: May 2016

Background Adjuvant! is an online risk prediction tool that can support breast cancer patients and physicians in clinical decision-making regarding adjuvant systemic treatment. The aim of this study was to validate Adjuvant! on a Dutch population-based cohort of women diagnosed in 2003 and assess its calibration and discriminatory accuracy.

Methods All Dutch patients diagnosed with invasive primary breast cancer in 2003 in the Netherlands meeting the criteria of Adjuvant!; unilateral, unicentric invasive breast cancer, no evidence of metastatic or residual disease, pathologically staged I-III and no pT4 features, were included. Local treatment consisted of breast conserving therapy or ablative surgery and axillary staging. Adjuvant systemic treatment was given according to national guidelines. Patient, tumor and treatment characteristics were retrieved from the Netherlands Cancer Registry. Endpoints were ten-year overall survival, breast cancer specific survival and event free survival.

Findings A total of 8,195 patients were included. Out of all patients, 4,389 (53.6%) received some form of adjuvant systemic therapy. Throughout a ten-year follow-up, 2,156 (26.3%) patients died and 1,953 (23.8%) patients developed a recurrent disease (locoregional, distant or contralateral invasive cancer or DCIS). Ten-year observed overall survival was underestimated by -1.4% (95% CI -2.3 to -0.4, p=0.006), breast cancer specific survival was underestimated by -3.3% (95% CI -4.1 to -2.6, p<0.0001) and event free survival was underestimated by -3.5% (95% CI -4.5 to -2.6, p<0.0001). Discrimination was moderate for overall survival and breast cancer specific survival but poor for event free survival.

Interpretation Adjuvant! does not accurately predict breast cancer specific survival and event free survival in this Dutch population-based study. Dutch patients showed better ten-year survival rates than predicted by Adjuvant!. For specific patient groups, the model could be used to estimate overall survival. We conclude that Adjuvant! should be used with caution in clinical practice in the Netherlands but probably also in other countries and the US.

Citation Format: Siesling S, van Kleef JJ, Bretveld R, Groothuis-Oudshoorn CGM, van der Palen J, Jobsen JJ, Struikmans H. Population-based validation study of Adjuvant! for primary breast cancer patients in the Netherlands. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-68.
Abstract P3-09-04: Growth inhibitory effects of Cornus officinalis on a model for triple negative breast cancer
Authors: Telang NT , Nair HB , Wong GYC
Published: May 2016

Background: The triple negative breast cancer (TNBC) molecular subtype is characterized by the absence of estrogen receptor-α (ER-α), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expressions. TNBC is refractory to endocrine and to HER-2 selective therapy, while options for the treatment of choice involving high dose Anthracyclin/Taxol based conventional chemotherapy and/or small molecule inhibitor based targeted therapy are associated with systemic toxicity and acquired tumor resistance, leading to compromised efficacy. These limitations emphasize a need to identify efficacious non-toxic agents for secondary prevention/therapy of TNBC. Cornus officinalis (CO) is a Chinese herb of a nutritional nature in the form of a fruit. It is a major ingredient herb in some well-known Chinese herbal formulations for health management purposes. Growth inhibitory efficacy of CO in a model for ER positive Luminal A molecular subtype of clinical breast cancer is associated with abrogation of estradiol promoted growth via generation of anti-proliferative estradiol metabolites [Telang et al: Mol. Med. Rep. 5: 20-28, 2012].The present study examines the growth inhibitory effects of CO, and identifies possible molecular targets for its efficacy in a pre-clinical cell culture model for TNBC.

Experimental model, Herbal Extract and Biomarkers: The human mammary carcinoma-derived ER-α negative, PR negative and HER-2 negative MDA-MB-231 cell line represents the model for TNBC. Non-fractionated aqueous extract from CO represents the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation, cell cycle progression, cellular apoptosis and relevant pathway specific mechanistic assays represent the biomarkers for efficacy.

Results: Treatment of MDA-MB-231 cells with CO extract induces substantial dose dependent cytostatic growth arrest (IC50:0.1%; IC90:0.5%), and strongly inhibits AI colony formation. Within the cytostatic range CO inhibits G1 to S phase transition leading to G1 arrest that is accompanied by decreased expressions of Cyclin D1 and p-RB. Cellular apoptosis induced by CO is associated with modulation of the BAX-BCL-2 pathway, and up-regulation of the pro-apoptotic Caspase 3/7 activity.

Conclusions: These data provide a mechanistic evidence for efficacy of CO as a naturally occurring nutritional substance in a cell culture model for TNBC. The present study validates a mechanism based approach to prioritize efficacious non-toxic herbal extracts for secondary prevention/therapy of the TNBC molecular subtype of clinical breast cancer.

Citation Format: Telang NT, Nair HB, Wong GYC. Growth inhibitory effects of Cornus officinalis on a model for triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-09-04.
Abstract P3-12-09: Neoadjuvant radiochemotherapy in breast cancer- A safe and effect method for patients
Authors: Matuschek C , Boelke E , Budach W , Audretsch W , Wollandt S , Speer V , Nestle-Krämling C
Published: May 2016

BACKGROUND:

Neoaduvant radiochemotherapy (NRT-CHT) is the standard of care for many solid tumors. It could be also an alternative option for treating patients with locally advanced non inflammatory breast cancer (LABC). Surgeons are afraid of wound healing problems and fear bad cosmetic results. The purpose of this investigation was to find out if there are any acute or late side effects in breast conserving and mastectomy patients after NRT-CHX.

PATIENTS AND METHODS:

From 1991 to 1998 a total of 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with a consecutive electron boost in 214 cases or - in case of breast conservation - a 10-Gy interstitial boost with (192)Ir afterloading before EBRT. Chemotherapy was given prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. Also we investigated the acute side effects in 10 patients with NRT-CHX who were treated with this method from 2012-2015.

The cosmetic outcome was assessed by patient questionnaire, panel evaluation, and breast retraction assessment (BRA). Quality-of-life was investigated by EORTC QLQ-C30 and BR23 and acute and late radiation side effects by LENT/SOMA scale

RESULTS:

The long term results of 64 patients after breast conserving surgery and 152 patients after mastectomy were available. Most patients rated their overall cosmetics as excellent or good (94% breast conserving, 55.8% mastectomy). Patient and panel ratings on all cosmetic outcomes were similar between the two groups. After a follow up of 14-23 years we did not detect any grade III or IV fibrosis in any of our groups. The median BRA score after breast conserving surgery was 2.9 and the over-all quality of life (QLQ-C30) was rated "excellent" or good in 82%. Furthermore we did not detect any grade 3 or 4 acute side effects in our 10 patients who were recently treated with NRT-CHX.

CONCLUSION:

NRT-CHX is safe method and it is not associated with severe grade 3 or 4 acute or late side effects.

Citation Format: Matuschek C, Boelke E, Budach W, Audretsch W, Wollandt S, Speer V, Nestle-Krämling C. Neoadjuvant radiochemotherapy in breast cancer- A safe and effect method for patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-09.
Abstract P3-12-10: Overall survival in triple-negative breast cancers - Prognostic influence of type of surgery and adjuvant radiotherapy: A systematic review and meta-analysis
Authors: O'Rorke MA , Murray LJ , Bhoo Pathy N
Published: May 2016

BACKGROUND: Triple negative breast cancers (TNBC) are an aggressive, poorer prognostic tumour subtype which are negative for oestrogen, progesterone and human epidermal growth factor receptor 2 (HER-2) expression. Whilst the role of radiotherapy (RT) following breast conserving therapy (BCT) is widely accepted, there is no agreed consensus on the use of post-mastectomy RT, particularly in early-stage TNBC patients.

METHODS: Four electronic databases were searched from their inception to April 2015 including PubMed, MEDLINE, EMBASE and web of science. Observational studies investigating overall survival and locoregional/distant recurrence outcomes in women with TNBC according to type of surgery and radiotherapy receipt were included. Authors were contacted directly for further data. A random effects model was used to pool study effect estimates using mastectomy (MT) only patients as the reference group.

RESULTS: 8 studies including data from 3,456 patients were included. The median age and duration of follow-up was 54 years and 3.6 years respectively. The adjusted pooled hazard ratio (HR) and 95% confidence interval (CI) for overall survival comparing BCT and MT+RT to MT only was 0.52 (95% CI 0.31, 0.87; I2= 70.9%) and HR 0.60 (95% CI 0.38, 0.96; I2=41.5%) respectively. In subgroup analysis of MT+RT vs. MT alone, there was no significant interaction with early (T1-2, N0-1) vs. late stage (T3-4, N2-3) disease p=0.773 or age at diagnosis (<40, 40-64, ≥65 years) p=0.320. 5 studies evaluated local regional recurrence. Comparing BCT and MT+RT to MT only, the pooled HR was 0.61 (95% CI 0.41, 0.92) and HR 0.83 (95% CI 0.55, 1.26) respectively, with low heterogeneity detected (I2 0.0%). 4 studies assessed distant metastases. The pooled HR comparing BCT and MT+RT to MT only was 0.88 (95% CI 0.62, 1.23; I2= 0.0%) and HR 1.95 (95% CI 0.85, 4.49; I2= 75.1%) respectively.

CONCLUSIONS: The addition of adjuvant radiotherapy appears to favourably impact overall survival, irrespective of the type of surgery received. BCT may reduce the risk of locoregional recurrence in comparison to MT only. The small number of contributing studies and often high study heterogeneity suggest cautious interpretation of the findings. Further epidemiological studies or pooled analyses of individual patient data are warranted.

Citation Format: O'Rorke MA, Murray LJ, Bhoo Pathy N. Overall survival in triple-negative breast cancers - Prognostic influence of type of surgery and adjuvant radiotherapy: A systematic review and meta-analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-10.
Abstract P3-12-17: Can radiation dosimetric parameters explain severe skin reaction during adjuvant whole breast irradiation applying field-in-field technique?
Authors: Yoon WS , Lee NK , Lee JA , Yang DS , Kim CY , Son GS , Chang YW
Published: May 2016

Aim: Although modern radiotherapy such as field-in-field technique decreased the radiation toxicity, skin reaction is still frequent and main problem during adjuvant whole breast irradiation. Our study investigated various radiation dosimetric and clinical parameters as the risk factors of severe skin reaction.

Methods: From January 2012 to December 2014, total 219 patients with breast conserving surgery and adjuvant whole breast irradiation were retrospectively reviewed. All patients took both whole breast irradiation (50 Gy/25 fractions) and boost to the tumor bed (10 - 15 Gy). Skin reaction was measured by comparing the photography of radiation field between the first day of whole breast irradiation and boost therapy. For each axilla and inferior fold, the intensity (score 1 to 5) and extent (score 0 to 1) of erythema were recorded and summed. The severe skin reaction was defined as score 5 or 6. The relations of various radiation dosimetric parameters for radiotherapy planning, personal breast characteristics and clinical factors to severe skin reaction were evaluated using the Logistic regression tests.

Results: Total 75 (34%) and 57 (26%) patients showed the severe skin reaction to axilla and inferior fold, respectively. The variables of P < 0.2 in univariate analyses including age, the body mass index, the breast height, the V100, the calculated point dose in radiation planning system, the breast separation, the field size, and the gradient of inferior fold entered the multivariate analyses. Age (P=0.013 (OR = 0.950, 95% CI 0.913 - 0.989)), the body mass index (P = 0.015 (OR = 1.123, 95% CI 1.023 - 1.233)), the calculated axilla point dose (P = 0.091 (OR = 1.064, 95% CI 0.990 - 1.142)), and the gradient of inferior fold (P = 0.073 (OR = 1.029, 95% CI 0.997 - 1.063)) were risk factors for severe axilla skin reaction, whereas age (P = 0.018 (OR = 0.948, 95% CI 0.907 - 0.991)) and the V100 (P < 0.001 (OR = 1.005, 95% CI 1.003 - 1.007)) were for severe inferior fold skin reaction.

Conclusion: In addition to clinical factor and personal breast characteristics, the radiation dosimetric parameters such as calculated point dose and V100 could be another predictive factors of severe skin reaction.

Citation Format: Yoon WS, Lee NK, Lee JA, Yang DS, Kim CY, Son GS, Chang YW. Can radiation dosimetric parameters explain severe skin reaction during adjuvant whole breast irradiation applying field-in-field technique?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-17.
Abstract P3-13-02: Surcigal management of ipsilateral breast tumor recurrence
Authors: Kolben T , Schwarz TM , Goess C , Blume C , Degenhardt T , Engel J , Wuerstlein R , Ditsch N , Harbeck N , Kahlert S
Published: May 2016

PURPOSE

Approximately 10-15% of breast cancer patients treated by breast conserving surgery (BCS) and adjuvant radiotherapy (RT) will develop ipsilateral breast tumor recurrence (IBTR).

International guidelines suggest total mastectomy as treatment of choice for IBTR following lumpectomy and RT. Nevertheless, there is evidence that second BCS might be equally sufficient.

PATIENTS AND METHODS

Patients with IBTR diagnosed between 1990 and 2014 after BCS and RT were included (n=170).

34.1% women underwent secondary BCS, whereas 65.9% were treated by mastectomy. We determined predictive factors for time to local progression (TTP), disease free survival (DFS), and overall survival (OS) comparing these two groups.

RESULTS

Median follow-up after primary IBTR was 49 months (59 months for patients still alive at time of analysis). Five-year IBTR-free rate after secondary BCS was 77.6% (SD±6.1%) and 75.0% (SD±4.5%) for patients after mastectomy. Five-year DFS was 57.3% (SD±8.2%), and 61.9% (SD±5.5%), five-year OS was 84.7% (SD±5.8%), and 72.6% (SD±5.1%), respectively.

Prior adjuvant systemic therapy, muscular invasion, and skin infiltration were independent significant risk factors for a shorter TTP.

Additionally, lymphovascular infiltration (LVI) in the IBTR increased the risk for a shorter DFS.

LVI, muscular invasion, and skin infiltration were identified as independent significant risk factors for a shorter OS.

CONCLUSION

No significant difference in local control, DFS, and OS was seen between IBTR patients treated either by secondary BCS or mastectomy. Our data suggest that secondary BCS for IBTR patients after initial BCS and RT is feasible in selected patients.

Citation Format: Kolben T, Schwarz TM, Goess C, Blume C, Degenhardt T, Engel J, Wuerstlein R, Ditsch N, Harbeck N, Kahlert S. Surcigal management of ipsilateral breast tumor recurrence. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-13-02.