Late Breast Research Articles

Opportunities for post-market surveillance of high cost medicines in Australia: Observing trastuzumab-treated women from early through late stage HER2-positive breast cancer (HER2BC)

ABSTRACT
 ObjectivesIn 2001 the Australian government circumvented traditional drug subsidy listing processes to create the Herceptin Program (HP) for HER2 metastatic breast cancer (MBC) patients; in 2006 trastuzumab was subsidised for early breast cancer (EBC) on the Pharmaceutical Benefits Scheme (PBS) creating opportunities for data linkage and observing patients across both treatment settings. Clinical trials established the efficacy of trastuzumab for MBC in trastuzumab-naïve patients but little is known about patients initiating trastuzumab in the adjuvant setting and subsequently receiving trastuzumab for MBC. We characterise patterns of treatment and outcomes for these patients in Australia. We estimate time from adjuvant trastuzumab initiation to metastatic trastuzumab initiation and overall survival (OS).
 ApproachWe identified a cohort of patients with a trastuzumab claim in both PBS and HP records. We calculated duration of EBC treatment as date of first trastuzumab dispensing until 21 days after the last PBS dispensing for trastuzumab or observation of a trastuzumab dispensing record in HP claims, whichever came first. We used Kaplan-Meier methods to estimate time-to-MBC treatment and OS.
 ResultsOf 11,477 EBC patients treated with trastuzumab between December 2006 and December 2012, 637 were also treated with trastuzumab for MBC. Median age at EBC treatment initiation was 53 (range 17 – 87). 94% of EBC patients received a taxane, anthracycline, cyclophosphamide and/or carboplatin as part of their treatment protocol. 61% of MBC patients received trastuzumab with a taxane, 18% as monotherapy and 7% with capecitabine. Median duration of trastuzumab therapy in EBC and MBC therapy was 11.3 (95% CI 10.7-11.6) and 9.3 (8.6-10.4) months, respectively. Median time-to-MBC therapy was 27.3 (25.5-28.2) months. Median OS from initiation of EBC and MBC treatment was 58.1 (52.9-65.7) and 23.2 (20.5-25.4) months, respectively.
 ConclusionHER2BC patients initiating trastuzumab for EBC therapy and progressing to MBC treatment are little examined in the clinical trial and observational literature. Australia’s unique funding arrangements allowed us to clearly distinguish between treatment for EBC and MBC which is not always possible in dispensing claims alone. We demonstrated: most EBC patients are treated according to guideline recommendations; that this patient cohort receive approximately 20 months of trastuzumab therapy across both settings; and median OS from initiation of MBC trastuzumab is approximately 2 months shorter than in the pivotal clinical trial (25.1 months).

Impact of Urban Neighborhood Disadvantage on Late Stage Breast Cancer Diagnosis in Virginia.

Research suggests that residents of inner-city urban neighborhoods have higher rates of late stage cancer diagnosis. Identifying urban neighborhoods with high rates of both concentrated disadvantage and late stage cancer diagnosis may assist health care providers to target screening interventions to reduce disparities. The purposes of this study were to (1) create an index to evaluate concentrated disadvantage (CD) using non-racial measures of poverty, (2) determine the impact of neighborhood CD on late stage breast cancer diagnosis in US cities, and (3) to understand the role of obesity on this relationship. We used census block group- (CBG) level poverty indicators from five Virginia cities to develop the index. Breast cancer cases of women aged 18-65 who lived in the five cities were identified from the 2000-2012 Virginia Cancer Registry. A logistic regression model with random intercept was used to evaluate the impact of disadvantage on late stage breast cancer diagnosis. CBG-level maps were developed to geographically identify neighborhoods with both high rates of CD and late breast cancer staging. Over 900 CBGs and 6000 breast cases were included. Global fit of the concentrated disadvantage model was acceptable. The effect of disadvantage on late stage was significant (OR = 1.0083, p = 0.032). Inner-city poverty impacts risk of late stage breast cancer diagnosis. Area-level obesity is highly correlated with neighborhood poverty (ρ = 0.74, p < 0.0001) but the mediating direct and indirect effects are non-significant. Intervening in these high poverty neighborhoods may help combat disparities in late stage diagnosis for urban poor and for minorities living in these underserved neighborhoods, but more study is needed to understanding the complex relationship between concentrated neighborhood poverty, obesity, and late stage diagnosis.

Extended Endocrine Therapy: Is 5Years Enough?

Women with hormone receptor (HR)-positive breast cancer remain at risk for cancer recurrence for decades. In this review, we address recent data regarding the benefits and risks of extended endocrine therapy. Ten years of treatment with either tamoxifen or an aromatase inhibitor resulted in superior disease-free survival compared to 5years of treatment. However, there are risks associated with extended therapy with either class of medication. Multiparameter genetic tests are in development to individualize the risk of late breast cancer recurrence and predict benefit from extended endocrine treatment. Extended endocrine therapy is a promising strategy to reduce breast cancer recurrence in women with HR-positive breast cancer. This approach should be considered based on individual risk of cancer recurrence compared to potential benefit, comorbidities, and tolerance of therapy.

Abstract P2-05-13: Negative progesterone receptor is associate early breast cancer relapse, even among good prognosis tumors

Abstract Background/objective: A minority of estrogen-receptor (ER) positive breast cancers lack progesterone receptor (PR) expression, but little is known of the clinical meaning of PR negativity (PR-). In the present study we sought to clarify the association between PR- and outcomes of ER+, human-epidermal growth factor (HER2)-negative breast cancers using a large, single institution database. Methods: We retrospectively analyzed consecutive, non-metastatic, unilateral HER2- invasive breast cancers diagnosed between 2000 and 2011. Records were reviewed for age at diagnosis, disease stage, tumor features, and histologically confirmed recurrence. ER+ and PR+ status was defined as ≥1% immunoreactive cells. We used Kaplan-Meier curves to determine the association between PR- and early (≤5 years) and late (&amp;gt;5 years) disease recurrence, defined as locoregional or distant breast cancer relapse &amp;gt;6 months after diagnosis. Results: We identified 1,933 patients with TN (n=337) or ER+/HER2- (n=1,596) breast cancer. Patients with ER+/PR- (n=107) vs. ER+/PR+ (n=1,489) tumors did not differ in age or disease stage at diagnosis; however, PR- tumors were more frequently high grade (37.9% vs. 17.8%, p&amp;lt;0.001), with higher median Ki67 indices (20.0% vs. 10.0%, p&amp;lt;0.001). Median ER expression was also lower in PR- as compared to PR+ tumors (80.0% vs. 90.0%, p&amp;lt;0.001). Over a median follow-up of 84 months, there were 119 early and 54 late locoregional or distant breast cancer relapses. Negative PR was strongly associated with early relapse, with PR- tumors demonstrating a 2.1-fold higher hazard of relapse in the first 5 years as compared to PR+ tumors (95% CI 1.0-4.2) Hazards of early (&amp;lt;5 years) breast cancer relapse by hormone status. Shown are univariable Cox proportional hazard ratios and 95% confidence intervals among all tumors, and in subsets defined by %ER, node status, Ki67, and grade. All tumors n=1,933High ER (80-100%) n=1,383TN3.9 (2.6-5.6)*--PR 0%2.1 (1.0-4.2)*1.7 (0.6-4.6)PR 1-100%ReferenceReference Node-negative n=1,299Node-positive n=634TN4.3 (2.5-7.5)*3.6 (2.1-6.0)*PR 0%2.7 (1.0-7.0)*1.6 (0.6-4.5)PR 1-100%ReferenceReference Ki67 &amp;lt;14% n=768Ki67 ≥14% n=997TN**2.4 (1.5-3.8)*PR 0%4.1 (1.2-14.1)*1.6 (0.7-3.8)PR 1-100%ReferenceReference Grade 1/2 n=1,337Grade 3 n=564TN3.4 (1.4-7.9)*1.9 (1.2-3.3)*PR 0%2.0 (0.7-5.7)1.2 (0.4-3.5)PR 1-100%ReferenceReference*p&amp;lt;0.05; **too few subjects/events for analysis. Negative PR remained significantly associated with a higher hazard of early relapse even in node-negative (HR 2.7, 95%CI 1.0-7.0) and low-proliferating tumors (Ki67&amp;lt;14%, HR 4.1, 95%CI 1.2-14.1). There was no significant association between PR- and late breast cancer relapse (HR 0.7, 95%CI 0.2-2.9). Conclusions: Compared to ER+/PR+ breast cancers, ER+/PR- breast cancers have a significantly greater risk of early recurrence, similar to triple-negative cancers. These results suggest that negative PR expression is importantly and independently associated with early breast cancer prognosis, and may be an indicator of unique tumor biology. Citation Format: Winner M, Rosman M, Mylander C, Jackson RS, Pozo ME, Wolff AC, Tafra L, Umbricht CB. Negative progesterone receptor is associate early breast cancer relapse, even among good prognosis tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-13.

Abstract PD7-07: Discovery of molecular predictors of late breast cancer specific events (BCSE) in ER+, node+ breast cancer – new transcriptome expression whole gene analysis of the phase III adjuvant trial SWOG S8814

Abstract BACKGROUND: Unique genes and pathways were identified for prognosis on tamoxifen (T, 5 yrs) and prediction on CAF-T vs T in S8814 using whole transcriptome RNA-Seq from archival FFPE tissue. (Albain, et al; Cherbavaz, et al; SABCS 2015) Discovery was robust for early DFS events but sparse for late. The aims of this new analysis were to 1) utilize a new endpoint BCSE for gene discovery of late events, prognosis and prediction and 2) add intronic counts to the previous exonic results to define whole genes impacting on late BCSE. METHODS: Charts of patients (pts) on CAF-T (212) vs T (142) were reviewed to define the BCSE endpoint (local/regional, contralateral, distant). Deaths without BC were treated as competing risks. BCSE models (including metagenes) of late prognosis and prediction used cumulative incidence functions. Consolidated intronic regions counts within genes were added to exonic regions counts. Using these “whole gene” (WG) counts, association of gene expression with time to BCSE was assessed by Cox regression. A multiple WG score (MWGS) for BCSE prognosis beyond 5 yrs (to 12.5 yrs) was constructed and evaluated for 1-3 and 4+ node (N) groups. False discovery rate was controlled at 10%. RESULTS: More exons and WG were discovered for prognosis on T alone over 12.5 yrs with the BCSE endpoint than DFS. For prognosis of late BCSE after 5 yrs, more genes were discovered using WG (n=111) than by exons (n=9). There were significantly fewer genes for late BCSE on CAF-T (8, WG; 0, exons). The functions of WG prognostic for late BCSE were: cell cycle/proliferation-26 genes, chromosome segregation/mitotic spindle-22, DNA repair/maintenance-10, transcriptional/translational control-5, cell adhesion/migration-4, immune-3, diverse/unknown-32 and growth factor/hormone receptor signaling-9 (this group was only found by WGs, not exons). Of these 111 WG, a MWGS prognostic for late BCSE on T used 57 previously discovered genes pre-specified for this analysis. Probability of BCSE beyond 5 yrs for low vs high MWGS was 8% vs 21% in N1-3+ and 17% vs 42% in N4+. Late prognosis on T differed by low vs high risk defined in a metagene model: cumulative BCSE at year 10 was 0% vs 47% (low vs high risk, p=0.001). Prediction of 10-yr incidence of BCSE varied by risk level by treatment in a metagene model: low risk- CAF-T=47%, T=0% (p=0.045); high risk- CAF-T=35%, T=45% (p=0.027). CONCLUSIONS: Gene discovery for prognosis of late BCSE is enhanced with a novel WG transcriptome expression approach. Use of chemotherapy (CT) before T significantly attenuated gene discovery, so that molecular tools for decisions on extending endocrine therapy (ET) may not be reliable in a setting of prior CT. Some pts on ET for 5 yrs may not require either longer ET or CT, given a N+ cohort was defined with no BCSE observed over 12.5 yrs. For prediction of CT benefit, CAF-T appeared to be inferior to T in a low risk metagene model for BCSE. In sum, these results add more evidence that ET alone may be sufficient (perhaps better) in select N+ settings. Validation in SWOG S1007 (RxPONDER) is planned. SUPPORT: NCI CA180888, 180819, 180821, 180820, 180863; in part, Genomic Health, Inc. Citation Format: Albain KS, Crager MR, Barlow WE, Baehner FL, Bergamaschi A, Rae JM, Ravdin PM, Tripathy D, Gralow JR, Livingston RB, Osborne CK, Ingle JN, Pritchard KI, Davidson NE, Carey LA, Cherbavaz DB, Sing AP, Shak S, Hortobagyi GN, Hayes DF. Discovery of molecular predictors of late breast cancer specific events (BCSE) in ER+, node+ breast cancer – new transcriptome expression whole gene analysis of the phase III adjuvant trial SWOG S8814 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD7-07.

Abstract 33. Late Shape Distortion after SPAIR Mammaplasty Secondary to Seroma Induced Scar Contracture

Purpose: Previous reports have documented the safety and efficacy of the short scar periareolar inferior pedicle reduction (SPAIR) mammaplasty. This technique utilizes an inferior pedicle, circumvertical skin resection pattern, and purse-string peri-areolar closure to achieve a stable and aesthetic breast shape. Late breast distortion from seroma formation is rare complication than may occur after an initially satisfactory result. Contraction of the seroma cavity may cause the surrounding breast tissues to deform. The purpose of this case series is to describe the treatment of this unique complication after SPAIR mammaplasty. Methods: The senior author’s database was retrospectively reviewed to identify all cases with late breast shape distortion after SPAIR mammoplasty. Patients treated operatively and non-operatively were statistically compared. Furthermore, a literature search was conducted to identify any further studies reporting this similar complication. Results: Over an 18 year period, 747 SPAIR mammaplasty procedures were performed. Late breast distortion from seroma contracture was identified in 16 patients (2.1%). In seven of these patients (12 breasts), the distortion resolved with non-operative management. In nine patients (17 breasts), persistent shape distortion prompted operative exploration and excision of the seroma cavity. In the operative group, eight patients experienced complete resolution of symptoms, while one patient experienced a mild recurrence and declined further treatment. Conclusion: Late breast distortion due to a contracted seroma cavity after SPAIR mammoplasty is a previously unrecognized complication. Persistent shape alterations may require excision of the seroma cavity. Proper management of this complication allows restoration of an aesthetic breast shape.

Effects of Shugan Jianpi Formula () on myeloid-derived suppression cells-mediated depression breast cancer mice.

To observe the intervention effect of Shugan Jianpi Formula (, SGJPF) on a breast cancer mouse model with depression and investigate the underlying mechanism of SGJPF in preventing the development of breast cancer. The breast cancer model was induced by inoculation of breast cancer cells, the depression model was induced by chronic stress stimuli, and the depression cancer model was established by combining the two factors. The mice were divided into 7 groups: normal control, depression model, tumor model, depression tumor model, SGJPF, chemotherapy, and SGJPF+chemotherapy groups. The last 3 groups were depression breast cancer mice and treated respectively with SGJPF, chemotherapy drug gemcitabine (GEM), and SGJPF alongside GEM. The condition of the mice was evaluated by the expression of 5-hydroxytryptamine in hippocampus after the sucrose water test and open field test, weight change, and survival time. Tumor growth was monitored with in vivo imaging. Flow cytometry was used to analyze the level of myeloid-derived suppression cell (MDSC) in the mouse spleen, T cell subsets, and the early apoptosis of CD8+ T cells. The SGJPF+GEM group had the highest inhibition rate and the longest survival time (P<0.01). The MDSC level and the apoptosis rate of CD8+ T cells was the highest in the SGJPF+GEM group (P<0.05). Depressive disorders and tumor growth could suppress the immune function of mice to different degrees, and the microenvironment in late 4T1 inflammatory breast cancer may play an important role in the pathological process. SGJYF could regulate the immune microenvironment by reducing CD8+ T lymphocyte apoptosis and tumor cell activity, increasing immune surveillance capability, and inhibiting MDSC proliferation, thus prolonging the survival time of tumor-bearing mice.

Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?

There is an ongoing debate on the optimal sequence of radiation and breast reconstruction. The purpose of this article was to (a) assess the impact of radiation on autologous breast reconstruction and (b) analyze the best timing for autologous breast reconstruction in the setting of radiation in a Chinese population. A retrospective review of patients undergoing breast reconstruction with autologous lower abdominal flaps between 2001 and 2014 in the Tianjin Medical University and Cancer Hospital was performed. Patients were grouped by their irradiation status (irradiated vs nonirradiated). The irradiated group was further stratified into 2 groups by the timing of irradiation (immediate breast reconstruction followed by radiation vs prior radiation and delayed breast reconstruction). The primary outcomes were early and late breast complications, secondary and revision surgeries to the reconstructed breast, whereas the secondary outcomes were aesthetic and psychological evaluations of the patients. Logistic regression was used to assess the potential association between irradiation, patient and treatment variables, and surgical outcomes. Three hundred sixty patients with 370 reconstructed breasts were included in the study. Two hundred seventy-eight cases were nonirradiated, of which 158 were immediate and 120 were delayed. Ninety-two cases were irradiated, of which 61 were immediate, and 31 were delayed. Three hundred thirty-two cases underwent pedicled transverse rectus abdominis myocutaneous flap, 38 had deep inferior epigastric perforator flap. The irradiated group had a significant increase in secondary surgery due to fat necrosis (P < 0.001) and in late complications (P = 0.011). A significant increase in flap contracture (P = 0.043) and an increasing trend in the severity of fat necrosis were observed when radiation was performed after breast reconstruction. However, radiation and its timing did not have an adverse impact on patients' aesthetic and psychological evaluations by the Breast-Q survey. Radiation administered to the reconstructed breast mound increased the rate of late complications and the need for secondary surgery with increased abdominal flap shrinkage and contracture and the severity of flap fat necrosis. Irradiation on the reconstructed breast did not lead to worse aesthetic outcomes due to the generally different expectation in the Chinese female patients in that they were more focused on the breast shape when clothed. Immediate breast reconstruction followed by irradiated was a generally successful treatment sequence in the Chinese module.

1334P - A novel way to visualise tumour related angiogenesis and detect breast tumours in women: A combined clinical and optical method for breast cancer screening of well-women in Ghana

Late stage neoplastic breast lesions abound in Ghana, especially, late-stage early-age breast cancer and therefore low survival rates after treatment of breast cancer is prevalent. The median age at diagnosis for breast cancer is 39 years hence screening mammography (“the gold standard”) is not suitable and also not readily available in Ghana. Preliminary data suggests transillumination offers a new mode of early detection for neoplastic breast lesions and is not limited by age. In all, over 10,000 women who were manually screened for breast lesions during mobile breast screening clinics with the view to enhance early detection were offered transillumination with the breastlight/breast-i (optical torch devices used to detect angiogenesis) as well. These optical devices, (the breastlight/breast-i) developed by David J. Watmough were used to visually observe angiogenesis around breast tumours and lesions. The breastlight/breast-i operates on the principles of light travelling through tissues and the specific wavelength of light absorption by Heamoglobin in blood Here we report on a total of 9,962 “well women", initially using Breastlight but since 2014 using a new improved instrument Breast-i. The significance of a dark shadow arises because light is multiply scattered within the breast tissues and excess absorption of red light occurs at a wavelength of around 620nm when a cancer is present, caused by angiogenesis. A sensitivity of 94.4% was obtained for detecting breast cancer. The advantage of Breast-i is that there is no radiation exposure, no tissue compression and it is quick and easy to carry out the examination. This is probaly the largest study of its kind in the world.

Is early breast milk fortification more effective in preterm infants?: a clinical trial.

Breast feeding alone does not provide adequate nutrition for growth in preterm infants; therefore, fortifiers are added when over 70-80 cc/kg/day of breast milk is tolerated. As there are few studies comparing early and late breast milk fortification, the following study was conducted. This double-blind clinical trial was performed on 80 preterm infants (gestational age of 28-34 weeks, birth weight <2 kg). The newborns were randomly divided into two groups to receive either early or late fortification. The primary and secondary outcomes were the difference in growth indices and complications (including feeding intolerance, necrotizing enterocolitis (NEC), and septicemia) between the two groups, respectively. Both groups showed increases in growth indices; however, there was no statistically significant difference in increments of growth indices and complications between the two groups. Our findings suggest that early fortification from the first feeding in neonates with exclusive breast feeding did not improve growth in the first 4 weeks in preterm neonates in comparison with late fortification; so early fortification may not be cost effective.

Partial breast irradiation for early breast cancer.

Breast-conserving therapy for women with breast cancer consists of local excision of the tumour (achieving clear margins) followed by radiotherapy (RT). RT is given to sterilize tumour cells that may remain after surgery to decrease the risk of local tumour recurrence. Most true recurrences occur in the same quadrant as the original tumour. Whole breast radiotherapy (WBRT) may not protect against the development of a new primary cancer developing in other quadrants of the breast. In this Cochrane review, we investigated the delivery of radiation to a limited volume of the breast around the tumour bed (partial breast irradiation (PBI)) sometimes with a shortened treatment duration (accelerated partial breast irradiation (APBI)). To determine whether PBI/APBI is equivalent to or better than conventional or hypo-fractionated WBRT after breast-conserving therapy for early-stage breast cancer. We searched the Cochrane Breast Cancer Group Specialized Register (4 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 5), MEDLINE (January 1966 to 4 May 2015), EMBASE (1980 to 4 May 2015), CINAHL (4 May 2015) and Current Contents (4 May 2015). We searched the International Standard Randomised Controlled Trial Number Register (5 May 2015), the World Health Organization's International Clinical Trials Registry Platform (4 May 2015) and ClinicalTrials.gov (17 June 2015). We searched for grey literature: OpenGrey (17 June 2015), reference lists of articles, several conference proceedings and published abstracts, and applied no language restrictions. Randomized controlled trials (RCTs) without confounding, that evaluated conservative surgery plus PBI/APBI versus conservative surgery plus WBRT. Published and unpublished trials were eligible. Two review authors (BH and ML) performed data extraction and used Cochrane's 'Risk of bias' tool, and resolved any disagreements through discussion. We entered data into Review Manager 5 for analysis. We included seven RCTs and studied 7586 women of the 8955 enrolled.Local recurrence-free survival appeared worse for women receiving PBI/APBI compared to WBRT (hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.11 to 2.35; six studies, 6820 participants, low-quality evidence). Cosmesis (physician-reported) appeared worse with PBI/APBI (odds ratio (OR) 1.51, 95% CI 1.17 to 1.95, five studies, 1720 participants, low-quality evidence). Overall survival did not differ with PBI/APBI (HR 0.90, 95% CI 0.74 to 1.09, five studies, 6718 participants, high-quality evidence).Late radiation toxicity (subcutaneous fibrosis) appeared worse with PBI/APBI (OR 6.58, 95% CI 3.08 to 14.06, one study, 766 participants, moderate-quality evidence). Acute skin toxicity appeared reduced with PBI/APBI (OR 0.04, 95% CI 0.02 to 0.09, two studies, 608 participants). Telangiectasia (OR 26.56, 95% CI 3.59 to 196.51, 1 study, 766 participants) and radiological fat necrosis (OR 1.58, 95% CI 1.02 to 2.43, three studies, 1319 participants) appeared worse with PBI/APBI. Late skin toxicity (OR 0.21, 95% CI 0.01 to 4.39, two studies, 608 participants) and breast pain (OR 2.17, 95% CI 0.56 to 8.44, one study, 766 participants) appeared not to differ with PBI/APBI.'Elsewhere primaries' (new primaries in the ipsilateral breast) appeared more frequent with PBI/APBI (OR 3.97, 95% CI 1.51 to 10.41, three studies, 3009 participants).We found no clear evidence of a difference for the comparison of PBI/APBI with WBRT for the outcomes of: cause-specific survival (HR 1.08, 95% CI 0.73 to 1.58, five studies, 6718 participants, moderate-quality evidence), distant metastasis-free survival (HR 0.94, 95% CI 0.65 to 1.37, four studies, 3267 participants, moderate-quality evidence), relapse-free survival (HR 1.36, 95% CI 0.88 to 2.09, three studies, 3811 participants), loco-regional recurrence-free survival (HR 1.80, 95% CI 1.00 to 3.25, two studies, 3553 participants) or mastectomy rates (OR 1.20, 95% CI 0.77 to 1.87, three studies, 4817 participants, low-quality evidence). Compliance was met: more than 90% of the women in all studies received the RT they were assigned to receive. We found no data for the outcomes of costs, quality of life or consumer preference. It appeared that local recurrence and 'elsewhere primaries' (new primaries in the ipsilateral breast) are increased with PBI/APBI (the difference was small), but we found no evidence of detriment to other oncological outcomes. It appeared that cosmetic outcomes and some late effects were worse with PBI/APBI but its use was associated with less acute skin toxicity. The limitations of the data currently available mean that we cannot make definitive conclusions about the efficacy and safety or ways to deliver of PBI/APBI. We await completion of ongoing trials.

Correlation of Expression of ER, PR with the onset age, histopathological grading, size of tumor and metastatic behavior of invasive duct cell carcinoma breast

Carcinoma breast is a heterogeneous malignancy with distinct age of onset pattern. Age specific incidence profile of breast carcinoma shows exponential rise until menopause and then slow after menopause. Largely early onset breast carcinoma represents inherited cause and late onset breast cancer following extended exposure to cancer promoters. Expression of ER shows gradual increase beginning in 3rd decade to a plateau by 6th decade. The present study is aimed at the correlation of expression of ER, PR with the onset of age of breast cancer, histopathological grading, size of tor and metastatic behavior. Material and Method: The study was carried out in 80 cases of invasive duct cell carcinoma. Clinicopathological findings, histopathological grading and immunohistochemistry for ER and PR expression were performed. Result and Conclusion: Majority cases (85%) of invasive duct cell carcinoma fall in 31 to 60 years of age group. Most of the patients show more than 2 cms size (90%). Majority of the patients fall in histopathological grade II (67.5%) followed by grade I (27.5%). Lymph node metastasis was seen in 45% cases in all grades. ER and PR expression show declining trend with age of onset of breast carcinoma. It reflects dysregulated ER and PR expression which contribute to the breast carcinoma etiology. Loss of ER expression result in to distinct age of onset pattern, therefore early onset breast cancer may be benefitted by hormone therapy. Metastatic behavior is independent of ER and PR expression.

A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer.

Breast cancer (BC) in young adult patients (YA) has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA). We proposed that differentially expressed miRNAs could regulate genes and proteins underlying aggressive phenotypes of breast tumors in YA patients when compared to those arising in MA patients. Objective: Using integrated expression analyses of miRs, their mRNA and protein targets and stromal gene expression, we aimed to identify differentially expressed profiles between tumors from YA-BC and MA-BC. Methodology and Results: Samples of ER+ invasive ductal breast carcinomas, divided into two groups: YA-BC (35 years or less) or MA-BC (50–65 years) were evaluated. Screening for BRCA1/2 status according to the BOADICEA program indicated low risk of patients being carriers of these mutations. Aggressive characteristics were more evident in YA-BC versus MA-BC. Performing qPCR, we identified eight miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with aggressive clinicopathological characteristics. The expression profiles by microarray identified 602 predicted target genes associated to proliferation, cell cycle and development biological functions. Performing RPPA, 24 target proteins differed between both groups and 21 were interconnected within a network protein-protein interactions associated with proliferation, development and metabolism pathways over represented in YA-BC. Combination of eight mRNA targets or the combination of eight target proteins defined indicators able to classify individual samples into YA-BC or MA-BC groups. Fibroblast-enriched stroma expression profile analysis resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC. Conclusion: We defined a set of differentially expressed miRNAs, their mRNAs and protein targets and stromal genes that distinguish early onset from late onset ER positive breast cancers which may be involved with tumor aggressiveness of YA-BC.

Late recurrent cutaneous breast angiosarcoma in an elderly woman: A case report.

Breast angiosarcomas are malignant tumours of the vascular endothelium that arise frequently following radiation therapy. Their clinical and radiological aspects are highly heterogeneous. The current study reports an unusual case, never previously reported, of a late recurrent breast angiosarcoma occurring in an 83-year old female patient 11 years after a breast-conserving surgery followed by radiation therapy for an invasive ductal carcinoma, and 5 years after her initial angiosarcoma excision. The first physician to examine the patient noted a palpable mass near the scar and, following ultrasonography, described the breast lesion as suggestive of an abscess, despite the previous history of neoplasia. Typically, recurrences of breast angiosarcoma occur within the first postsurgical year. The present patient remains alive at 25 months after her last surgical treatment, and no evidence of any local or distant disease is observable.

Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes.

The onset and progression of breast cancer are linked to genetic and epigenetic changes that alter the normal programming of cells. Epigenetic modifications of DNA and histones contribute to chromatin structure that result in the activation or repression of gene expression. Several epigenetic pathways have been shown to be highly deregulated in cancer cells. Targeting specific histone modifications represents a viable strategy to prevent oncogenic transformation, tumor growth or metastasis. Methylation of histone H3 lysine 4 has been extensively studied and shown to mark genes for expression; however this residue can also be acetylated and the specific function of this alteration is less well known. To define the relative roles of histone H3 methylation (H3K4me3) and acetylation (H3K4ac) in breast cancer, we determined genomic regions enriched for both marks in normal-like (MCF10A), transformed (MCF7) and metastatic (MDA-MB-231) cells using a genome-wide ChIP-Seq approach. Our data revealed a genome-wide gain of H3K4ac associated with both early and late breast cancer cell phenotypes, while gain of H3K4me3 was predominantly associated with late stage cancer cells. Enrichment of H3K4ac was over-represented at promoters of genes associated with cancer-related phenotypic traits, such as estrogen response and epithelial-to-mesenchymal transition pathways. Our findings highlight an important role for H3K4ac in predicting epigenetic changes associated with early stages of transformation. In addition, our data provide a valuable resource for understanding epigenetic signatures that correlate with known breast cancer-associated oncogenic pathways.

Different Factors Influencing Early Stages of Intestine Microbiota Formation

Thanks to modern molecular-genetic microbiota analysis, numerous previously unstudied bacteria were identified. As a result, the conception of human microbiocenosis was significally changed, particularly the conception of intestinal microbiota, which substantially determines human health. The ways the bacteria affect the metagenome, endocrine regulation and function of the nervous system have been described in recent years. At its early stages, the formation of intestinal microbiota depends on such factors as a complicated gestation course, prematurity, surgical delivery, late breast latching, artificial feeding since birth or antibiotic therapy. However, the results of latest studies indicate that the microbial factor affects children long before their birth. Present scientific hypothesis regarding torpid microbial inflammation in uterine cavity as a cause of disturbanses in the gestation course or of preterm labour was also formed in connection with investigating placenta and amniotic fluid microbiocenoses. This survey presents analysis of the latest data concerning the affection of both antenatal and postnatal factors at early stages of intestinal microbiota conditioning in children.

Abstract A182: Targeting the topoisomerase I enzyme in cancer cells with acquired resistance to SN-38

Abstract De novo or acquired resistance to anti-cancer drugs represents a major obstacle to successful treatment of cancer patients. In order to improve future cancer drug development we have established the DEN-50R cell line panel which when fully developed will consist of isogenic pairs of drug sensitive and resistant human cancer cell lines representing the 5 most common cancer types. Based on the DEN-50R we have tested a number of novel anti-cancer drugs in this panel of cell lines. One class of drugs that includes the indenoisoquinolines LMP400 and LMP776, which have topoisomerase 1 inhibitory activity and recently passed phase 1 clinical studies, showed very interesting features in the cell line studies. When tested in SN-38 (the active metabolite of irinotecan) -sensitive and -resistant isogenic colorectal cancer cell lines and breast cancer cell lines, LMP400 showed significant dose related cytotoxicity independent of the state of SN-38-resistance (Table). As these resistant cell lines have significant up-regulation of either the BCRP and/or mdr-1 protein, it can be concluded that the indenoisoquinoline LMP400 can target topoisomerase 1 enzyme without being a substrate for these drug efflux pumps. We are now planning to initiate two clinical phase II studies (Simon's two stage design) with LMP400; one in irinotecan-failed metastatic colorectal cancer patients and one in late stage metastatic breast cancer patients. Patients for these studies will be preselected based on an LMP400-responsiveness profile we generated by gene expression data where associations between gene expression profiles and growth inhibition were compared in a panel of cell lines exposed to LMP400. A second step included filtering the identified gene expression profile against mRNA expression from a collection of 3200 human tumors. Only genes being differentially expressed in the clinical tumor material were retained in the model. Sensitivity to LMP776 and LMP400 of human colorectal and breast cancer cell lines with acquired resistance to SN-38 Cell lineCross-resistantSensitiveHCT116-SN-38*LMP400; LMP776HT29-SN-38LMP776LMP400LoVo-SN-38LMP776LMP400MDA-MB-231- SN-38LMP776LMP400MCF-7- SN-38LMP776; LMP400* HCT-116-SN38 resistant cells have gained a mutation in the binding site of SN38 and LMP400 during acquisition of SN-38 resistance. Citation Format: Jan Stenvang, Niels Frank Jensen, Haatisha Jandu, Steen Knudsen, Keli Agama, Thomas Jensen, Anker Hansen, Peter Buhl Jensen, Yves Pommier, Mark Cushman, Nils Brünner. Targeting the topoisomerase I enzyme in cancer cells with acquired resistance to SN-38. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A182.

Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

ABSTRACT: Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10-14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.

Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer.

Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients.

Identification of Involved Internal Mammary Lymph Node(s) on Pretreatment Breast MRI Correlated With Aggressive Histology and Poorer Outcomes

Conclusion: IORT with 50 kv-X ray using INTRABEAM is well tolerated with little late skin toxicity and very good cosmetic outcome. Although our inclusion criteria were substantially stricter than those of the TARGIT-A trial, around 30% of the patients had to receive external WBRT after IORT. This, however, leads to a significantly higher risk for developing late high grade skin and breast toxicity compared to patients treated with IORT alone. As such, patient’s selection optimization is needed in order to further reduce the risk of late severe toxicity. Author Disclosure: S. Key: None. P. Miglierini: None. S. Vourch: None. O. Miranda: None. J. Mahlaire: None. P. Dupre: None. O. Pradier: None. U. Schick: None.