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Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo -like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors., (©2021 American Association for Cancer Research.)

Background: Carcinoid tumors are rare tumors most commonly found in the gastrointestinal tract. They represent the most common malignancies of the appendix. As a distinct entity from both adenocarcinomas and carcinoids, Goblet cell carcinoid (GCC) was initially described in the literature in 1969. The GCC is almost exclusive to the appendix, but rarely can be found in rectum, ileum and colon. More than 50% of the patients at the time of diagnosis already have advancedstage disease. The most common metastatic sites are the peritoneal surfaces of the pelvis and abdominal cavity, and ovaries in women. Surgery is the main form of treatment in patients with GCC., Case Presentation: A 49-year-old woman was treated at the Institute of Oncology and Radiology of Serbia with histopathological findings of GCC. In a 8-year period the patient was treated with initial appendectomy and three more operations because of locoregional disease progression. The last operation was performed in March 2016 because of endometrial metastases. Since then the patient is on regular follow up without disease progression., Conclusion: GCC is a very rare entity. Multidisciplinary approach is necessary for adequate patient treatment.

Purpose: Breast cancer (BC) is the most common malignancy among women, while isolated operable liver metastases (LMs) from BC are very rare and occur in only 1-5% of the patients. Besides, positive steroid receptor (SR) status for oestrogen and/or progesterone is known as a factor which improves disease free survival (DFS) and overall survival (OS). The primary aim of this study was to examine the impact of SR status on DFS and OS after liver metastasectomy in female patients with primary BC., Methods: We analyzed 32 medical records of female patients diagnosed and treated for primary BC with LMS as the first and only site of disease progression, at the Institute of Oncology and Radiology of Serbia (IORS), during 2006- 2009. All of them underwent primary BC surgery as well as LMs resection., Results: Patients with metachronous BC and LMs and positive SR status in both BC and LM (BC+/LM+) had a median time from BC to LM occurrence (TTLM) of 36 months, compared to BC+/LM- and BC-/LM- subgroups, whose medians for TTLM were 30.5 and 14.5 months, respectively (p<0.01). For all patients, positive SR status showed high correlation with longer DFS and OS after LM resection (medians according survival analysis for DFS/OS in subgroups BC-/LM-, BC+/LM- and BC+-LM+ were 10/19, 25/45, 50/not reached months respectively; p<0.01 for DFS/ OS). Cox regression analysis confirmed that the subgroup of patients with BC-/LM- had 10.8 and 18.8 higher risk of events for DFS (disease relapse or death) and event for OS (death only), respectively, compared to BC+/LM+ subgroup of patients., Conclusion: Positive SR status in BC and LM has a high impact not only on time from BC to LM occurrence, but also on longer DFS and OS after LM resection.

Inflammatory breast cancer (IBC) is a rare and aggressive type of locally advanced breast cancer. The purpose of this study was to determine the value of microscopic tumour histomorphology texture for prognosis of local and systemic recurrence at the time of initial IBC diagnosis. This retrospective study included a group of 52 patients selected on the basis of non-metastatic IBC diagnosis, stage IIIB. Gray-Level-Co-Occurrence-Matrix (GLCM) texture analysis was performed on digital images of primary tumour tissue sections stained with haematoxylin/eosin. Obtained values were categorized by use of both data- and outcome-based methods. All five acquired GLCM texture features significantly associated with metastasis outcome. By accuracies of 69-81% and AUCs of 0.71-0.81, prognostic performance of GLCM parameters exceeded that of standard major IBC clinical prognosticators such as tumour grade and response to induction chemotherapy. Furthermore, a composite score consisting of tumour grade, contrast and correlation as independent features resulted in further enhancement of prognostic performance by accuracy of 89%, discrimination efficiency by AUC of 0.93 and an outstanding hazard ratio of 71.6 (95%CI, 41.7-148.4). Internal validation was successfully performed by bootstrap and split-sample cross-validation, suggesting that the model is generalizable. This study indicates for the first time the potential use of primary breast tumour histology texture as a highly accurate, simple and cost-effective prognostic indicator of metastasis risk in IBC. Clinical relevance of the obtained results rests on the role of prognosis in decisions on induction chemotherapy and the resulting impact on quality of life and survival.

Purpose: Isolated liver metastases (LMs) from breast cancer (BC) occur in only 1-3% of the cases. Resection of isolated LMs improves survival. We examined the prognostic factors for time to LM development, disease free survival (DFS) and overall survival (OS) after BCLM resection., Methods: From 2006 to 2009, 32 patients underwent LM resection. All of them had breast cancer surgery for their primary tumor and developed resectable LMs as the first and only site of disease progression., Results: LMs developed after a median of 25 months. With a median follow up of 37 months (range 7-66) after metastases resection, median DFS and OS (with 95% CI) were 22.5 (12-40) and 37 (≥23) months, respectively. Tumor size ≥3 vs <3 cm and adjuvant chemotherapy vs no adjuvant chemotherapy correlated with shorter time to LM development (p<0.01 for both parameters). These parameters and BC negative estrogen (ER)/ progesterone receptors (PR) (ER?/PR? vs other) were related with shorter DFS. Positive (vs negative) axillary lymph nodes and BC negative ER/ PR (ER?/PR? vs other) status correlated with shorter OS (p<0.01 for both parameters). A period to metastases development ≥ 24 months (vs ≤24) and single (vs multiple) metastases were related with longer DFS and OS (p<0.01 for both conditions)., Conclusion: Despite the relatively small number of patients in this study, we believe that positive ER/PR status for both BC and LMs, negative axillary lymph nodes, time to liver metastases development >24 months and single liver metastases predict longer DFS and OS after LM resection.

Purpose: Human epidermal growth factor receptor 2 overexpression (HER2 3+) is reported in retrospective studies as a factor that contributes to higher incidence of brain metastases (BM) in patients with metastatic breast carcinoma. Although there are some reports suggesting higher incidence of BM in adjuvant trastuzumab trials, the true incidence, as well as the time of occurrence of BM in early-stage high risk breast carcinoma patients, has not been widely prospectively explored. The main objective of this study was to prospectively explore the incidence of BM during and after adjuvant trastuzumab administration in HER2 3+ early-breast carcinoma patients., Methods: Two hundred and fifty-eight patients with early, HER2 3+ breast carcinoma have been included in this analysis. Brain computed tomography (CT) scan was scheduled once during adjuvant trastuzumab therapy and thereafter only if central nervous system (CNS) symptoms occurred., Results: Eighty-five patients (33%) underwent brain CT in the absence of CNS symptoms. The median number of trastuzumab cycles at the time of brain CT was 9 (range 4-18). There were no BM detected by brain CT in these 85 asymptomatic patients. However, during a median follow up of 18 months 5/258 patients (1.93%) developed BM, but only 2 (0.77%) while still receiving adjuvant trastuzumab. The median time from breast cancer diagnosis to BM was 24 months (range 14-43)., Conclusion: BM are a rare event during adjuvant trastuzumab treatment and brain CT screening is not justified in asymptomatic patients with early HER2 3+ breast carcinoma.

Purpose: To evaluate clinical and pathological characteristics of patients with inflammatory breast carcinoma (IBC). Also, to evaluate the importance of achieved clinical and pathological responses to induction chemotherapy (iCT) and their role in the prognosis of IBC., Methods: The medical records of 81 female patients with stage IIIB IBC, diagnosed between January 2008 and December 2010 at the Institute for Oncology and Radiology of Serbia (IORS) were evaluated. Almost all of the patients received anthracycline-based iCT. After 3-4 cycles of iCT, the clinical response (defined as complete response/CR, partial response/PR, stable disease/SD and disease progression/ PD) was assessed. Also, pathological response to iCT (defined as pathological complete response/pCR, near complete response/pNCR, partial response/pPR and no change/ pNC) was estimated in patients who had undergone surgery. All first metastatic sites were recorded., Results: Clinical CR/PR was observed in 61.8% of the patients, while the pathological response (pCR, pNCR/near complete response, and pPR) rate in patients who had undergone surgery was 70%. During follow-up 22 (27.2%) patients developed PD (8 responders and 14 non-responders). Most common metastatic sites were the skeleton in non-responders and the liver in responders. Central nervous system (CNS) metastases developed in 24% of non-responders while no responder developed such metastases. Non-responders had shorter OS compared to responders, but without statistical significance., Conclusion: Although the number of the patients analysed in this study is relatively small, we believe that response to iCT could be used as a prognostic marker, since patients who initially failed to respond to iCT showed a higher risk for PD with development of distant metastases, primarily in bones and CNS, and shorter survival.

Purpose: It has been estimated that approximately 5-10% of the general population have a family history that is indicative of hereditary cancer, predominately breast and colorectal. However, it is not precisely known how many patients have positive family history of cancer. The purpose of this study was to determine how many cancer patients have positive family history of cancer., Methods: Patients were interviewed during the first visit to Daily Chemotherapy Hospital (DCH) of the Institute for Oncology and Radiology of Serbia, Belgrade. Data about patient cancer type and cancer types among family members were recorded in the hospital chart and analyzed., Results: During an 8-month period, 677 newly diagnosed cancer patients with 9 cancer types were referred to DCH for chemotherapy. Positive family history (at least one first degree relative) for any cancer type was recorded in 163 (24.1%) patients and in 47 (6.9%) patients for the same cancer type. The highest percentage of the positive family history for the same type of cancer showed patients with breast cancer (9.9%), followed by colorectal (7.2%) and brain tumors (6.25%)., Conclusion: The overall incidence of positive family cancer history was 31.0% and was higher than expected. Cancer can be more disturbing for persons who already had experience with this disease in a close family member. Those patients need special attention with more intensive and carefully preplanned psychological support.