Data from Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets
Justin M. BalkoJennifer M. GiltnaneKai WangLuis J. SchwarzChristian D. YoungRebecca S. CookPhillip OwensMelinda E. SandersM. Gabriela KubaVioleta SánchezRichard KurupiPreston D. MooreJoseph A. PintoFranco D. DoimiHenry GómezDai HoriuchiAndrei GogaBrian D. LehmannJoshua A. BauerJennifer A. PietenpolJeffrey S. RossGary A. PalmerRoman YelenskyMaureen CroninVincent A. MillerP. J. StephensCarlos L. Arteaga
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<div>Abstract<p>Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC.</p><p><b>Significance:</b> This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted therapies immediately after mastectomy before these metastases become evident. <i>Cancer Discov; 4(2); 232–45. ©2013 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 131</p></div>Keywords:
Profiling (computer programming)
Triple-negative breast cancer
Triple negative
Neoadjuvant Therapy
Purpose: Triple negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2/neu negative) is associated with high risk of recurrence and poor prognosis. We investigated the characteristics and prognosis of triple negative early-stage breast cancer. Methods: We reviewed the records of 821 early-stage breast cancer patients treated at our hospital from 1995 to 2005. We studied the differences between a triple negative group compared with a non-triple negative group. Results: Of 821 early-stage breast cancer patients, 200 (24.4%) were classified as triple negative. Large tumors (>2 cm) in the triple negative group were significantly more than those in the non-triple negative group (P=0.042). Histologic and nuclear grade of the triple negative group were significantly higher than those of the non-triple negative group (P<0.001). The median follow-up time is 50 months (1~135). There have been 50 local recurrences, 98 distant metastases, and 65 deaths. There were high rates of local recurrence in the triple negative group but no difference in 5-year disease free survival rates (P=0.178). The 5-year overall survival rate showed 85% in the triple negative group but 92.8% in the non-triple negative group (P=0.008). The relative risk for overall survival was 1.93 times higher in the triple negative group. Conclusion: Triple negative breast cancer patients in early stages have poor pathologic findings and prognoses. Careful treatment and follow-up are important and further investigation is necessary for triple negative breast cancer. (J Korean Surg Soc 2009;77:37-42)
Triple-negative breast cancer
Triple negative
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Objective To analyze the relationship of clinicopathologic Features and prognosis of triple negative breast cancer. Methods A total of 196 cases with operable breast cancer received in our hospital between January 2002 and February 2007 were analyzed. We used immunohistochemistry to determine Her2, ER, and PR status. The patients were divided into the triple negative breast cancer group (ER negative,PR negative, and Her-2 negative)and the non-triple negative breast cancer group. The clinicopathologic features of the two groups were compared. The 3-year disease-free survival (DFS) was analyzed. Results Of the 196 patients, 13.27% (26/196) had triple negative breast cancer. The percentage of cases with tumor exceeded 5 cm or grade Ⅲ was higher in the triple negative group than in the non-triple negative group (P ＜ 0.05 ). No significant difference was found in other clinicopathologic features between the two groups.The 3-year DFS was 84.62% (22/26) in the triple negative group and 92.94% ( 158/170)in the non-triple negative group. Conclusion Compared with non triple negative breast cancer, triple negative breast cancer has an increased possibility of local recurrence or distant metastasis,leading to a poorer prognosis.
Key words:
Triple negative breast cancer; Pathology; Clinical; Prognosis
Triple-negative breast cancer
Triple negative
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Background:The aim of this study was to compare the clinicopathological characteristics of Triple Negative Breast Carcinomas with Non Triple Negative Breast Carcinomas (NTNBC).Evaluation of expression of Epidermal Growth Factor Receptor (EGFR), CK5/6 in TNBC and their comparison with NTNBC was done.Methods: 25 TNBC and 35 NTNBC were selected.The clinicopathological parameters of these two groups were compared.Each group was further immunostained for basal markers(CK5/6 and EGFR).The expression of markers in these two groups was studied and compared with each other. Results:The mean age of TNBC and NTNBC were 47 and 49 years respectively.The majority (48%) of cases from TNBC as well as NTNBC (45%)were in size range of 2-5 cm(T2 stage).IDC-NOS was predominant histological type seen in 92% of TNBC and 100% NTNBC.TNBCs had a significantly higher tumor grade than NTNBC at presentation.LVI was seen in 40% TNBC cases and 42% NTNBC cases.Majority (52%) of TNBC cases were node negative while majority (37.14%) of NTNBC cases belonged to N1 stage.IIA was the most common stage in 36% TNBC cases .In NTNBC, majority of the cases (34%) belonged to Stage IIIA.Expression of basal markers was significantly associated with triple negative breast cancers. Conclusion:TNBCs had a significantly higher tumor grade than NTNBCs at presentation.Expression of basal markers was significantly associated with TNBCs.Since EGFR was significantly associated with triple negative phenotype, TNBC could potentially benefit from EGFR targeted therapeutic strategies.
Triple-negative breast cancer
Triple negative
Basal (medicine)
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Background: While 18F-Fluoromisonidazole (18F-FMISO) is the most frequently used positron emission tomography (PET) tracer for detecting hypoxia, it has not been studied in a metastatic triple-negative [lack expression of estrogen receptor (ER), progesterone receptor (PR) and human EGF receptor 2 (HER2)] human breast cancer cell xenografts model to our best knowledge. This study focuses on whether 18F-FMISO can detect the hypoxic status of triple-negative human breast cancer (TNBC).Methods: The TNBC cells MDA-MB-231 were successfully inoculated in right forelimb of nude mice. Nude mice models with TNBC xenografts were assessed by micro-PET imaging with 18F-FMISO, and hypoxic status of the TNBC xenografts was determined by immunohistochemistry. We also compared 18F-FDG uptake, the most commonly used PET tracer in clinical practice, with 18F-FMISO uptake to find out its correlation in MDA-MB-231 xenografts.Results: For 18F-FMISO, intestines and liver as well as bladder could be seen in micro-PET images. 18F-FDG showed physiologically high uptake in brain, heart, bladder and intestinal tracts. The quantitative radioactivity of 18F-FMISO and 18F-FDG in tumor were 2.18±0.15 and 3.84±0.54%ID/g, respectively. The quantitative radioactivity of 18F-FMISO and 18F-FDG in muscle were 1.23±0.08 and 0.59±0.09%ID/g, respectively. The tumor-to-muscle ratios were 1.79±0.015 and 7.11±2.84 for 18F-FMISO and 18F-FDG, respectively. Immunofluorescent images from MDA-MB-231 cryosections showed significant hypoxia.Conclusions: 18F-FMISO PET may be used for detection of hypoxia in tumor microenvironment of triple negative human breast cancer.
Triple-negative breast cancer
Triple negative
PET Imaging
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Objective To analyze the clinicopathologic features of 747 cases of triple negative breast cancer.Methods 747 cases of operable breast cancer between March 2003 and Novenmber 2003 were analyzed.Immunohistochemistry was used to determine Her-2,ER and PR status.The patients were divided into the triple negative breast cancer group(ER negative,PR negative and Her-2 negative) and the non-triple negative breast cancer group.The clinicopathologic features of the two groups were compared.Results Of the 747 patients,21.3%(159/747)had triple negative breast cancer and 78.7%(588/747)had non-triple negative breast cancer.The percentage of cases with medullary type or grade Ⅲ was higher in the triple negative groups than in the non-triple negative group.There was significant difference in histological grade between the two groups(P0.05).Recurrence and metastasis of triple negative breast cancer group was higher than that of non-triple negative breast cancer group,but there was no significant difference(P=0.236).Conclusion Compared with non-triple negative breast cancer,triple negative breast cancer has a higher histological grade and a worse prognosis.
Triple-negative breast cancer
Triple negative
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Triple-negative breast cancer
Triple negative
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Breast cancer is a heterogeneous disease that can be classified into diverse subtypes with distinct biology and prognosis. The purpose of this study is to compare clinicopathological features and prognostic of patients with Triple Negative Breast Cancer (TNBC) and non-TNBC. Clinicopathological features and prognosis of 266 patients from north Morocco (56 TNBC and 210 non-TNBC) were evaluated using SPSS 20 software. The incidence of TNBC was 21%. Compared with non-TNBC, TNBC patients tend to be younger at diagnosis and had slightly larger tumors and higher stage. Higher histological grade was strongly associated with TNBC. Lymph nodes and histological type were similar in the two groups. Bone was the most frequently metastatic site in all breast cancers, but TNBC was strongly associated with liver metastases. No significant difference was observed in 5-year Disease-Free Survival (DFS) and 5-year Overall Survival (OS) between TNBC and non-TNBC. In conclusion, TNBC is associated with particular clinicopathological features and poor prognosis compared to non-TNBC.
Triple-negative breast cancer
Triple negative
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Prognostication of breast cancer using clinico-pathologic variables, although useful, remains imperfect. Recent research has focused on finding new markers of prognosis using gene expression profiling. Panels of proteins assessed by immunohistochemistry might also be useful in this regard. This study focused on Bcl-2 protein expression in triple-negative (TNBC) and non- triple-negative breast cancer (non-TNBC) with correlation to clinico-pathologic variables.We analyzed Bcl-2 expression in 77 women with primary breast carcinoma divided into two groups; triple-negative and non- triple-negative according to expression of estrogen (ER), progesterone (PR) and human epidermal growth factor receptors (Her2/neu). Bcl-2 expression was assessed in relation to age, histo-pathological subtype, grade, nodal status and tumor size.Bcl-2 was expressed in 74% of triple-negative breast cancers and 70% of non- triple-negative cancers. In TNBC, expression was significantly correlated with invasive ductal subtype, while in non-TNBC it was significantly correlated with age and negative nodal status. In both groups higher Bcl-2 expression associated with favourable prognostic factors in breast cancer, but no significant statistical correlations were found.Frequency of Bcl-2 expression does not differ between TNBC and non-TNBC, but different prognostic factors correlate with Bcl-2 in the two cases.
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