Associations in tumor infiltrating lymphocytes between clinicopathological factors and clinical outcomes in estrogen receptor-positive/human epidermal growth factor receptor type 2 negative breast cancer

The value of assessing tumor infiltrating lymphocytes (TILs) in estrogen receptor (ER) positive/human epidermal growth factor receptor type 2 (HER2) negative breast cancer has yet to be determined. In the present study, a total of 184 cases with early distant recurrence detected within 5 years following the primary operation, 134 with late distant recurrence diagnosed following 5 years or longer and 321 controls without recurrence for >10 years following starting the initial treatment for ER-positive/HER2 negative breast cancer, registered in 9 institutions, were analyzed. The distributions of TILs and their clinical relevance were investigated. TIL distributions did not differ significantly among the early, late and no recurrence groups, employing a 30% cut-off point as a dichotomous variable. In those who had received adjuvant chemotherapy as well as endocrine therapy, a trend toward higher TIL proportions was detected when the early recurrence group was compared with the no recurrence group employing the 30% cut-off point (P=0.064). The TIL distributions were significantly associated with nodal metastasis (P=0.004), ER status (P=0.045), progesterone receptor (PgR) status (P=0.002), tumor grade (P=0.021), and the Ki67 labeling index (LI) (P=0.002) in the no recurrence group and with the Ki67 LI in the recurrence groups (P=0.002 in early recurrence group, P=0.023 in late recurrence group). High TIL distributions also predicted shorter survival time following the detection of recurrence (P=0.026). However, these prognostic interactions were not significant in multivariate analysis (P=0.200). The present retrospective study demonstrated no significant interaction between TIL proportions and the timing of recurrence. However, higher TIL proportions were observed in breast cancer patients with aggressive biological phenotypes, which tended to be more responsive to chemotherapy. The clinical relevance of stromal TILs for identifying patients who would likely benefit from additional therapies merits further investigation in a larger patient population

Clinicopathological factors predicting early and late distant recurrence in estrogen receptor-positive, HER2-negative breast cancer

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than ten years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age

Carcinoma-Associated Fibroblasts Are a Promising Therapeutic Target

Human carcinomas frequently exhibit significant stromal reactions such as the so-called “desmoplastic stroma” or “reactive stroma”, which is characterised by the existence of large numbers of stromal cells and extracellular matrix proteins. Carcinoma-associated fibroblasts (CAFs), which are rich in activated fibroblast populations exemplified by myofibroblasts, are among the predominant cell types present within the tumour-associated stroma. Increased numbers of stromal myofibroblasts are often associated with high-grade malignancies with poor prognoses in humans. CAF myofibroblasts possess abilities to promote primary tumour development, growth and progression by stimulating the processes of neoangiogenesis as well as tumour cell proliferation, survival, migration and invasion. Moreover, it has been demonstrated that CAFs serve as a niche supporting the metastatic colonisation of disseminated carcinoma cells in distant organs. Their contribution to primary and secondary malignancies makes these fibroblasts a potential therapeutic target and they also appear to be relevant to the development of drug resistance and tumour recurrence. This review summarises our current knowledge of tumour-promoting CAFs and discusses the therapeutic feasibility of targeting these cells as well as disrupting heterotypic interactions with other cell types in tumours that may improve the efficacy of current anti-tumour therapies

Metastatic colonic and gastric polyps from breast cancer resembling hyperplastic polyps

Abstract Breast cancer metastasis to the gastrointestinal tract is relatively rare and is generally found when patients complain of symptoms such as gastrointestinal obstruction. Herein, we report a case with metastatic colonic and gastric lesions from breast cancer, with the formation of mucosal polyps which resembled typical hyperplastic polyps. A 47-year-old woman underwent curable surgery for breast cancer and received standard systemic treatments. Her primary tumor was composed of a mix of invasive lobular and ductal carcinomas. During adjuvant endocrine therapy, she developed multiple colonic metastases, identified by colonoscopy performed as part of a general health check-up. She had no symptoms. Small elevated sessile polyps in the transverse colon and rectum showed histological features of signet-ring cell type adenocarcinoma, similar to the invasive lobular component of the primary breast cancer. During treatments for recurrent disease, she also developed multiple gastric metastases, with the same endoscopic and pathological features as the colonic lesions. Her treatment regimen was switched to oral chemotherapy, and she has since maintained stable disease for nearly 3 years. Multiple bone metastases eventually developed, and she was again switched to another systemic treatment but, to date, has remained free of symptoms. We emphasize that the endoscopic findings of the metastatic lesions in the colon and stomach in this case highly resembled hyperplastic polyps. Since biopsy is not always performed for hyperplastic polyps in the gastrointestinal tract, we believe that this case report may encourage endoscopists to offer biopsies to the patient who has a history of breast cancer

Effects of Carbon-ion Beam and Lapatinib Alone, or in Combination in HER2 Positive Breast Cancer Stem-like Cells

In the present study, we attempt to investigate effects of carbon-ion beam alone, or in combination with lapatinib, a dual tyrosine kinase inhibitor, on targeting HER2-positive breast cancer stem-like cells (CSCs). Spheroid formation assays confirmed that ESA+/CD24- cells have CSC properties compared to ESA-/CD24+ cells in HER2-positive breast cancer cells. Carbon-ion beam combined with lapatinib significantly suppressed spheroid formation compared to X-rays combined with lapatinib or carbon ion beam alone. Carbon-ion beam combined with lapatinib greatly enhanced apoptosis and also induced autophagy-related expression of Beclin1 and LC3 compared to carbon-ion beam alone, X-rays alone, or X-rays combined with lapatinib. In addition, a large-sized gammaH2AX foci in CSCs were induced by carbon ion beam combined with lapatinib treatment in CSCs compared to cells receiving X-rays or carbon-ion beam alone. In conclusion, combination of carbon-ion beam irradiation and lapatinib has a high potential to kill HER2-positive breast CSCs, causing severe irreparable DNA damage, enhanced autophagy, and apoptosis.第78回日本癌学会学術総

Biological Effectiveness of Carbon-Ion Radiation on Various Human Breast Cancer Cell Lines

Introduction: Carbon-ion radiotherapy (C-ion RT) is known as a highly effective local treatment and its relative biological effectiveness (RBE) has been valuated for various types of malignant tumors. There are only a few studies on C-ion radio sensitivity in breast cancer, and there has been no evaluation by subtypes. To estimate the impact of C-ion RT for breast cancer, RBE of C-ion beams of various types of human breast cancer cell lines was evaluated by comparison with X-rays.Methods: Six human breast cancer cell lines with different subtypes, Luminal-human epidermal growth factor receptor 2 (HER2)-negative (MCF-7), Luminal-HER2-positive (BT-474), Her2-enriched (SK-BR-3), Basal-like (MDAMB- 468, HCC1937) and ductal carcinoma in situ (MCF10DCIS.com) were used. Radio sensitivities were assessed with survival curves created from colony-forming assay (CFA) and high-density surviving assay (HDS). An X-ray generator was used with 200 kV, 20 mA. The Heavy Ion Medical Accelerator in Chiba (HIMAC) was used for C-ion irradiation, with 290 MeV/u, mono-peak, linear energy transfer (LET) of 80 KeV/μm Results: CFA was not suitable for BT474, SK-BR-3, MDA-MB-468, and HCC1937 because of their low plating efficiency. The differences between the D10 values on HDS were large with X-ray, and the survival curve shouldersfor MCF7, MDA-MB-468, and MCF10DCIS.com were wide. On the other hand, the differences between the D10 values were small with C-ion beams, and the survival curves were linear without shoulders for all cell lines except a small shoulder with MCF10DCIS.com. The RBE value of C-ion beams was 2.3 to 3.6, median 2.9 in all cell lines by CFA and HDS.Conclusion: RBE around 3 by C-ion beams was seen in many types of ductal cancer. The small survival curve shoulder on MCF10DCIS.com suggested that non invasive ductal carcinoma is relatively more resistant than invasive cancer