The fact that reproductive factors have significant influence on the risk of breast cancer is well known. Early age of first full-term birth is highly protective against late-onset breast cancers, but each pregnancy, including the first one, increases the risk of early-onset breast cancer. Estradiol and progesterone induce receptor activator of NF-kappa B ligand (RANKL) in estrogen receptor (ER)- and progesterone receptor (PgR)-positive luminal cells. RANKL then acts in a paracrine fashion on the membranous RANK of ER/PgR-negative epithelial stem cells of the breast. This reaction cascade is triggered by chorionic gonadotropin during the first trimester of pregnancy and results in the morphological and functional development of breast tissue. On the other hand, the administration of non-steroidal anti-inflammatory drugs in the early steps of weaning protects against tumor growth through reduction of the acute inflammatory reaction of post lactation remodeling of breast tissue. This is experimental evidence that may explain the short-term tumor-promoting effect of pregnancy. The protective effect of prolonged breast feeding may also be explained, at least in a part, by a reduced inflammatory reaction due to gradual weaning. Delay of first birth together with low parity and short duration of breast feeding are increasing social trends in developed countries. Therefore, breast cancer risk as a result of reproductive factors will not decrease in these countries in the foreseeable future. In this review, the significance of reproductive history with regard to the risk of breast cancers will be discussed, focusing on the age of first full-term birth and post lactation involution of the breast.
Abstract Background: Tumor infiltrating lymphocytes (TILs) are immune cells that have migrated to the tumor tissue and the local microenvironment. Recently, evidence has emerged the presence of TILs affects the clinical outcomes of breast cancer patients. We hypothesize that immune cell infiltration profile of the primary tumors affects the timing and type of breast cancer recurrence. We evaluated the relationship between the timing and type of cancer recurrence and clinical factors, gene expression profiles, and immune cell infiltration profile utilizing two published large cohorts, TCGA and METABRIC. Methods: 308 primary BCs in TCGA were analyzed and categorized as: recurrence ≤2 years (Early), between 2-5 years (Mid), recurrence >5 years (Late), and no recurrence >5 years (Survivors). 1,727 primary BCs in METABRIC were analyzed and categorized similarly: Early, Mid, Late, and Survivors, and further subdivided according to the type of recurrence (distant or local recurrence) Results: We found that Early tumors demonstrated more aggressive clinical characteristics such as larger tumor, more lymph node metastases, higher pathological grades, higher Stages, and negative estrogen and progesterone receptors, compared with Survivors. On the other hand, no clinical characteristics of Late tumors were significantly different from Survivors, which implicate that clinical characteristics cannot distinguish late recurrence from Survivors. Utilizing pre-ranked gene set enrichment analyses, we showed that primary tumors of Survivors were associated with anti-cancer signaling such as interferon-α/-γ response and TNF-α signaling, compared with all recurrence groups. Furthermore, we found that host defense immunity (leukocyte fraction, lymphocyte infiltration, and macrophage fractions) was decreased in Late tumors compared with Survivors. Utilizing the CIBERSORT algorithm, we showed anti-cancer lymphocytes, memory CD4+ T cells and γδT cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Late tumors compared with Survivors. In distant recurrence analysis, we found that anti-cancer M1 macrophages were higher in Early and Mid compared to Survivors. Pro-cancerous regulatory T cells were significantly higher in Mid compared to Survivors. Interestingly, in local recurrence analysis, there was no statistically significant difference between timing of cancer recurrence and Survivors. Cytolytic activity score that assesses immune cell cytolytic activity was significantly lower in Late compared with Survivors, which suggest it to be a prognostic factor for Late recurrence. Conclusions: We demonstrated that host defense immunity, pro-cancerous immune cells, and immune cell cytolytic activity in primary breast tumors affect the timing and type of breast cancer recurrence. Citation Format: Takashi Takeshita, Li Yan, Kazuaki Takabe, Hiroko Yamashita. Pro-cancerous immune profile in primary breast tumors affects the timing and type of breast cancer recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1607.
Purpose: To identify the prognostic value of biological markers at initial operation for metastatic breast cancer, we measured the presence of estrogen receptor-alpha (ERα), progesterone receptor (PgR) and human epidermal growth factor receptor type 2 (HER2),and histological grade (HG) of tumors. Methods: One-hundred and seventy-six patients, aged 29 to 90 (median: 51 years), with recurrent breast cancer underwent primary operation at our department during the period from 1983 to 2000. Clinicopathological factors examined at primary operation included menopausal symptoms, presence of axillary lymph node metastasis, tumor size, HG, HER2, ERα and PgR.Factors examined at recurrence included site of primary recurrence, disease-free interval(DFI) and tumor markers, such as CEA and CA15-3. The relationship between these factors and prognosis following recurrence was assessed. Results: Menopausal status, axillary lymph node metastasis and tumor size at primary operation had no significant effect on prognosis. Patients with low HG, positive expession of ERα and PgR, and low HER2 expression had a good prognosis, similar to those with long DFI and distant metastases. After distant metastases, HER2 was found to be the most important prognostic factor following recurrence and in predicting response to drug therapy.Conclusion: Biological factors indicating tumor malignancy at the time of the first operation are also important prognostic factors following tumor recurrence.
Key words:
Breast cancer; Biological marker; Prognosis
CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.
BackgroundThe clinical value of estrogen receptor (ER) β and its variants has been investigated. However, reported results have frequently been discordant.
A 65-year-old male visited our hospital because of fever and difficulty in walking. He was suffering from left-sided hypochondrial pain for a month. Laboratory tests performed on admission revealed a white blood cell count of 1700/μl and C-reactive protein level of 9.51mg/dl, which were suggestive of severe inflammation. Contrast-enhanced computed tomography revealed a subphrenic abscess around the spleen, which we considered to be caused by gastric penetration into the gastrosplenic ligament. Upper esophagogastroduodenoscopy revealed a gastric ulcer together with a fistula that connected to the left subphrenic abscess. We thus performed endoscopic transgastric drainage through the fistula. Antibiotics and a proton pump inhibitor were administered, and drainage was continued. The patient's clinical and inflammatory symptoms subsequently improved. We thus consider that endoscopic transgastric drainage is an appropriate treatment option for subphrenic abscesses.
Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment. In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601). Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14 % and 52 % of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25 % vs 67 % for clinical response, p = 0.011, N = 51; 0 % vs 41 % for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not. Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE. UMIN C000000345 (2006/03/06)
