The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2022 edition.

The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.

A Case of Pneumothorax Required Surgical Treatment as a Complication of Paclitaxel with Bevacizumab Treatment.

A 63-year-old woman had a history of neoadjuvant chemotherapy, mastectomy, and adjuvant endocrine therapy for 5 years before being diagnosed with recurrent lesions involving the right anterior chest wall, multiple lymph nodes, and pulmonary metastases. The patient was subsequently initiated on a paclitaxel and bevacizumab regimen. During this treatment, the patient complained of palpitations and malaise. Chest radiography revealed a left pneumothorax. Despite attempts at conservative treatment, the pneumothorax did not improve and a thoracoscopic approach was required. One of the metastatic tumors in the left lower lobe appeared to rupture, and this area was estimated to be the cause of air leak. The tumor was covered with a tissue seal sheet, and the patient's condition improved with no recurrence of pneumothorax. This case highlights the importance of early conversion to surgical treatment when conservative treatment for pneumothorax is unresponsive due to the potential side effects of bevacizumab. The findings of this case report may be of interest to oncologists, pulmonologists, and other healthcare professionals involved in the care of patients with breast cancer and pulmonary metastases who are undergoing bevacizumab chemotherapy.

A case of breast angiosarcoma clearly delineated by contrast-enhanced ultrasonography.

We present a case of breast angiosarcoma. Although B-mode ultrasonography did not indicate a tumor, contrast-enhanced ultrasonography (CEUS) was successfully delineated it. CEUS helped identify the tumor and its extent.

Effectiveness of Intraoperative Indocyanine Green Fluorescence-Navigated Surgery for Superior Mesenteric Vein Thrombosis that Developed During Treatment for Intravascular Lymphoma: A Case Report.

BACKGROUND Superior mesenteric vein thrombosis (SMVT) is a relatively rare form of acute abdominal disease; less than 0.1% of laparotomy surgeries are performed for SMVT. In the presence of severe intestinal ischemia or necrosis caused by SMVT, immediate surgical intervention is required. Macroscopic diagnosis of intestinal viability is sometimes difficult; its over-resection may carry the risk of short bowel syndrome. A near-infrared fluorescence imaging system with indocyanine green (ICG) has recently been developed for intraoperative, real-time evaluation of intestinal perfusion. This is the first report on the use of ICG fluorescence imaging during surgery for intestinal ischemia caused by venous thrombosis. CASE REPORT A 70-year-old man presented with a general feeling of weariness. On examination, he was diagnosed with intravascular large B cell lymphoma. R-CHOP therapy was initiated. On day 3 of initial R-CHOP therapy, the patient experienced sudden severe abdominal pain while in the hospital. Contrast-enhanced computed tomography revealed SMVT and loss of contrast effect in the small intestine. We diagnosed small bowel necrosis caused by SMVT, and exploratory laparotomy was performed, which revealed a continuous ischemia of 150 cm. Intraoperative ICG fluorescence imaging was utilized, and the color boundary was consistent with the ischemic area detected by visualization. The necrotic small intestine was excised and anastomosed. The patient was transferred to the hematology department on postoperative day 10 with no severe complications such as anastomotic leakage or re-thrombosis, and re-embolization was not observed 6 months later. CONCLUSIONS Venous thrombosis should be listed as a differential diagnosis when acute abdominal disease presents during chemotherapy for malignant lymphoma. ICG fluorescence imaging may be useful in the evaluation of intestinal blood flow for venous thrombosis.

A Benign Appendiceal-Colonic Fistula, Diagnosed and Managed Laparoscopically: A Case Report.

BACKGROUND Treatment methods for appendiceal-colonic fistulas differ greatly depending on whether lesions are benign or malignant. If the tumor is malignant, appendectomy with lymph node resection (ileocecal resection or right hemicolectomy) should be performed. There is no consensus on the method of surgery for organs infiltrated by appendiceal cancer. Furthermore, there are no reported laparoscopic cases that could be prevented from over-surgery by laparoscopy examination or rapid intraoperative pathological examination. CASE REPORT A 76-year-old man presented with positive fecal occult blood. Lower endoscopy revealed a 10-mm tumor in the rectosigmoid colon accompanied by white moss. A biopsy showed inflammatory granulation and no malignancy. Fluorodeoxyglucose-positron emission tomography showed highly increased accumulation at the tip of the appendix, and the standardized uptake value max was 7.3. We suspected a benign lesion rather than appendiceal cancer with infiltration into the rectosigmoid colon; therefore, we performed laparoscopic appendectomy and wedge-shaped resection of the rectum of the sigmoid colon. An intraoperative rapid pathological examination showed no appearance of malignancy; therefore, additional resection was omitted, and an ileostomy was created in the right lower quadrant. A permanent pathological examination showed complicated appendicitis, with no appearance of malignancy. The ileostomy was closed on postoperative day 25, and the patient was discharged on postoperative day 32. CONCLUSIONS In cases where there is difficulty in identifying whether the appendiceal-colonic fistula lesion is benign or malignant, laparoscopy and intraoperative rapid pathological examination may be useful in avoiding excessive treatment.

Difficult Diagnosis and Surgical Procedure for Scirrhous Gastric Cancer Complicated by Upside-Down Stomach: A Case Report.

BACKGROUND The upper stomach can be involved in 1 type of esophageal hiatal hernia in which the degree of stomach insertion is considerable and accompanied by a twist in the shaft of the stomach. The diagnostic accuracy of upper endoscopy or barium meal examination decreases in patients with upside-down stomach, thus making diagnosis of stomach lesions very difficult. No previous reports have described scirrhous gastric cancer in a patient with upside-down stomach. CASE REPORT An 85-year-old woman presented with loss of appetite and vomiting after eating oxalic acid-containing food 2 months previously. Computed tomography revealed an upside-down stomach, and upper endoscopy revealed loss of distensibility and superficial gastritis of the entire stomach. Upside-down stomach was diagnosed; accordingly, laparoscopic hernia repair was planned. Laparoscopic exploration revealed retention of serous fluid (i.e., ascites) containing gastric carcinoma cells (pathologically identified intraoperatively) and induration of the entire stomach. After converting to laparotomy, induration of the stomach was confirmed, continuing to the adjacent 4 cm of the distal esophagus. The patient was diagnosed with scirrhous gastric cancer. Esophageal hiatus hernia repair was performed due to the patient's age and the risks associated with esophagojejunostomy. Preoperative complaints of symptoms disappeared. The patient was transferred to the medical hospital on postoperative day 52 with no complications. CONCLUSIONS Specific symptoms of gastric cancer can mimic those of esophageal hiatal hernia in patients with hernia. In cases of upside-down stomach with loss of distensibility and increased wall thickness, physicians should be aware of the possibility of scirrhous gastric cancer.

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.

Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer.

BACKGROUND: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. METHODS: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. RESULTS: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. CONCLUSION: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

Differences in expression of the cancer stem cell marker aldehyde dehydrogenase 1 among estrogen receptor-positive/human epidermal growth factor receptor type 2-negative breast cancer cases with early, late, and no recurrence.

BACKGROUND: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown. METHODS: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group. RESULTS: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059). CONCLUSIONS: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

Differences in morphological features and minimum apparent diffusion coefficient values among breast cancer subtypes using 3-tesla MRI.

PURPOSE: To compare the morphology and minimum apparent diffusion coefficient (ADC) values among breast cancer subtypes. METHODS: Ninety-three patients, who underwent breast MRI and collectively had 98 pathologically proven invasive carcinomas, were enrolled. Morphology was evaluated according to BIRADS-MRI. Minimum ADC was measured. Morphology and minimum ADC were compared among subtypes. Multivariate logistic regression analyses were used to identify the characteristics associated with different subtypes. RESULTS: Oval/round shape was significantly associated with triple-negative (TN) cancer (TN vs. non-TN: 90.9% vs. 45.2%; p=0.0123). Rim enhancement was significantly less frequent in Luminal A (Luminal A vs. non-Luminal A: 34.2% vs. 76.1%; p=0.0003). The minimum ADC of Luminal A was significantly higher than that of Luminal B (HER2-negative) (834 vs. 748×10(-6)mm(2)/s; p<0.025). The minimum ADC of the TN-special type was significantly higher than that of TN-ductal (997 vs. 702×10(-6)mm(2)/s; p<0.025). On the multivariate analysis comparing the characteristics associated with Luminal A vs. Luminal B (HER2-negative), the internal enhancement characteristics of the mass and minimum ADC were significant factors. CONCLUSION: Morphology and minimum ADC would be useful in distinguishing breast cancer subtypes.

Fulvestrant 500 mg in postmenopausal patients with metastatic breast cancer: the initial clinical experience.

BACKGROUND: Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies. METHODS: A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated. RESULTS: Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms. CONCLUSIONS: Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

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 10 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.

Strong cytoplasmic expression of NF-κB/p65 correlates with a good prognosis in patients with triple-negative breast cancer.

PURPOSE: Recent studies have indicated that constitutive NF-κB activity could be involved in the proliferation of triple-negative breast cancer. METHODS: The NF-κB/p65 expression and the effects of a NF-κB inhibitor, (-)-DHMEQ, were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed for their expression of NF-κB/p65, Bcl2 and Ki67 by immunohistochemistry in pre- and post-treatment specimens. The factors predicting the response to neoadjuvant chemotherapy and the prognosis were analyzed. RESULTS: NF-κB/p65 was predominantly expressed in the cytoplasm of MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-κB/p65 expression was detected in the nuclei of a few cells in seven tumors before neoadjuvant chemotherapy, while the expression of NF-κB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. The expression levels of NF-κB/p65 were not associated with the response to neoadjuvant chemotherapy, although the cytoplasmic NF-κB/p65 staining intensity was significantly decreased in the post-treatment tumor samples compared with the pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-κB/p65 expression before neoadjuvant chemotherapy are currently disease free. CONCLUSION: Our results suggest that strong cytoplasmic NF-κB/p65 expression could be a prognostic marker for patients with triple-negative breast cancer.

[Adjuvant hormonal treatment for estrogen receptor-positive breast cancer-a questionnaire survey conducted by Japanese breast cancer society-authorized facilities in Hokkaido].

According to the Japanese Breast Cancer Society national breast cancer registration, 71.8%of breast cancer cases reported in 2004 and 79.8% of cases reported in 2010 were estrogen receptor(ER)positive. The frequency of ER-positive breast cancer is increasing annually in Japan. Many clinical trials have proven that adjuvant hormonal treatment affects both progression- free survival and overall survival in ER-positive breast cancer cases. However, some clinical questions remain, including those regarding the definition of preoperative hormonal treatment, appropriate dosage period, and therapeutic drug choice. In January 2013, we conducted a questionnaire survey of 53 medical doctors engaged in breast cancer treatment at 15 Japanese Breast Cancer Society-authorized facilities in Hokkaido. This survey included 6 clinical questions about preoperative hormonal treatment, 5 clinical questions about postoperative hormonal treatment for premenopausal breast cancer, and 4 clinical questions about postoperative hormonal treatment for postmenopausal breast cancer. We obtained replies from 35 medical doctors at 27 facilities. The response rate was 66%. We accumulated and analyzed these data. The discussion of questionnaire results in the medical administration field facilitates the sharing of information regarding differences in the approaches of different facilities to breast cancer patients. As a result, standardization of the breast cancer medical treatment system in this area has been accomplished.

Earlier and better high-resolution single breast imaging during bilateral breast dynamic scans at 3-T MRI: comparison with post dynamic high-resolution imaging.

BACKGROUND: Breast MRI protocols have been improved by using a combination of dynamic scans for bilateral breasts and high-resolution imaging for a single breast which can be obtained during dynamic scans by recent technological advances. The purpose of this study was to compare high-resolution imaging during dynamic scans (HR-intra) with high-resolution imaging obtained post dynamic scans (HR-post). METHODS: Fifty-five women with pathologically proven breast cancer who underwent breast dynamic scans at 3-T MRI from February to September 2009 were enrolled in this study. Tumoral contrasts to the background breast tissue were compared by three radiologists independently in a blinded fashion. Results of visual assessment were categorized into three groups as follows: HR-intra being better (IB), equal (E), and HR-post being better (PB). The contrast to noise ratio (CNR) of the tumor and the signal to noise ratio of the normal breast gland (SNR) were compared between HR-intra and HR-post. RESULTS: Two patients were excluded because of poor MR imaging quality. Three radiologists separately categorized 64.2, 79.2, and 77.4 % of lesions as IB. The CNR of the tumor of HR-intra (mean ± SD = 6.9 ± 4.0) was significantly higher than that of HR-post (6.0 ± 3.7, p < 0.0001). The SNR of the normal breast gland of HR-intra (9.5 ± 1.7) was significantly lower than that of HR-post (10.0 ± 1.9, p < 0.0001). CONCLUSION: HR-intra during dynamic MRI provided earlier and better tumor to normal breast gland contrast than HR-post.

Prognostic significance of pathologic complete response and Ki67 expression after neoadjuvant chemotherapy in breast cancer.

BACKGROUND: Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. METHODS: Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. RESULTS: Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) <14 %) and 22 as luminal B (Ki67 LI ≥ 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. CONCLUSIONS: It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

Prognostic significance of pre-treatment neutrophil: lymphocyte ratio in Japanese patients with breast cancer.

BACKGROUND: The neutrophil:lymphocyte ratio (NLR) has been reported to reflect systemic inflammation and to have independent prognostic value for patients with various cancers. In this study, we analyzed the association between NLR and clinicopathological factors and verified the significance of NLR as a prognostic factor for Japanese patients with breast cancer. PATIENTS AND METHODS: A total of 167 Japanese female patients with stage I-III breast cancer were retrospectively recruited into this study. Associations with clinicopathological factors and NLR were assessed, and disease-free survival and breast cancer-specific survival were estimated. RESULTS: In multivariate analysis, lymph node metastases and NLR were significantly associated with disease-free survival and breast cancer-specific survival. NLR was significantly higher in patients with lower body-mass index. CONCLUSION: Preoperative NLR may be an independent prognostic factor for survival in Japanese patients with breast cancer. Reduction of body mass index has been implicated in NLR elevation, particularly in postmenopausal women.

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer.

Estrogen receptor (ER) is essential for estrogen-dependent growth, and its level of expression is considered a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer. On the other hand, the clinical role of progesterone receptor (PgR) in ER-positive breast cancer remains controversial, although testing of PgR by immunohistochemistry (IHC) has become routine. Recent studies indicated that plasma estradiol levels were related to the expression levels of estrogen-responsive genes in ER-positive breast cancer tissues in both pre- and postmenopausal women. In this study, we analyzed the expression levels of estrogen-responsive genes (PgR and TFF1), a progesterone-responsive gene (RANKL), ER-related genes (FOXA1 and GATA3), HER2, Ki67 and p53 in ER-positive, HER2-negative breast cancer tissues by IHC. Correlations between the expression levels of these molecular markers and clinicopathological factors, including prognosis, were compared between pre- and postmenopausal women. Serum levels of estrone, estradiol, progesterone, and testosterone were also measured. Expression levels of PgR, TFF1, RANKL, and GATA3 were significantly higher in premenopausal women than in postmenopausal women. Serum estradiol levels were positively correlated with Ki67 labeling index (LI) in premenopausal women, but not in postmenopausal women. High expression of FOXA1 and GATA3 was significantly associated with improved disease-free survival in premenopausal women, but not in postmenopausal women, whereas high expression of PgR and low expression of p53 were significantly correlated with the improved disease-free survival in postmenopausal women, but not in premenopausal women. Moreover, the best cutoff points of Ki67 LI for disease-free survival were 30 % for premenopausal women and 14 % for postmenopausal women. Expression levels of ER, TFF1, and RANKL were not associated with the disease-free survival in either pre- or postmenopausal women. Our results suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status.

p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors.

Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)-positive breast cancer in postmenopausal women. However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. Whole genome analysis identified that a TP53 gene mutation exists in ER-positive breast cancers, although the frequency of TP53 gene mutation in luminal tumors is lower compared with basal-like or human epidermal growth factor receptor type 2 (HER2)-positive breast cancers. We examined expression of p53, as well as ER, progesterone receptor, HER2 and Ki-67 using immunohistochemistry in postmenopausal ER-positive breast cancer patients who were treated with aromatase inhibitors as adjuvant endocrine therapy. There were 53 (21%) tumors that contained 10% or more p53-positive cells. High p53 expression was positively correlated with tumor grade, HER2 score and Ki-67 expression. Significant association was observed between disease-free survival and high p53 expression in multivariate analysis (P < 0.0001). Compared with women without recurrence, women with early recurrence had significantly higher p53 expression (P < 0.0001), as did women with late recurrence (P = 0.037). The present study demonstrates that p53 accumulation is a strong predictor of both early and late recurrence in ER-positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy. TP53 gene alteration might be a key biological characteristic of ER-positive breast cancer.