A prospective analysis of two studies that used the 5-mm interval slices and 5-mm margin-free method for ipsilateral breast tumor recurrence after breast-conserving surgery without radiotherapy.

BACKGROUND: Breast-conserving surgery with radiotherapy is one of standard treatments for early breast cancer. However, it is regarded as an option to treat elderly patients with small hormone receptor-positive breast cancer with breast-conserving surgery and hormone therapy without radiotherapy. We conducted two sequential prospective studies to examine the feasibility of breast-conserving surgery without radiotherapy since 2002 and present the results. PATIENTS AND METHODS: Primary female breast cancer patients who fulfilled the strict eligibility criteria were prospectively enrolled in two sequential studies named WORTH 1 and 2. The surgical materials were sliced in 5-mm intervals and all slices were examined microscopically. Postoperative radiotherapy was not allowed, but tamoxifen or anastrozole was administered for 5 years. Ipsilateral breast tumor recurrence (IBTR)-free survival was the primary outcome. RESULTS: The data of the two studies were combined (N = 321). The median follow-up period for IBTR was 94 months (4-192 months). Only three patients were treated with adjuvant chemotherapy. The 5- and 10-year IBTR-free rates were 97.0% and 90.5%, respectively. The age at operation and PR status affected IBTR rates independently. When we calculated IBTR-free rates of patients who were 65 years of age or older at the time of surgery and had PR-positive tumors, the 5- and 10-year IBTR rates were both 98.4%. CONCLUSIONS:  Our "5-mm-thick slice and 5-mm free-margin" method may be effective to select patients who can be treated by breast-conserving surgery and hormone therapy without radiotherapy.

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors.

BACKGROUND/AIM: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib. PATIENTS AND METHODS: A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP. RESULTS: The cut-off values of ALC, NLR, PLR, and CRP for PFS were determined from the receiver operating characteristic curve using the Youden index for area under the curve and set at 1,212/µl, 1.964, 170 and 0.220 mg/dl, respectively. In the abemaciclib-treated group, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151) and multivariate analysis revealed that ALC was an independent prognostic factor for PFS (p=0.0085). In the palbociclib-treated group, there was no significant relationship between any peripheral blood biomarkers and PFS. In both treatment groups, ALC-high patients showed significantly better OS than ALC-low patients (p=0.0169 and 0.0290, respectively). Multivariate analysis revealed ALC was an independent prognostic factor for OS in both abemaciclib- and palbociclib-treated groups (p=0.0112 and 0.0202, respectively). CONCLUSION: ALC is an independent prognostic factor for estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer patients treated with the CDK4/6 inhibitors abemaciclib and palbociclib.

[A Case of Recurrent Breast Cancer Detected with Diplopia Caused by Sphenoid Bone Metastasis].

We report a case of sphenoid bone metastasis from breast cancer detected with diplopia, as first site of recurrence. Forty- year-old woman with left breast cancer underwent breast-conserving surgery and sentinel lymph node biopsy. The diagnosis was papillotubular carcinoma, pT1pN0, ER(+), PgR(+), HER2(-). Tweleb years later, the examination of diplopia revealed left abducens nerve palsy for sphenoid bone metastasis from breast cancer. Radiation therapy(a total dose of 36 Gy with VMAT)was administrated as topical treatment, but diplopia did not improve. After that, systemic treatment was performed, and 2 years and 6 months have passed since the recurrence was found, she is still alive. We need to be careful of orbital metastasis as a symptom of metastasis from breast cancer.

[Five Patients with Gastric Metastasis from Breast Cancer-A Case Report].

Five patients with gastric metastasis from breast cancer were treated in our hospital. About the histopathological types of primary breast cancer, 4 patients were invasive ductal carcinomas and 1 was invasive lobular carcinoma. One patient was found by gastrointestinal fiberscopy for a detailed examination of her high CEA, 2 for stenosis, 1 for bleeding and 1 for epigastralgia. After the diagnosis of gastric metastasis, 2 patients were treated with chemotherapies, 1 with hormone therapy and 2 with palliative treatments. One of them was treated with gastroduodenal stenting for pyloric stenosis, but she was died by bleeding from gastric lesion. Based on the results, constriction and bleeding with gastric metastasis is considered to be severe condition in the treatment of metastatic breast cancer.

[Occult Breast Cancer Presenting with a Swelling Axillary Lymph Node-A Case Report].

The patient was a 56-year-old woman. who was aware of a tumor in her left axilla and consulted a nearby doctor. She was referred to our hospital for a detailed examination. No abnormalities were found in the breast by visual inspection, mammography, or breast ultrasound examination. One 29 mm swollen lymph node was found in the axilla. Fine needle aspiration cytology revealed malignant lymphoma; thus, so axillary lymph node excision biopsy was performed, and a diagnosis of axillary lymph node metastasis of breast cancer was made. However, no abnormalities were found. Based on the information presented above, the patient was diagnosed with occult breast cancer cT0N1M0, Stage ⅡA, and breast preservation plus axillary lymph node dissection up to level Ⅱ was performed. No metastases were found in the dissected lymph nodes. The treatment policy for occult breast cancer has not yet been established. We report this case with a review of the literature.

[A Case of Late Recurrence of Breast Cancer with Chest Wall Recurrence 43 Years after Surgery].

The patient is an 85-year-old female who had previously undergone a mastectomy for right breast cancer at the age of 42 years. In September 2020, she visited our hospital with a chief complaint of a chest wall tumor. Physical examination revealed a 3×3 cm ulcerative lesion on the right side of the center chest wall. She underwent a skin biopsy of the tumor under local anesthesia and was diagnosed with a recurrence of right breast cancer(ER positive, PR positive, HER2 negative). PET-CT revealed localized skin thickening on the right side of the sternum and FDG accumulation in the same area, with no other findings suggestive of distant metastasis. Treatment was started with anastrozole and is still ongoing. In this article, we report a very rare case of recurrence 43 years after surgery.

[A Case of Stage â £ Breast Cancer Treated with Mastectomy after Spontaneous Removal of a Cosmetic Breast Implant].

A 51-year-oldwoman came to our hospital complaining of a skin ulcer in the left breast. She hadpreviously undergone cosmetic breast augmentation by placement of a bag prosthesis under each mammary gland. She was diagnosed with Stage Ⅳ(T4bN1M1)breast cancer with multiple bone metastases. Following the diagnosis, 3 regimens of hormonal therapy were sequentially administered. The treatment was then switched to chemotherapy following confirmation of tumor progression in the left breast tumor. After 3 cycles of paclitaxel andbevacizumab as the second-line of chemotherapy, the size of the left breast tumor was remarkably reduced. Mastectomy with axillary lymph node sampling and removal of the implant were scheduled for local control. However, due to gradual exposure of the implant under the left breast, it was spontaneously removedfrom the original position when the patient was waiting for the surgery. Therefore, only mastectomy with axillary lymph node sampling was performed, followed by 45 Gy/25 times of postmastectomy and locoregional lymph node irradiation. Six months after the surgery, the patient is alive with no signs of local recurrence.

[Long-Term Survival in a Case of Breast Cancer with Brain Metastases and No Other Distant Metastases Treated by Surgical Removal and Gamma Knife Radiosurgery].

A 44-year-oldwoman was diagnosedwith right breast cancer andund erwent mastectomy andaxillary lymph node dissection in February 2006. She was pathologically diagnosed with invasive ductal carcinoma without lymph node metastasis. Immunohistochemical examination showedthat the tumor was estrogen receptor positive, progesterone receptor negative, andhada HER2 status score of 0. She received 4 cycles of AC, followedby leuprorelin andtamoxifen. Several metastases were identified in the right supraclavicular lymph nodes in August 2008 during the endocrine therapy. Then, she received S-1 as the first-line chemotherapy. Although metastases showed complete response, she developed an eye disorder caused by S-1 and thus the treatment agent was changedto leuprorelin andanastrozole. She complainedof headache andright homonymous hemianopsia in November 2013. MRI showeda 42mm diameter tumor in the left occipital lobe, suspectedto be brain metastasis from breast cancer. Craniotomy was performedto remove the brain tumor, which was pathologically diagnosedas metastasis from breast cancer. In the brain tumor, the estrogen receptor status hadchangedto negative, but the HER2 status remained unchanged, showing a score of 0. Vinorelbine was administered after the brain surgery. Unfortunately, brain metastasis was foundin the dura mater near the surgical cavity, andgamma knife radiosurgery was performedin January 2014. Thereafter, brain metastases were repeatedly found, and gamma knife radiosurgery was again performed in January 2015, September 2016, and February 2017. In addition, a large tumor appearedin the left occipital lobe andwas surgically removed in June 2016. No other distant metastases were found, andvinorelbine was continueduntil February 2018. Because the patient developed dyslexia caused by gamma knife-induced radiation necrosis, bevacizumab was administered between November 2018 and April 2019. MRI showed that the edema due to radiation necrosis reduced and dyslexia symptoms improved. As of now, she has survivedfor 5 years and 6 months after the diagnosis of brain metastases.

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel.

BACKGROUND: Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). METHODS: Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/µL, 2, and 250, respectively. RESULTS: PFS was significantly improved in patients with ALC ≥1500/µL compared to those with ALC 1000-, <1500/µL or ALC < 1000/µL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/µL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735-0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/µL was observed irrespective of visceral metastasis or chemotherapy regimen. CONCLUSIONS: Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. TRIAL REGISTRATION: UMIN000012375 , registration date: 21NOV2013, and UMIN000006838 , registration date: 6DEC2011.

Significant Association Between Low Baseline Neutrophil-to-Lymphocyte Ratio and Improved Progression-free Survival of Patients With Locally Advanced or Metastatic Breast Cancer Treated With Eribulin But Not With Nab-Paclitaxel.

INTRODUCTION: Although eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC. PATIENTS AND METHODS: A total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3. RESULTS: The progression-free survival (PFS) of patients with an NLR < 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of ≥ 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR < 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens. CONCLUSION: A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin.

Independent prognostic impact of preoperative serum carcinoembryonic antigen and cancer antigen 15-3 levels for early breast cancer subtypes.

BACKGROUND: Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. METHODS: A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. RESULTS: The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3-high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges.

[A Case of Stage IV Metaplastic Breast Cancer in Which Primary Tumor Was Removed after Treatment with Anti-HER2 Systemic Therapy].

The patient was a 58-year-oldpostmenopausal woman. Vacuum assistedbiopsy of the left breast tumor revealedinvasive ductal carcinoma. Immunohistochemical examination was negative for estrogen receptor(ER), negative for progesterone receptor(PgR), andshowedan HER2 score of 3+. FDG-PET/CT revealedmultiple metastases to the left supracravicular and axillary lymph nodes and lungs. She was diagnosed with HER2-positive T3N3M1, Stage IV breast cancer. A 2-year regimen of chemotherapy with trastuzumab andvinorelbine achieveda complete response with regardto the metastatic sites; however, the size of the primary tumor increasedd espite the chemotherapy, andsurgical resection of the left breast with axillary lymph node dissection was performed for local control. Pathological examination of the surgical specimen revealed metaplastic carcinoma with sarcoma component surrounded by non-invasive ductal carcinoma. No component of invasive ductal carcinoma was found. Immunohistochemically, metaplastic carcinoma was negative for ER, negative for PgR, andrevealedan HER2 score of 0. There was discordance of HER2 status between pre- andpost -chemotherapy. The patient receivedno further chemotherapy following surgery andhas been without disease progression for 6 years. We suggest there is heterogeneity, that is, the metastatic sites andthe partial primary tumor were HER2-positive invasive ductal carcinoma and the remainder of the primary tumor was triple negative metaplastic carcinoma. As a result, the patient was able to discontinue chemotherapy with higher quality of life.

Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases.

BACKGROUND: Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared. METHODS: For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment. RESULTS: Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173-1630 mU/dL) decreased to 137 mU/dL (91-795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment. CONCLUSIONS: Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.

Prognostic significance of preoperative 18F-FDG PET/CT for breast cancer subtypes.

Adjuvant treatments for operable breast cancers are determined according to subtypes defined based on estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. The ER+/HER2- subtype can be divided into luminal A and luminal B usually by Ki67 expression levels. Although tumor size, lymph node metastasis and tumor grade have been widely accepted in daily clinical practice, the identification of further prognostic indicators especially in the ER+/HER2- subtype is warranted. A total of 387 operated breast cancers for which maximum standardized uptake value (SUVmax) on the 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) were available at baseline were retrospectively analyzed. The optimal cutoff value of SUVmax for relapse-free survival (RFS) was determined to be 3.585 by means of the receiver operating characteristics curve with an area under the curve of 0.6795 (95% CI: 0.5972 to 0.7618, p = 0.0006, sensitivity: 78.8%, specificity: 57.1%). The RFS of patients with SUVmax-high (n = 178) was significantly (p = 0.0003) worse compared with those with SUVmax-low (n = 209). This significant association was prominently recognized in the ER+/HER2- subtype. By multivariable analysis, SUVmax (hazard ratio: 3.83, 95% confidence interval: 1.28-11.51, p = 0.017), tumor size (4.22, 1.39-12.82, p = 0.011) and lymph node metastasis (4.44, 1.81-10.87, p = 0.0012) were significant and independent prognostic factors for RFS. The ER+/HER2- subtype demonstrated consistently worse RFS in the SUVmax-high patients both in the luminal A (p = 0.037) and luminal B (p = 0.047) subtypes. Combination of Ki67 and SUVmax appears to be useful for selecting patients who have inferior prognosis and need further adjuvant treatment of the ER+/HER2- subtype.

[A Case of Local Recurrence after Conserving Therapy for Occult Breast Cancer with Immediate Breast Reconstruction].

We report the case of a 70-year-oldwoman with local recurrence of occult breast cancer after conserving therapy. Breast cancer metastasis to an axillary lymph node was suspected when she was 62-years-old. Even with mammography, ultrasound sonography, positron emission tomography/computedtomography, andmagnetic resonance imaging, the primary disease lesion could not be identified. She underwent axillary dissection, and received 5 years of endocrine therapy. Eight years after surgery, a new ipsilateral breast tumor was detectedusing ultrasoundsonography andvacuum assistedbiopsy, confirmedas invasive carcinoma. This time the patient had no distant metastases; therefore, she was diagnosed with local recurrence, and mastectomy with immediate breast reconstruction was performed. Breast conserving surgery aims to reduce the psychological burden on the patient but must be closely followed-up in case of local recurrence. Any incidences of local recurrence can also be treatedusing breast reconstruction surgery.

[A Case of Pure Squamous Cell Carcinoma of the Breast in an Elderly Woman Diagnosed by Cytology].

A n 85-year-old woman presented with a mass in the left breast. A3 7mm lobulated mass including enhancement of a cyst of 37mm was detected by sonography. An axillary lymph node had increased to 16 mm. Atypical cells dyed by light green and orange G were identified by fine needle aspiration and cytology. She was diagnosed with left breast cancer(cT2N1M0, Stage II B), histologically suspected to be squamous cell carcinoma. She underwent a left-breast-conserving surgery and axillary lymph node dissection. On pathology, a cyst of 34×30mm was noted. The tumor grew from inside the cyst to the surround- ing tissue and it had a trend for keratinocytes. Lymph node metastases affected 1/11. By immunostaining, the tumor was found to be ER(+), PgR(-), HER2(-), CK5/6(+), p40(+), mammaglobin(-), and GCDFP15(-). There was no component of ductal carcinoma. She received radiotherapy to the left breast and tamoxifen as an adjuvant therapy. Squamous cell carcinoma of the breast is rare. We encountered a case of pure squamous cell carcinoma of the breast in an elderly woman. We report this case with a discussion of the relevant literature.

Prognostic significance of geminin expression levels in Ki67-high subset of estrogen receptor-positive and HER2-negative breast cancers.

BACKGROUND: Indication for chemotherapy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers is determined on the basis of Ki67 expression level. However, since Ki67-high cancers are not necessarily sensitive to chemotherapy, identification of such patients who do not need chemotherapy is an important issue. PATIENTS AND METHODS: We used immunohistochemical staining to examine the expression levels of ER, progesterone receptor (PgR), Ki67, and geminin, a marker of S to G2/M phases, in 80 ER-positive/HER2-negative breast cancers. The labeling indices of Ki67 and geminin were determined and cutoff values were set at 15 and 6 %, respectively. RESULTS: Ki67 and geminin expression levels were significantly associated with nuclear grade. In the Ki67-low subset, 26 out of 28 (92.9 %) cancers were geminin low and in the Ki67-high subset, 31 out of 52 (59.6 %) were geminin high. Distant disease-free survival (DDFS) of the geminin-high subset was significantly poorer than that of the geminin-low subset (P = 0.009). In the Ki67-low subset, only one patient showed recurrence. Metastasis was detected in eight out of 31 (25.8 %) patients in the geminin-high group of the Ki67-high subset, but no recurrence was observed in the geminin-low group of the Ki67-high subset. CONCLUSION: Geminin-high breast cancers are significantly associated with worse prognosis. Since poorer prognosis was recognized only in the geminin-high group in Ki67-high cancers, we speculate that geminin may be useful for identifying patients in the Ki67-high subset who can avoid unnecessary chemotherapy.

Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers.

BACKGROUND: Residual cancer burden or Ki67 expression levels in residual tumors reportedly provided significant prognostic information for a non-pathological complete response subset after neoadjuvant chemotherapy (NAC). However, the significance of Ki67 reduction for clinical response during chemotherapy in each subtype or menopausal status is yet to be determined. METHODS: A total of 183 breast cancers surgically removed after chemotherapy were recruited for this study. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki67 were determined immunohistochemically for semiquantitative measurement and these biomarkers were compared in pre- and post-NAC samples from pathological non-responders (n = 125). Responses to chemotherapy were evaluated both clinically and pathologically. RESULTS: Ki67 expression levels after NAC (median 5 %, range 0-70 %) were significantly reduced compared with before NAC (25, 1-80 %, P < 0.0001), but only in patients who attained clinical response. This significant suppression of Ki67 in clinical responders was consistently observed in breast cancers from the ER-positive subset, but not the ER-negative subset in the total test set (n = 120). These observations were also made in the validation set (n = 63). Among premenopausal, but not postmenopausal patients, a significant decrease in PgR expression levels was detected in breast cancers of patients who attained clinical response (pre-NAC 50, 0-100 %, post-NAC 5, 0-20 %; P = 0.0003). CONCLUSION: The impact of Ki67 suppression on clinical response seems to be restricted to ER-positive breast cancers. Since PgR expression levels of premenopausal ER-positive cancers were significantly reduced in clinical responders, inhibition of estrogen signaling due to chemotherapy-induced amenorrhea may be involved in this association.

High levels at baseline of serum pyridinoline crosslinked carboxyterminal telopeptide of type I collagen are associated with worse prognosis for breast cancer patients.

It is speculated that adjuvant use of bisphosphonate reduces recurrence in breast cancer patients through suppression of bone resorption. To determine the prognostic impact of bone resorption markers, we investigated serum levels of the pyridinoline crosslinked carboxyterminal telopeptide of type I collagen (1CTP) and N-terminal crosslinking telopeptides of type I collagen (NTX). 1CTP and NTX were measured at baseline (before operation or neoadjuvant therapies) and afterward in 469 patients operated on breast cancer. The optimal cutoff value of 1CTP for relapse-free survival (RFS) was set at 3.6 ng/ml with an area under the receiver operating characteristics curve of 0.641 [95% confidence interval (CI) = 0.560-0.721; p = 0.0011]. However, we were unable to determine a significant cutoff value for NTX. RFS was significantly worse for 1CTP-high patients with than for those with low levels of 1CTP (p = 0.0002). Multivariate analysis with tumor size, lymph node metastasis, and nuclear grade showed that 1CTP was a significant independent prognostic factor (hazard ratio = 2.04, 95% CI = 1.13-3.68; p = 0.018). Worse prognosis for the subset with high 1CTP levels applied only to postmenopausal patients (p = 0.0002). RFS of 130 patients whose 1CTP changed from low at baseline to high at 6 months postoperatively showed RFS almost as poor as that for patients with high 1CTP throughout. These findings suggest that 1CTP may be useful not only for identifying patients with unfavorable prognosis, but also for selecting patients who may benefit from administration of bone-modifying agents in an adjuvant setting.

[Efficacy and Safety of the Selective Estrogen Receptor Down-Regulator "Fulvestrant" in Japanese Patients with Advanced, Recurrent, ER-Positive Postmenopausal Breast Cancer].

Fulvestrant is a novel endocrine therapy for breast cancer that exerts both anti-estrogenic and down-regulatory effects by binding to and degrading estrogen receptors (ERs). In the present study, the safety and effectiveness of 500 mg fulvestrant in 69 patients with advanced, recurrent, ER-positive postmenopausal breast cancer were investigated retrospectively. Outcomes were favorable for fulvestrant. The objective response rate was 24.6%, the clinical benefit rate was 49.2%, the median progression-free survival (PFS) was 203 days, and the median overall survival was 794 days. PFS tended to be longer in patients without a history of previous treatment or visceral metastasis. The main adverse events included injection site reactions and hot flushes; however, the majority of these events were mild to moderate. The present findings suggest that, among Japanese patients with advanced, recurrent, ER-positive postmenopausal breast cancer, 500 mg fulvestrant is effective and safe in those without metastasis and a minimal history of receipt of previous treatment regimens.