[Disseminated Bone Marrow Carcinomatosis from Breast Cancer Improved by Capecitabine-A Clinical Case Report].

A 63-year-old woman who underwent breast cancer surgery 9 years ago visited our hospital with palpitations. Laboratory examination revealed severe anemia and thrombocytopenia. Positron emission tomography-computed tomography(PET- CT)demonstrated fluorodeoxyglucose(FDG)uptake at several vertebrae, including the pelvis, ribs, and sternum. Accordingly, bone marrow aspiration cytology was performed and atypical large cells were confirmed. After the diagnosis of disseminated carcinomatosis caused by multiple bone metastases from breast cancer, capecitabine monotherapy was started. At 6 months after the diagnosis, the anemia and thrombocytopenia improved to within normal limits. FDG uptake of multiple bones also improved according to PET-CT. Capecitabine administration was stopped at 30 months due to cancer progression. Chemotherapy with docetaxel, epirubicin, cyclophosphamide(EC), and vinorelbine was alternately continued after capecitabine; nevertheless, the cancer progressed gradually. She died at 62 months without either anemia or thrombocytopenia.

Clinicopathological features of breast cancer patients with internal mammary and/or supraclavicular lymph node recurrence without distant metastasis.

BACKGROUND: Internal mammary and/or supraclavicular (IM-SC) lymph node (LN) recurrence without distant metastasis (DM) in patients with breast cancer is rare, and there have been few reports on its clinical outcomes. METHODS: We enrolled 4237 patients with clinical stage I-IIIC breast cancer treated between January 2007 and December 2012. Clinicopathological features of patients with IM-SC LN recurrence and patients with DM were retrospectively reviewed. RESULTS: With a median follow-up time 78 (range, 13-125) months after the primary operation, 14 (0.3%) had IM-SC LN recurrence without DM and 274 (6.5%) had DM at the first recurrence among 4237 patients. No statistical differences were found in the baseline characteristics of the primary tumor between the two groups. The 5-year overall survival (OS) rate after recurrence in patients with IM-SC LN recurrence was 51% compared with 27% in patients with DM (P = 0.040). In patients with IM-SC LN recurrence, clinically positive axillary LN at diagnosis and pathologically positive axillary LN at primary surgery were poor prognostic factors for distant disease-free survival (DDFS) (P = 0.004 and 0.007, respectively). Clinical and pathological axillary nodal status at primary surgery was associated with OS (P = 0.011 and 0.001, respectively). CONCLUSIONS: Patients with IM-SC LN recurrence without DM who had no clinical and pathological axillary LNs involved at primary surgery had a favorable prognosis. A larger validation study is required.

Prognostic impact and possible pathogenesis of lymph node metastasis in ductal carcinoma in situ of the breast.

PURPOSE: Ductal carcinoma in situ (DCIS)-preinvasive breast cancer-with lymph node metastasis can clinically be treated as different stages: occult invasive cancer with true metastasis (T1N1) or pure DCIS with iatrogenic dissemination (TisN0). In this retrospective cohort study, we aimed to elucidate the prognostic impact and possible pathogenesis of nodal metastasis in DCIS to improve clinical management. METHODS: Subjects were comprised of 427 patients with routine postoperative diagnosis of DCIS who underwent sentinel node (SN) biopsy using molecular whole-lymph-node analysis. Clinicopathological characteristics and prognosis were compared between SN-positive and -negative patients. Primary tumour tissues of SN-positive patients were exhaustively step-sectioned to detect occult invasions, and predictive factors for occult invasion were investigated. Median follow-up time was 73.6 months. RESULTS: Of the 427 patients, 19 (4.4%) were SN-positive and 408 (95.6%) were SN-negative. More SN-positive patients received adjuvant systemic therapy than SN-negative patients (84.2% vs. 5.4%). Seven-year distant disease-free survivals were favourable for both cohorts (SN-positive, 100%; SN-negative, 99.7%). By examining 1421 slides, occult invasion was identified in 9 (47.4%) of the 19 SN-positive patients. Tumour burdens in SN and incidence of non-SN metastasis were similar between patients with and without occult invasion, and no predictive factor for occult invasion was found. CONCLUSIONS: Node-positive DCIS has favourable prognosis with adjuvant systemic therapy. Half of the cases may be occult invasive cancer with true metastasis. In practical settings, clinicians may have to treat these tumours as node-positive small invasive cancers because it is difficult to predict the pathogenesis without exhaustive primary tumour sectioning.

Characteristics of adverse events of endocrine therapies among older patients with breast cancer.

PURPOSE: To clarify the profile of adverse events from endocrine therapies in older patients. METHODS: We surveyed 15 subjective symptoms including hot flashes, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, lethargy, forgetfulness, depressive state, irritated state, genital bleeding, leukorrhea increase, vaginal dryness, bone fracture, and weight gain by a questionnaire among 2044 patients over 55 years old (total number of answered sheets, 8875) and compared the results according to age (56-69 years old vs. ≥ 70 years old) and type of therapy (aromatase inhibitors (AIs) vs. selective estrogen receptor modulators (SERMs)). Among patients 56-69 years old, 6093 and 314 responses were from patients treated with AIs (1477 patients) and SERMs (123 patients), respectively, and 2292 and 176 responses were from those ≥ 70 years old treated with AIs (581 patients) and SERMs (51 patients), respectively. RESULTS: In patients ≥ 70 years old, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, and lethargy were significantly more frequent/severe with AIs than with SERMs. In those aged 56-69, knuckle stiffness and vaginal dryness were significantly more frequent with AIs than with SERMs, but the opposite occurred for hot flashes, leukorrhea increase, genital bleeding, and weight gain. CONCLUSIONS: Among patients ≥ 70 years old, many symptoms were significantly more frequent/severe with AIs than with SERMs, compared with those aged 56-69, which suggests a difference in the profile of adverse events according to the type of endocrine therapy and the patient's age. It is important to consider the benefits and risks of each treatment to optimize endocrine therapy for older patients.

Pattern of Tumor Shrinkage during Neoadjuvant Chemotherapy Is Associated with Prognosis in Low-Grade Luminal Early Breast Cancer.

Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P < .001 and P < .001, respectively). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .001) and OS (P = .009) rate. In the validation set, the median follow-up period was 56.9 months. Recurrence was observed in 20 patients (16.5%) and eight (6.6%) deaths were related to breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P ≤ .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion The CS pattern as revealed at MR imaging during NAC had the only significant independent association with prognosis in patients with low-grade luminal breast cancer. © RSNA, 2017.

Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations.

In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

A new molecular-based lymph node staging classification determines the prognosis of breast cancer patients.

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can detect metastasis in a whole lymph node based on cytokeratin 19 mRNA copy number. This cohort study aimed to establish an OSNA-based nodal staging (pN(mol)) classification for breast cancer. METHODS: The cohort consisted of 1039 breast cancer patients who underwent sentinel node (SN) biopsy using the OSNA assay. Cutoff value of the SN tumour burden stratifying distant disease-free survival (DDFS) was determined, and predictive factors for DDFS and breast cancer-specific survival (BCSS) were investigated. pN(mol) classification of the SN status was defined as: pN0(mol)(sn), SN negative; pN1mi(mol)(sn), SN positive and tumour burden

Lesion Size on Ultrasonography Predicts Potential Invasion in Ductal Carcinoma in situ Preoperatively Diagnosed by Breast Needle Biopsy.

Ductal carcinoma in situ (DCIS) of the breast has no potential to metastasize, but over 20% of cases preoperatively diagnosed as DCIS are upstaged on final pathology. The rates of upstaging and the predictors for invasion on final pathology were evaluated. For 240 primary breast cancers, radiological findings on mammography, ultrasonography, and magnetic resonance imaging were investigated along with pathological and clinical information. Univariate and multivariate analyses were performed to identify predictors of potential invasion. Of the 240 breast cancers, 68 (28.3%) showed invasion on final pathology, and 5 (2.5%) had sentinel node metastasis. The multivariate analysis identified five independent predictors: non-mass lesions >2.4 cm on ultrasonography (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.02-7.95, p=0.047), comedo-type histology (OR 6.89, 95% CI 1.89-25.08, p<0.01), solid-type histology (OR 7.97, 95% CI 2.08-30.49, p<0.01), palpable mass (OR 2.63, 95% CI 1.05-6.64, p=0.04), and bloody nipple discharge (OR 4.61, 95% CI 1.20-17.66, p=0.02). These five predictors were associated with invasion on final pathology and may help select candidates for sentinel node biopsy.

[Secondary Dementia Due to Leptomeningeal Metastasis of Breast Cancer Improved by Whole Brain Radiation].

A 62-year-old woman received chemotherapy for breast cancer with bone metastasis and malignant pleural and pericardial effusion. She was examined by imaging for progressive cognitive impairment and headache. Enhanced MRI findings showed multiple solid tumors on brain surface, and brain perfusion scintigraphy showed blood flow decrease in both parietal lobes. She was diagnosed with secondary dementia due to leptomeningeal metastases of breast cancer, and whole brain external irradiation was performed(30 Gy/15 Fr). After treatment, multiple tumors were decreased in size and her cognitive impair- ment was improved.

Eribulin-induced liver dysfunction as a prognostic indicator of survival of metastatic breast cancer patients: a retrospective study.

BACKGROUND: Eribulin is a non-taxane, microtubule dynamics inhibitor that increases survival of patients with metastatic breast cancer. Although eribulin is well tolerated in patients with heavily pretreated disease, eribulin-induced liver dysfunction (EILD) can occur, resulting in treatment modification and subsequent poor disease control. We aimed to clarify the effect of EILD on patient survival. METHODS: The medical records of 157 metastatic breast cancer patients treated with eribulin between July 2011 and November 2013 at Cancer Institute Hospital were retrospectively analyzed. EILD was defined as 1) an increase in alanine aminotransferase or aspartate aminotransferase levels >3 times the upper limit of normal, and/or 2) initiation of a liver-supporting oral drug therapy such as ursodeoxycholic acid or glycyron. Fatty liver was defined as a decrease in the liver-to-spleen attenuation ratio to <0.9 on a computed tomography scan. RESULTS: EILD occurred in 42 patients, including one patient for whom eribulin treatment was discontinued due to severe EILD. The patients who developed EILD had significantly higher body mass indices (BMIs) than those who did not develop EILD (24.5 vs. 21.5, respectively; P < 0.0001), with no difference in the dose intensity of eribulin between the two groups (P = 0.76). Interestingly, the patients with EILD exhibited significantly longer progression-free survival (PFS) and overall survival (OS) than those without EILD (P = 0.010 and P = 0.032, respectively). Similarly, among 80 patients without liver metastasis, 19 with EILD exhibited significantly longer PFS and OS than the others (P = 0.0012 and P = 0.044, respectively), and EILD was an independent prognostic factor of PFS (P = 0.0079) in multivariate analysis. During eribulin treatment, 18 patients developed fatty liver, 11 of whom developed EILD, with a median BMI of 26.7. CONCLUSIONS: Although EILD and fatty liver occurred at a relatively high frequency in our study, most of the patients did not experience severe adverse effects. Surprisingly, the development of EILD was positively associated with patient survival, especially in patients without liver metastases. EILD may be a clinically useful predictive biomarker of survival, but further studies are needed to confirm these findings in another cohort of patients.

Prognostic significance of histological therapeutic effect in preoperative chemotherapy for breast cancer.

To establish a prognostic prediction system, we examined the relationships between prognosis and histological therapeutic effect or ypTNM classification in 258 breast cancer patients who received neoadjuvant chemotherapy. The case distribution according to therapeutic effect was nine patients (3.5%) with Grade 0, 169 (65.5%) with Grade 1, 58 (22.5%) with Grade 2, and 22 (8.5%) with Grade 3. The 5-year overall survival (OS) rate by therapeutic effect was 56% in Grade 0, 81% in Grade 1, 87% in Grade 2, and 96% in Grade 3. The higher the therapeutic effect the better the prognosis, with a significant difference among the groups (P = 0.008). The case distribution according to ypTNM classification was 20 patients (7.8%) with Stage 0, 83 (32.2%) with Stage I, 77 (29.8%) with Stage II, and 78 (30.2%) with Stage III. The 5-year OS rate by ypTNM classification was 95% in Stage 0, 94% in Stage I, 89% in Stage II, and 59% in Stage III. While prognosis was mostly comparable in Stages 0 and I, in the other stages it became significantly worse as residual cancer increased (P < 0.001). The prognosis of breast cancer patients with neoadjuvant chemotherapy can be predicted by histological therapeutic effect and staging classification of residual cancer.

Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic breast cancer.

PURPOSE: Although improved long-term prognoses for patients with metastatic breast cancer (MBC) have been demonstrated, few reports address overall survival (OS) with sufficient follow-up. Furthermore, the relevance of immunohistological subtypes to OS in MBC has not been clarified. METHODS: We evaluated, retrospectively, the OS of patients who had been initiated on systemic therapy for MBC between 2000 and 2008. RESULTS: The subjects of this study were 527 patients with MBC treated by systemic therapy. The median survival time (MST) was 55.5 months. The MST for each immunohistological subtype was as follows: luminal, 59.9 months; luminal-HER2, not reached; triple-negative, 18.6 months; and HER2-enriched, 49.9 months. According to multivariate analysis, metastasis-free intervals of ≥2 years and treatment with anthracycline for MBC were predictive of better OS. The predictors of shorter OS included disease progression after first-line treatment for MBC, triple-negative, and all histological factors, except papillotubular carcinoma, with liver metastasis, and having three or more initial metastatic sites. CONCLUSIONS: The prognosis of the patients with MBC in this series was better than that reported before 2000, which is probably attributable to the use of novel, improved pharmacological agents. For example, luminal-HER2 tumors can be treated using both aromatase inhibitors and trastuzumab. Because of the lower toxicities, it is now possible to administer these agents for longer periods, resulting in better prognoses.

Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy.

BACKGROUND: Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. In breast cancer, however, Bcl-2 expression has been reported to be a favorable prognostic factor. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. We constructed a large systematic study to determine whether Bcl-2 has an independent role in breast cancer. METHODS: Bcl-2 expression was immunohistochemically evaluated and compared with other clinicopathological factors, including clinical outcome, in 1081 breast cancer cases with long follow-up, separately analyzing 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy. The χ (2)-test for independence using a contingency table, the Kaplan-Meier method with the log-rank test, and a Cox proportional hazards model were used for the comparison of clinicopathological factors, assessment of clinical outcome, and multivariate analyses, respectively. RESULTS: In both patient groups, Bcl-2 expression strongly correlated with positive ER/PR status, low grade, negative human epidermal growth factor receptor 2 (HER2) status, and small tumor size, as previously reported. Bcl-2 expression did not independently predict clinical outcome in patients with ER-positive and/or PR-positive tumors or in those who received tamoxifen treatment; however, it was an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative (ER-negative/PR-negative/HER2-negative) tumors who received no adjuvant therapy. The latter was even more evident in postmenopausal women: those with hormone receptor-negative or triple-negative tumors lacking Bcl-2 expression showed a favorable outcome. CONCLUSION: Bcl-2 expression is an independent poor prognostic factor in patients with hormone receptor-negative or triple-negative breast cancers, especially in the absence of adjuvant therapy, suggesting that the anti-apoptotic effect of Bcl-2 is clearly exhibited under such conditions. The prognostic value of Bcl-2 was more evident in postmenopausal women. The present findings also highlight Bcl-2 as a potential therapeutic target in breast cancers lacking conventional therapeutic targets such as triple-negative tumors. The favorable prognosis previously associated with Bcl-2-positive breast cancer probably reflects the indirect effect of frequently coexpressed hormone receptors and adjuvant endocrine therapy.

Four types of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery: classification of IBTR based on precise pathological examination.

We classified ipsilateral breast tumor recurrences (IBTRs) based on strict pathological rules. Ninety-six women who were surgically treated for IBTR were included. IBTRs were classified according to their origins and were distinguished based on strict pathological rules: relationship between the IBTR and the primary lumpectomy scar, surgical margin status of the primary cancer, and the presence of in situ lesions of IBTR. The prognosis of these subgroups were compared to that of new primary tumors (NP) in the narrow sense (NPn) that occurred far from the scar. Distant-disease free survival of IBTR that occurred close to the scar with in situ lesions and a negative surgical margin of the primary cancer (NP occurred close to the scar, NPcs) was similar to that of NPn. In contrast, IBTR that occurred close to the scar without in situ lesions (true recurrence (TR) that arose from residual invasive carcinoma foci, TRinv) had significantly poorer prognosis than NPn. IBTR that occurred close to the scar with in situ lesions and a positive surgical margin of the primary cancer (TR arising from a residual in situ lesion, TRis) had more late recurrences than NPcs. Precise pathological examinations indicated four distinct IBTR subtypes with different characteristics.

Extensive analysis of signaling pathway molecules in breast cancer: association with clinicopathological characteristics.

BACKGROUND: The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance. METHODS: We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p-MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics. RESULTS: The proportion of patients displaying high expression levels were as follows: p-AKT, 75%; cyclin D1, 12%; P27, 53%; p-p70S6 K, 37%; p-4EBP1, 19%; and p-MAPK/ERK, 3%. Patients were classified into two groups on the basis of staining scores. Group 1 (39%) included more positive cases for p-4EBP1, p-MAPK/ERK, and p-p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61%). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P < 0.001), nuclear grade (P < 0.001) and histological subtype (P = 0.034). A strong positive correlation was identified between p-AKT and P27, cyclin D1 and P27, p-p70S6 K and p-4EBP1, p-p70S6 K and p-MAPK/ERK, and between p-4EBP1 and p-MAPK/ERK. Levels of p-p70S6 K were significantly related to recurrence in both univariate (RR = 0.75, P < 0.001) and multivariate (RR = 0.71, P = 0.049) analyses. CONCLUSIONS: The present study helps us to understand the characteristics of signaling pathway status in breast cancers. Moreover, p-p70S6 K expression may be of use in predicting clinical outcome.

Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ.

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole-node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle-biopsy diagnosis of DCIS who underwent SN biopsy using the one-step nucleic acid amplification assay in the period 2009-2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro- and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro- and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS.

Lapatinib-associated mucocutaneous toxicities are clinical predictors of improved progression-free survival in patients with human epidermal growth factor receptor (HER2)-positive advanced breast cancer.

This study is aimed to identify clinical predictors, other than HER2 overexpression, for the response to lapatinib plus capecitabine (LAPCAP) in patients with HER2-positive advanced breast cancer (HER2ABC). Data from our medical records of 76 patients from June 2009 to March 2013 were analyzed. Evaluations of these patients with HER2ABC treated with LAPCAP included baseline characteristics, dose modifications, efficacy, and incidence of adverse events (AEs). With a median follow-up of 20 months, the median number of prior therapies for ABC before LAPCAP was 2 (range 0-13), and 66 patients had previously received trastuzumab. For LAPCAP, the overall response rate was 21 %, and the clinical benefit rate was 60 %. During the initial 12-month observation period, 93 % of patients had AEs. The most common AE was hand-foot syndrome (HFS) in 55 patients. Progression-free survival (PFS) was better in patients who had HFS than in those who did not (p = 0.0002). Since HFS is a well-known AE associated with CAP, whether CAP dose affected PFS or not was investigated, but no positive relationship was found. Since several studies with EGFR-targeted agents have suggested a positive correlation between cutaneous toxicities and outcomes, whether the incidence of any AEs affected PFS or not was explored among 76 patients. HFS, diarrhea, and rash were significant favorable factors (p = 0.0002, 0.0088, and 0.0011). The median PFS of patients who had all three AEs was 13.2 months, compared with 2.6 months for those who did not (p = 0.00000174). Mucocutaneous toxicities may be predictors of the response to LAP in patients with HER2ABC.

[Current clinical issues and recent trends in hereditary breast and ovarian cancer in Japan-genetic testing for HBOC and risk-reducing surgery].

The recognition of hereditary breast and ovarian cancer (HBOC) is gradually spreading in Japan after a famous American actress made it public that she underwent risk-reducing mastectomy (RRM) based on mutation of BRCA1. HBOC is a cancer susceptibility syndrome involving breast, ovarian, or prostate cancers due to germline mutation of BRCA1 or BRCA2. Although the frequency is low, genomic rearrangement is also found in Japan; therefore, in addition to PCR-direct sequencing, multiplex ligation-dependent probe amplification (MLPA) should be performed in genetic testing for HBOC. Recently, candidate genes other than BRCA1/2, such as RAD51C, PALB2, and BRIP1, have been identified for hereditary breast cancers. Variants of uncertain significance are seen in approximately 4-6% of all genetic testing reports for BRCA1/2. ACMG recommends the use of the term"variant"in addition to a modifier such as pathogenic, benign, and so on, instead of terms such as mutation or polymorphism. The incidence of ovarian cancer is not increased in women from breast cancer-only families that test negative for BRCA1/2 mutations. Therefore, intensive gynecological surveillance may not be needed for these clients. Basic data such as penetrance and cumulative risks of HBOC in Japanese populations are insufficient for risk assessment in genetic counseling. The Japanese HBOC consortium was established, and as one of the activities of the consortium, the registration project will start to provide essential genetic information in clinical practice. In Japan risk-reducing surgeries are, albeit gradually, increasingly being performed to potentially protect mutation carriers against HBOC. Risk-reducing salpingo-oophorectomy (RRSO) is effective in the reduction of the incidence of breast cancer, as well as of ovarian cancer. Furthermore, RRSO is associated with improved overall survival in BRCA1/2 mutation carriers. RRM also reduces the risk of breast cancer by more than 90%, but the survival benefit remains unknown. Recently, contralateral RRM has shown improved overall survival in a prospective analysis. Pathological examination of resected surgical specimens from RRSO revealed that some serous ovarian carcinomas originated from fimbriae of the uterine tube, showing focal p53 overexpression (p53 signature) in the tubal epithelium. Therefore, initial bilateral salpingectomy followed by a delayed oophorectomy may be a proposed alternative to RRSO, but there is no prospective evidence on the efficacy of bilateral salpingectomy.

Time trend of breast cancer-related lymphedema according to body mass index.

PURPOSE: To clarify how body mass index (BMI) affects the development and temporal trend of breast cancer-related lymphedema (BCRL). METHODS: This is a prospective study in which patients with operable breast cancer were registered in a single institute between November 2009 and July 2010. The incidence of lymphedema at 1, 3, and 5 years after surgery was assessed according to BMI, and the trend of newly developed BCRL was examined. Obesity was defined as BMI ≥25 in accordance with the Japan Society for the Study of Obesity. RESULTS: A total of 368 patients were included in this study. The multivariate analysis of the whole population showed that high BMI, axillary dissection, and radiotherapy remained as risk factors for BCRL. Patients with high BMI showed a significantly higher incidence of new lymphedema than those with low BMI at 1 year (p < 00.001) regardless of axillary procedures (39.1 % vs 16.3 % for axillary dissection; 15.6 % vs 1.5 % for sentinel lymph node biopsy) but not at 3 and 5 years. Once BCRL developed, patients with high BMI showed slow recovery and 50.0 % of the patients retained edema at 5 years while patients with low BMI showed rapid recovery and 26.7 % retained after 3 years (p = 0.04). CONCLUSION: The preoperative BMI affected the incidence and temporal trend of BCRL regardless of axillary procedures or radiotherapy. Patients with high BMI should be given appropriate information about BCRL before surgery with careful follow-up for BCRL after treatment.

Detection of occult invasion in ductal carcinoma in situ of the breast with sentinel node metastasis.

By definition, ductal carcinoma in situ (DCIS) - pre-invasive breast cancer - does not metastasize to the lymph nodes. However, since the introduction of molecular whole-node analysis using the one-step nucleic acid amplification assay for sentinel node (SN) biopsies, the number of patients with DCIS and SN metastasis has increased. The pathogenesis and clinical management of DCIS with SN metastasis remain controversial. In this case-control study, in order to elucidate the pathogenesis of SN metastasis in DCIS, we compared occult invasions between the SN-positive and SN-negative DCIS and investigated predictive factors of occult invasion. The subjects were 24 patients selected from 285 patients with a routine postoperative diagnosis of DCIS who had undergone SN biopsy using the one-step nucleic acid amplification whole-node assay between 2009 and 2011. Of these 24 patients, 12 were SN-positive, and 12 were SN-negative. The 12 SN-negative patients make up the control group and were selected from the 273 SN-negative patients based on patient characteristics. All paraffin blocks of the primary tumor from each patient were step-sectioned with 500-µm intervals until the block was exhausted and histopathologically examined. We analyzed 1830 step-sectioned slides and found occult invasions were more frequent in the SN-positive group (7/12, 58.3%) than in the SN-negative group (3/12, 25.0%). All occult invasions were <5 mm. There was no correlation between occult invasion and SN tumor burden, non-SN metastasis, or patient characteristics. Our results suggest true metastasis from occult invasion may be a potent pathogenesis indicating nodal metastasis in postoperatively diagnosed DCIS. Patient follow-up is required to elucidate the prognostic impact of nodal metastasis and occult invasion.