Circulating tumor cells as a prognostic marker for efficacy in the randomized phase III JO21095 trial in Japanese patients with HER2-negative metastatic breast cancer.

PURPOSE: Prognostic effects of circulating tumor cells (CTCs) have been reported in metastatic breast cancer (MBC). However, few phase III trials have investigated the potential role of CTCs in treatment selection. We explored potential relationships between CTCs, efficacy, and differential treatment effects. METHODS: Patients with HER2-negative MBC were randomized to receive either concurrent capecitabine plus docetaxel (XT) or sequential single-agent docetaxel followed by single-agent capecitabine at progression (T â†’ X). Blood samples were collected at baseline, on day 1 of cycles 2 and 3, and at progression. CTCs were counted using the CellSearch® System. The relationship between baseline CTC count and outcomes was investigated using a pre-defined threshold of 2 CTCs/7.5 mL. RESULTS: At screening, 44% of the 148 enrolled patients had positive CTC score. In multivariate analyses of pooled treatment arms, positive baseline CTC and triple-negative disease were strongly associated with worse progression-free survival (PFS) and overall survival (OS). Patients with positive CTC score at the baseline had worse OS, irrespective of change in CTC (decreased versus remaining positive) at cycle 2. The prognostic effect of baseline CTC count on OS appeared slightly less pronounced in XT-treated pts. compared with T â†’ X. CONCLUSIONS: A baseline CTC count ≥2 CTCs/7.5 mL was associated with worse prognosis. However, some improvement in PFS and OS was shown with concurrent XT, thus baseline CTC could be a predictive marker. As the current trial was not designed to evaluate a change in chemotherapy according to on-treatment CTC changes, prospective investigation is required.

Invasive papillary carcinoma treated with neoadjuvant endocrine therapy in which pathological complete response was achieved.

BACKGROUND: Invasive papillary carcinoma is a rare type of invasive ductal carcinoma. Neoadjuvant endocrine therapy is now considered as an optional therapy for postmenopausal women with hormone receptor-positive breast cancers, including invasive papillary carcinoma. CASE PRESENTATION: We discuss the case of an 83-year-old postmenopausal Japanese female with hormone receptor-positive invasive papillary carcinoma who started treatment with an aromatase inhibitor and achieved pathological complete response after 12 months of endocrine treatment. CONCLUSION: Appropriate drugs and durations of neoadjuvant endocrine treatment have yet to be established. Continuing therapy with an aromatase inhibitor until the best clinical response is achieved may represent one of the best strategies in neoadjuvant endocrine therapy.

Prolonged survival after diagnosis of brain metastasis from breast cancer: contributing factors and treatment implications.

OBJECTIVE: The prognosis of breast cancer-derived brain metastasis is poor, but new drugs and recent therapeutic strategies have helped extend survival in patients. Prediction of therapeutic responses and outcomes is not yet possible, however. In a retrospective study, we examined prognostic factors in patients with breast cancer-derived brain metastasis, and we tested the prognostic utility of a breast cancer-specific Graded Prognostic Assessment in these patients. METHODS: Sixty-three patients diagnosed with brain metastasis from breast cancer treated surgically and adjuvantly were included. We examined clinical variables per primary tumor subtype: ER+/HER2- (luminal), HER2+ (human epidermal growth factor receptor type 2-enriched) or ER-/PR-/HER2- (triple negative). We also categorized patients' breast cancer-specific Graded Prognostic Assessment scores and analyzed post-brain metastasis survival time in relation to these categories. RESULTS: The breast cancers comprised the following subtypes: luminal, n = 18; human epidermal growth factor receptor type 2-enriched, n = 27 and triple-negative, n = 18; median survival per subtype was 11, 37 and 3 months, respectively. Survival of human epidermal growth factor receptor type 2-enriched patients was longer, though not significantly (P = 0.188), than that of luminal patients. Survival of triple-negative patients was significantly short (vs. human epidermal growth factor receptor type 2-enriched patients, P < 0.001). Karnofsky performance status, HER2 status and the disease-free interval (from initial treatment to first recurrence) were shown to be significant prognostic factors (Karnofsky performance status < 70: relative risk 2.08, P = 0.028; HER2+: relative risk 2.911, P = 0.004; disease-free interval < 24 months: relative risk 1.933, P = 0.011). Breast cancer-specific Graded Prognostic Assessment scores reflected disease-free intervals and survival times. CONCLUSIONS: Our data indicate that breast cancer-specific Graded Prognostic Assessment-based prediction will be helpful in determining appropriate therapeutic strategies for patients with brain metastasis from breast cancer.

[A case of primary breast cancer responding to pre-operative chemotherapy with the combination of paclitaxel and carboplatin for ovarian cancer].

A 62-year-old woman was diagnosed with primary left breast cancer during a follow-up for an ovarian tumor. She had at first undergone surgical resection of an ovarian tumor, and a pathological examination had revealed ovarian cancer. Gynecologists decided to treat her ovarian cancer with chemotherapy, and we were initially planning to provide treatment for breast cancer after that was completed. Sentinel lymph node biopsy performed before chemotherapy revealed no axillary metastases. The patient received six courses of intravenous PTX (175 mg/m2 on day 1, every 3 weeks) and intravenous CBDCA (AUC6 on day 1, every 3 weeks) as combination therapy. Abdominal lymph node dissection was performed between chemotherapy courses 3 and 4. The lump in the left breast showed partial clinical response, and partial resection of the left breast was performed after completion of chemotherapy. In Japan, few cases of primary breast cancer treated preoperatively using carboplatin-containing regimens have been described.

[Predictors of axillary node metastasis at breast surgery after neoadjuvant chemotherapy in patients with pre- chemotherapy-sentinel node positive breast cancer].

BACKGROUND: We investigated predictors for axillary node metastasis at breast surgery after neoadjuvant chemotherapy (NAC) in patients with pre-chemotherapy-sentinel node positive breast cancer. METHODS: Eighty-two patients were diagnosed as having positive sentinel lymph node (SLN), who had axillary lymph node dissection (ALND) performed after combination anthracycline/taxan based NAC, between 2002 and 2009. RESULTS: Eighteen (22.0%) of the 82 patients had residual axillary metastases after NAC. Multivariate analysis revealed that SLNs status before NAC was an important factor in predicting residual axillary metastases. Predictors of residual nodal disease were the number of macrometastases and the percentage (>50%) of positive SLNs in all SLNs. Among a subgroup of hormone-receptor positive and HER2-negative tumors, the risk of residual nodal metastases were high sensitivity of hormone receptor, with more than 50% of tumor cells staining positive for ER and PgR. CONCLUSION: Patients with two or more positive SLNs before NAC had a high risk of residual nodal metastasis after NAC.

Flare hypercalcemia after letrozole in a patient with liver metastasis from breast cancer: a case report.

INTRODUCTION: Tamoxifen may occasionally precipitate serious and potentially life-threatening hypercalcemia. However, to date, this has not been documented with aromatase inhibitors. CASE PRESENTATION: A 65-year-old Japanese woman with liver metastasis from breast cancer was admitted to our hospital with vomiting, anorexia, fatigue, arthralgia, muscle pain and dehydration. She had started a course of letrozole five weeks earlier. Our patient's calcium level was 11.6 mg/dL. She was rehydrated and elcatonin was administered. Our patient's parathyroid hormone and parathyroid hormone-related protein levels were not increased and a bone scintigram revealed no evidence of skeletal metastasis. After our patient's serum calcium level returned to within the normal range, letrozole was restarted at one-half of the previous dose (1.25 mg). There were no episodes of hypercalcemia. However, 84 days after restarting letrozole, our patient again complained of arthralgia and treatment was changed to toremifene. During these periods, repeated ultrasonograms revealed no progression of liver metastasis. CONCLUSION: To the best of our knowledge, this is the first case report of flare hypercalcemia after treatment with letrozole in a patient with metastatic breast cancer.

Clinicopathological analysis of ten patients with metaplastic squamous cell carcinoma of the breast.

PURPOSE: Primary squamous cell carcinoma (SCC) and metaplastic squamous cell carcinoma (MSCC) are rare types of breast cancer with specific histological features. They are characterized by rapid progression, a tendency toward cyst formation, and negativity for hormone receptors. Many studies have concluded that SCC of the breast carries a poor prognosis, based on the fact that conventional chemotherapy for ductal carcinoma of the breast is ineffective against SCC. This is a retrospective study of patients in a single center with SCC or MSCC. METHODS: We searched the records of the Tokyo Metropolitan Komagome Hospital for patients diagnosed with breast SCC or MSCC between 1979 and 2006. Squamous cell carcinoma was diagnosed when 100% of the malignant cells showed a squamous component (pure SCC) and MSCC was diagnosed when more than 50% of the malignant cells showed a squamous component. We analyzed the clinicopathological features, treatment methods, and outcomes of these patients. RESULTS: We identified 10 (0.28%) patients with SCC or MSCC from among 3565 patients with malignant breast tumors treated at our hospital during this period. Nine patients had adenocarcinoma with squamous metaplasia, and one had pure SCC. Ultrasound showed a central cystic-necrotic component in seven tumors, and all of the tumors were negative for hormone receptors and HER2. Recurrence developed in two patients with lymph node metastasis, but not in the other eight patients. The 5-year survival rate and median survival time were 85.7% and 97 months, respectively. CONCLUSIONS: Squamous cell carcinoma or MSCC of the breast with features of the triple-negative subtype seems to be associated with a poor prognosis; however, nodenegative patients are likely to have a favorable prognosis.

Predictive value of CD24 and CD44 for neoadjuvant chemotherapy response and prognosis in primary breast cancer patients.

PURPOSE: We investigated the significance of CD24 and CD44 expression for predicting responses to chemotherapy and prognosis in primary breast cancer patients. PATIENTS AND METHODS: Diagnosis of breast cancer was confirmed by core needle biopsy, and immunohistochemical studies were performed. Preoperatively, patients received anthracycline-containing chemotherapy. Expression of CD44 and CD24 was assessed immunohistochemically and the relationship with chemotherapy response and with prognosis was analyzed. RESULTS: Between 2001 and 2004, 139 women were enrolled in this study. In the correlation analysis, CD24 expression was negatively associated with pathological response to chemotherapy (p = 0.0003). A machine learning technique with an alternating decision tree (ADTree) showed that four logical rules are involved in predicting the response depending on the combination of CD24, HER2, tumor stage, CD44, progesterone receptor, and patient age. In the survival analysis, patients having CD44 (++) showed a significantly favorable prognosis as compared with others (p = 0.0002). A multivariate analysis showed that CD44 expression had an independent prognostic value (p < .0001). CONCLUSION: We found a significant correlation between CD44 expression and prognosis and between CD24 expression and response to chemotherapy. CD24 and CD44 expressions would be useful predictive markers, although further studies are needed.

HER-2/neu cytoplasmic staining is correlated with neuroendocrine differentiation in breast carcinoma.

HER2 oncoprotein plays an essential role in breast cancer growth and differentiation. Determination of HER2 status contributes not only to predicting survival but also to selecting the patients for anti-HER2 therapy. HER2 protein expressed in human cancer cells often contains variant forms as well as the full-length wild-type form. In the present study, we investigated the subcellular localization of HER2 protein in 1053 primary breast cancer tissues. HER2 protein was stained by various immunohistochemical methods and studied by immunoelectron microscopy to confirm the intracellular localization. Thirty-four of 1053 specimens showed cytoplasmic staining of the intracellular domain of HER2 protein by the HercepTest and CB-11. In contrast, no immunoreactivity to the antibodies against the extracellular domain was observed. None of the 34 specimens showed amplification of the HER2 protein by fluorescence in situ hybridization. Subsequently, we studied the association of the cytoplasmic expression of HER2 with neuroendocrine differentiation. Interestingly, all 34 specimens had some positive signals of neuroendocrine markers such as synaptophysin, chromogranin A, neuron-specific enolase, and CD56. Although the result is preliminary, it warrants further study on the role of the cytoplasmic variant form of HER2 in breast cancer growth, particularly in the aspect of neuroendocrine differentiation.

A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer.

Cancer cells induce proliferation and local accumulation of immunosuppressive cells, such as FOXP3-positive cells known as regulatory T cells (Tregs), leading to tumor-induced immune tolerance. Although cancer chemotherapy is usually considered immunosuppressive, some chemotherapeutic agents activate an anticancer immune response. Therefore, we postulated that the number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy (PSC) correlates with therapeutic outcomes in patients with breast cancer. Between September 2000 and January 2005, we examined 93 patients with breast cancer diagnosed by core-needle biopsy and treated with PSC. Core-needle biopsy (CNB) and surgical resected specimens were stained with a FOXP3 mouse monoclonal antibody to compare the numbers of FOXP3-positive cells in the tumors before and after PSC. A median cut-off value of >16.3/high power field (HPF) and >6.6/HPF defined high numbers of Tregs in CNB and in surgical specimens, respectively. We then assigned the patients into 4 groups (HH, high number of FOXP3-positive cells in both CNB and surgical specimen; LL, low number in both specimens; HL, high in CNB and low in the surgical specimen; LH, low in CNB and high in surgical specimen). Lymph vessel invasion-positive, clinically non-responder and ER-negative tumors contained significantly more FOXP3-positive cells after PSC (p=0.04, p=0.03 and p=0.04, respectively). Prognosis was better among patients with low numbers than high numbers of FOXP3-positive cells both in CNB and in surgically resected specimens. In multivariate analysis, LL group demonstrated significantly better recurrence-free survival with risk ratio of 5.81 (95%CI, 1.09-107.5; p=0.04) rather than that of non-LL group (LH, HL and HH). These findings suggest that the number of FOXP3-positive cells identified during PSC represents a promising predictive factor that might also be an important therapeutic target for breast cancer.

Early breast cancer.

Breast cancer remains a common disease throughout the world. Here we review new knowledge about early breast cancer obtained during the past 5 years. The prognosis of early breast cancer is generally favorable. Especially, ductal carcinoma in situ has been regarded as a non-life-threatening disease. Therefore, early diagnosis and early onset of the treatment has been important. Early age at menarche, late age at first birth, and late age at menopause are related to breast cancer risk. Examination by mammography and ultrasonography is still the most effective means of detection for premenopausal and postmenopausal women, respectively. Additionally, there have been important advances in MRI, sentinel lymph node biopsy, breast-conserving surgery, partial breast irradiation, neoadjuvant systemic therapy, and adjuvant systemic therapy. Another approach to keeping the disease under control is the elucidation of breast cancer's molecular biological features. Assessment of potential molecular targets can lead to early diagnosis and molecular targeted treatment.

Trastuzumab: updates and future issues.

Trastuzumab has had an enormous impact on the clinical management of breast cancer: the survival of Her-2-positive metastatic breast cancer patients has improved significantly and tumor Her-2 status has been built into the decision-making tree for primary breast cancer patients. Several pioneering studies have shown that trastuzumab-combined chemotherapy elicits high levels of pathological complete response in the neoadjuvant setting. Currently, therefore, a more precise understanding of the mechanisms of therapeutic response is needed so that trastuzumab-based therapies can be optimized more individually. It might also be important to investigate, with greater depth, the interaction between the Her-axis and the hormone-axis. This short review describes and discusses these topics.