Intractable axonal neuropathy with multifocal peripheral nerve swelling in neuromyelitis optica spectrum disorders: A case report.

We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances.

Epithelial Paradox: Clinical Significance of Coexpression of E-cadherin and Vimentin With Regard to Invasion and Metastasis of Breast Cancer.

BACKGROUND: E-cadherin and vimentin are regarded as major conventional canonical markers of the epithelial-mesenchymal transition. It is commonly assumed that E-cadherin is uniformly lost during the process of epithelial-mesenchymal transition. Breast tumor cells typically invade as a cohesive multicellular unit in a process called collective invasion. The aim of this study was to reveal the clinical importance of the expression pattern of E-cadherin and vimentin in breast cancer. METHODS: E-cadherin and vimentin protein expression was evaluated by immunohistochemistry in 176 invasive breast cancer samples. Among these, E-cadherin and vimentin expression were evaluated in the set of primary site and metastatic lymph nodes in 65 cases. In addition, E-cadherin and vimentin expression were analyzed by confocal laser scanning microscopy to see E-cadherin and vimentin localization in the breast cancer cells. RESULTS: Both at the primary site and metastatic lymph nodes, both E-cadherin- and vimentin-positive tumors had the worst disease-free and overall survival among all cases. In addition, E-cadherin and vimentin protein is colocalized within the same tumor cells in a human breast cancer specimen. CONCLUSION: Our present data suggest the existence of an aggressive subpopulation in the primary tumor nest of breast cancer.

The Clinical Usefulness of the LigaSure™ Small Jaw in Axillary Lymph Node Dissection in Patients with Breast Cancer.

BACKGROUND: The LigaSure™ small jaw (LS-SJ) multifunctional tissue sealing system is mainly used in cervical operations. We aimed to evaluate the clinical efficacy of the LS-SJ in axillary lymph node dissection (ALND) in comparison to the conventional method. PATIENTS AND METHODS: Ninety-two patients with breast cancer who underwent total mastectomy and ALND were included in this study. The patients were divided into the LS-SJ group (n=43) and the conventional-ALND (c-ALND) group (n=49). RESULTS: Patients with high body mass index values had a greater drainage volume and longer time to drain removal. The drainage volume was in the LS-SJ group was significantly lower than that in the c-ALND group. The time to drain removal and the hospitalization period were also significantly shorter in the LS-SJ group. The LS-SJ was more effective for ALND in obese patients. CONCLUSION: The results suggest the clinical usefulness of LS-SJ in ALND in patients with breast cancer, especially in obese patients.

Clinical Significance of the Wild Type p53-Induced Phosphatase 1 Expression in Invasive Breast Cancer.

BACKGROUND: Wild type p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), inhibits p53. PPM1D amplification has been reported in breast cancer. Breast cancer can sometimes develop without a tumor protein 53 (TP53) mutation. In these cases, the p53 pathway might be disrupted by alternative mechanisms, and Wip1 is reported to be a key molecule involved. MATERIALS AND METHODS: Primary invasive ductal carcinoma specimens were obtained from 201 cases, for which archival tissue samples for immunohistochemistry were available. We evaluated Wip1 and p21 protein expression (201 cases), Wip1 mRNA expression (63 cases), PPM1D DNA copy number (71 cases) and TP53 status (36 cases) using available samples among the 201 cases, and analyzed their relationships with clinicopathological factors and prognosis. RESULTS: The nuclear expression of Wip1 protein was positive in 21 cases (10.4%). The PPM1D DNA copy number was significantly correlated with Wip1 protein expression. All cases with PPM1D amplification by single-nucleotide polymorphism comparative genomic hybridization array showed positive nuclear Wip1 expression. Wip1 protein expression was positively correlated with p21 expression. The tumors with positive Wip1 and negative p21 expression showed the poorest prognosis among all tumor types. CONCLUSION: The protein expression of Wip1 might be regulated by PPM1D amplification, independent of TP53 status. Positive Wip1 and negative p21 expression was associated with the poorest prognosis and suggests the loss of p53 function.

A Locally Advanced Breast Cancer that Achieved pCR with Pertuzumab, Trastuzumab and Docetaxel: Case Report.

We herein report a case of locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer that achieved a pathological complete response (pCR) with pertuzumab, trastuzumab and docetaxel therapy. A 70-year-old female presented with an elastic hard mass, 5.0 cm in diameter with broad redness and edema of the skin in her right breast. Swollen lymph nodes were also recognized in the right axilla. The pathological diagnosis was invasive ductal carcinoma and its biological character was estrogen receptor (ER)-negative, progesterone receptor (PgR)-negative, HER2 3+ and Ki-67 index 60%. The patient was finally diagnosed with primary unresectable, locally advanced breast cancer and started on pertuzumab, trastuzumab and docetaxel combination therapy. The tumor subsequently reduced in size and, after 4 cycles of this therapy, she underwent surgery. The histopathological examination of the postoperative specimen showed pCR in both the primary tumor and axillary lymph nodes.

The relationship between the expression of FOXA1 and GATA3 and the efficacy of neoadjuvant endocrine therapy.

BACKGROUND: Estrogen receptor (ER)/GATA3/Forkhead box A1 (FOXA1) network is necessary for the ERα functional signature. High FOXA1 expression indicates a good prognosis in ER-positive breast cancer. However, little is known about the significance of FOXA1 and GATA3 expression in neoadjuvant endocrine therapy (NAE). The aim of this study is to investigate their predictive potential for NAE and their expression changes after NAE. METHODS: FOXA1 and GATA3 expression was evaluated using immunohistochemistry in 66 patients with ER-positive/HER2-negative breast cancer who had been treated with NAE. The association between biological marker expressions and the efficacy of NAE and their expression changes after NAE were analyzed. RESULTS: The median pre-treatment FOXA1 and GATA3 expressions were 94.6 and 90 %. Pre-treatment FOXA1 expression was positively correlated with GATA3 (P = 0.0003) and progesterone receptor (PgR) (P = 0.0138). There was no correlation between pre- or post-treatment FOXA1 and GATA3 expressions and the efficacy of NAE. Post-treatment Ki67 expression was significantly lower in tumors with partial response (PR) (P = 0.0007). In terms of the changes of the expression, PgR, Ki67, and FOXA1 expression significantly decreased after NAE (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). CONCLUSIONS: FOXA1 and GATA3 expression was not correlated with the efficacy of NAE, but FOXA1 expression was significantly reduced after NAE.

Expression of APOBEC3B mRNA in Primary Breast Cancer of Japanese Women.

Recent studies have identified the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) as a source of mutations in various malignancies. APOBEC3B is overexpressed in several human cancer types, including breast cancer. In this study, we analyzed APOBEC3B mRNA expression in 305 primary breast cancers of Japanese women using quantitative reverse transcription-PCR, and investigated the relationships between the APOBEC3B mRNA expression and clinicopathological characteristics, prognosis, and TP53 mutations. The expression of APOBEC3B mRNA was detected in 277 tumors and not detected in 28 tumors. High APOBEC3B mRNA expression was significantly correlated with ER- and PR-negativity, high grade and high Ki67 index. The APOBEC3B mRNA expression was highest in the triple-negative and lowest in the hormone receptor-positive/HER2-negative subtypes. The TP53 gene was more frequently mutated in the tumors with high APOBEC3B mRNA expression. High APOBEC3B mRNA expression was significantly associated with poor recurrence-free survival in all cases and the ER-positive cases. These findings were almost consistent with the previous reports from the Western countries. In conclusion, high APOBEC3B mRNA expression was related to the aggressive phenotypes of breast cancer, high frequency of TP53 mutation and poor prognosis, especially in ER-positive tumors.

Distant lymph node metastases caused by esophageal cancer invasion to the lamina propria: a case report.

BACKGROUND: Pathological examination after endoscopic submucosal dissection revealed that a 62-year-old male had esophageal squamous cell carcinoma with lamina propria mucosal invasion and lymphatic permeation. CASE PRESENTATION: The patient underwent subtotal esophagectomy and reconstruction as an additional therapy. At 3 years and 4 months after esophagectomy, enlargement of abdominal para-aortic lymph nodes metastases was detected by computed tomography scanning. A total of 50.4 Gy of radiation and two cycles of 5-fluorouracil plus cisplatin were administered. The lymph node metastases were markedly reduced by chemoradiotherapy; however, at 1 year and 1 month later (4 years and 5 months after esophagectomy), left adrenal gland recurrence was found. Although resection was performed, the patient died from cancer progression at 5 years and 4 months after esophagectomy. CONCLUSIONS: This case demonstrates that esophageal squamous cell carcinoma with invasion to the lamina propria and lymphatic permeation has the potential to cause distant metastases.

Impact of Expression of Vimentin and Axl in Breast Cancer.

BACKGROUND: The association between Axl and vimentin protein expression has been observed in several cell lines. However, the clinical importance of Axl and vimentin expression in breast cancer have not been fully determined. PATIENTS AND METHODS: The expressions of Axl and vimentin were evaluated by immunohistochemistry in a total of 343 patients with invasive ductal carcinoma. The relationships between expression of Axl and vimentin and clinicopathologic characteristics and prognosis were analyzed. RESULTS: Axl expression was classified into high (n = 170) and low (n = 173) expression groups. Axl expression alone was not associated with any clinicopathologic factor or prognosis. Coexistence of vimentin-positive and Axl-high expression was observed in 10.5% (n = 36). Vimentin-positive and Axl-high tumors were associated with triple-negative breast cancers (P = .0396) and with poor prognosis in terms of both recurrence-free survival (P = .0126) and overall survival (P = .0005) compared to the other groups, including vimentin-positive and Axl-low tumors, vimentin-negative and Axl-high tumors, and vimentin-negative and Axl-low tumors. Multivariate analysis showed that coexistence of vimentin-positive and Axl-high expression was an independent poor prognostic factor for recurrence-free survival (hazard ratio, 2.78; 95% confidence interval, 1.23-5.68; P = .0158) and overall survival (hazard ratio, 3.72; 95% confidence interval, 1.51-8.47; P = .0059). CONCLUSION: Coexistence of vimentin-positive and Axl-high expression is a poor prognostic factor for primary breast cancer. Vimentin and Axl expression might contribute to the aggressive phenotype in breast cancer.

Biological and clinical significance of loss of heterozygosity at the INPP4B gene locus in Japanese breast cancer.

PURPOSE: INPP4B is considered to function as a putative tumor suppressor through its inhibitory function of Akt. In various malignant tumors, loss of heterozygosity (LOH) at the chromosomal region containing INPP4B and lower expression of INPP4B has been reported. The purpose of this study was to examine the frequency of the INPP4B LOH and its association with the clinicopathological characteristics and prognosis in breast cancer of Japanese women. METHODS: The allelic alteration at the INPP4B and PTEN gene loci was analyzed in 277 invasive primary breast carcinomas. The relationships between INPP4B LOH and the clinicopathological features were investigated. RESULTS: Among the 238 informative cases for the evaluation, LOH at the INPP4B gene locus was observed in 43 tumors (18.1%). INPP4B LOH was significantly correlated with ER and PR negativity (p = 0.0009 and p = 0.0029, respectively), higher nuclear grade (p < 0.0001), higher Ki67 labeling index (p = 0.0006), triple-negative (TN) subtype (p = 0.0005) and PTEN LOH (p < 0.0001). INPP4B LOH was significantly associated with poorer prognosis, in terms of the relapse-free survival (RFS) and overall survival (OS). According to the multivariate analyses, INPP4B LOH was not independently associated with the prognosis. CONCLUSION: The incidence of INPP4B LOH was significantly higher in the TN subtype and positively correlated with PTEN LOH. INPP4B LOH was associated with more aggressive and proliferative phenotype. INPP4B LOH was also associated with poorer prognosis.

Epigenetic Inactivation of BRCA1 Through Promoter Hypermethylation and Its Clinical Importance in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases. PATIENTS AND METHODS: Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry. RESULTS: BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P < .0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P = .02), high nuclear grade (P = .05), low BRCA1 mRNA expression (P < .0001), and loss of BRCA1 protein expression (P = .0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P = .038). CONCLUSION: BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1.

Spontaneous regression of breast cancer with axillary lymph node metastasis: a case report and review of literature.

Spontaneous regression (SR) of cancer is a rare but well-documented biological phenomenon. However, the mechanism remains to be elucidated. We herein report a case of the SR of breast cancer at both the primary site and metastatic axillary lymph node with spontaneously-induced T cell-mediated immunological responses. A 52-year-old female with a lump in the left axilla was diagnosed to have a small breast carcinoma with a distinct axillary lymph node metastasis. During the preoperative systemic examination, she was diagnosed to have severe type 2 diabetes mellitus, was treated with insulin, and the hyperglycemia was normalized after one month. Surgery for left breast cancer was then performed. The postoperative histopathological examination revealed the SR of breast cancer at both the primary site and metastatic axillary lymph node. Immunohistochemical studies revealed that estrogen receptor positive, AE1/AE3-positive ductal carcinoma completely underwent necrosis associated with extensive infiltration of CD3-positive T cells in the tumor nodule in the lymph node. In addition, primary ductal carcinoma cells also underwent single cell necrosis with infiltration of T cells with lymph follicle-like organization of B cells in the mammary gland. The features were suggestive that the tumor eradication in the metastatic lymph node and regression of the primary ductal carcinoma could be due to host T cell response to the ductal carcinoma. As far as we know it is the first report that shows the spontaneous regression of breast cancer, probably due to the spontaneously-induced T cell response.

Molecular mechanisms regulating the hormone sensitivity of breast cancer.

Breast cancer is a heterogeneous disease. Approximately 70% of breast cancers are estrogen receptor (ER) positive. Endocrine therapy has dramatically improved the prognosis of ER-positive breast cancer; however, many tumors exhibit de novo or acquired resistance to endocrine therapy. A thorough understanding of the molecular mechanisms regulating hormone sensitivity or resistance is important to improve the efficacy of and overcome the resistance to endocrine therapy. The growth factor receptor signaling pathways, particularly the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway can mediate resistance to all forms of endocrine therapy. In contrast, FOXA1 transcription factor is a key determinant of ER function and endocrine response. Intriguingly, a link between hormone resistance induced by the PI3K/Akt/mTOR pathway and the function of FOXA1 has been suggested. In this review, we focus on the PI3K/Akt/mTOR pathway and functions of FOXA1 in terms of the molecular mechanisms regulating the hormone sensitivity of breast cancer.

A case of invasive micropapillary carcinoma of the breast involving extensive lymph node metastasis.

We herein report a case of invasive micropapillary carcinoma (IMPC) involving extensive lymph node metastasis with no recurrence for over 7 years. A 41-year-old female presented with pain and a swelling mass in the left axillary region, which had been present for several months. The tumor measured 1.6 cm in diameter in the middle of upper area of the left breast. Based on the findings of a core needle biopsy the pathological diagnosis was IMPC or mucinous carcinoma. The cytology of the left axillary lymph node was positive for metastatic carcinoma. The patient underwent a left mastectomy and a left axillary dissection (level I to III). The postoperative pathological diagnosis was IMPC with mucin production, and the number of metastatic lymph nodes was 59. The patient was given adjuvant chemotherapy (four courses of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and four courses of docetaxel), radiation for the left chest wall, supraclavicular and internal thoracic area, and then received tamoxifen for 5 years. The patient has remained recurrence-free for over 7 years. IMPC is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and a poor prognosis. It seems that long-term survival was obtained by performing sufficient medical treatment. Prognostic factors other than the number of lymph node metastases may also exist.

Early discontinuation of adjuvant hormone therapy is associated with a poor prognosis in Japanese breast cancer patients.

PURPOSE: It is important for patients to complete the planned hormone therapy to reduce both the recurrence and mortality rates of hormone receptor-positive breast cancer. We investigated the rates and factors related to the early discontinuation of adjuvant hormone therapy at our institution. METHODS: We identified 145 females prescribed adjuvant hormone therapy who were followed up for longer than 5 years. The rate of completing the planned hormone therapy and factors related to early discontinuation were examined. The relapse-free survival rate was examined between the completion group and the discontinuation group. RESULTS: The completion rate was 90.6 %. The primary reason for discontinuing hormone therapy within 5 years was side effects, such as arthritic pain. The primary factor related to early discontinuation was a significantly younger age. The relapse-free survival rate was significantly lower in the discontinuation group (p = 0.025). CONCLUSIONS: More than 90 % of the patients completed the planned adjuvant hormone therapy, and early discontinuation was related to a shorter RFS. To improve the rate of the successful completion of adjuvant hormone therapy, it is important to provide supportive care to reduce the occurrence of side effects and to care for young females with a desire to become pregnant.

Luteinizing hormone-releasing hormone agonist plus an aromatase inhibitor as second-line endocrine therapy in premenopausal females with hormone receptor-positive metastatic breast cancer.

PURPOSE: The aim of the current study was to explore the efficacy and safety of combination therapy using a luteinizing hormone-releasing hormone (LHRH) agonist plus an aromatase inhibitor (AI) as second-line therapy in premenopausal females with hormone receptor (HR)-positive recurrent or metastatic breast cancer (MBC). METHODS: A retrospective analysis was conducted in patients registered in the breast cancer database of our institution between January 2001 and December 2012. The breast cancer database identified 14 premenopausal patients who had been treated with an LHRH agonist plus AI for HR-positive recurrent or MBC. RESULTS: Fourteen patients with recurrent breast cancer (N = 10) or metastatic disease at primary diagnosis (N = 4) were included in the present study. All patients had previously been treated with an LHRH agonist plus tamoxifen. The clinical benefit rate was 71.4% and the median TTP was 11 months (95% confidence interval 1.7-20.3 months). One patient discontinued treatment because of liver dysfunction (grade 3). CONCLUSIONS: The combination of an LHRH agonist plus an AI is a treatment option for premenopausal females with HR-positive MBC that can prolong the chemotherapy-free interval and yield effective disease stabilization.

Differential impact of the expression of the androgen receptor by age in estrogen receptor-positive breast cancer.

We evaluated the expression of the androgen receptor (AR) to determine its significance in breast cancer. AR expression levels were analyzed in 250 invasive breast cancers by immunohistochemistry and any association with the clinicopathological features was evaluated. AR expression was higher in estrogen receptor (ER)-positive cases than in ER-negative cases (P < 0.0001). AR expression was associated with ER level, and it increased with age in ER-positive cases. The cut-off value was determined to be 75% (Cancer Res. 2009;69:6131-6140), and AR expression was considered to be high in 155 (62%) cases. High AR expression significantly correlated with lower nuclear grade (P < 0.0001), ER and progesterone receptor (PR) positivity (P < 0.0001 and P = 0.0022), HER2 negativity (P = 0.0113), lower Ki67 index (P < 0.0001) and a longer disease-free survival (DFS) and distant metastasis-free survival (DMFS) (P = 0.0003 and 0.0107). This association between a high AR expression and a good DFS and DMFS was significant for ER-positive tumors (P < 0.0001 and P = 0.0018); however, no association existed between AR expression and prognosis for ER-negative tumors. In patients ≤51 years old, a high AR expression level significantly correlated with a better prognosis, but this was not significant in patients who were 50 or younger. Multivariate Cox hazard analyses revealed AR expression to be independently associated with a good prognosis in overall patients (HR 0.46, P = 0.0052) and in the ER-positive cohort (HR 0.34, P = 0.0009). AR expression is associated with a less aggressive phenotype and a good prognosis in patients with ER-positive breast cancer. This is considered to be a specific phenomenon for postmenopausal breast cancer patients.

[Overlap case of Fisher syndrome and pharyngeal-cervical-brachial variant of Guillain-Barré syndrome].

A 29-year-old female developed diplopia, nasal voice and gait disturbance after an upper respiratory infection. On admission, she presented with bilateral external ophthalmoplegia, slight bilateral facial nerve palsy, dysarthria, dysphagia, cervical and brachial muscle weakness, ataxia and areflexia. She had serum anti-GT1a, anti-GQ1b and anti-galactocerebroside IgG antibodies. She was diagnosed with an overlap case of Fisher syndrome and pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Intravenous immunoglobulin therapy was effective for the ophthalmoplegia and ataxia, but did not improve the bilateral facial nerve palsy and brachial muscle weakness. The facial nerve palsy clearly worsened despite improvement in other symptoms, and therefore high-dose intravenous methylprednisolone therapy was added. The distinct response to treatment may be caused by different activity, production, clearance and reactivity to intravenous immunoglobulin of the autoantibodies. The present case suggests that treatment response and patterns of recovery differ according to the causative anti-ganglioside antibodies.

Can patients with metastatic breast cancer be cured after introduction of newer and more effective agents?

Unlike early stage breast cancer, metastatic breast cancer (MBC) is generally considered incurable except for a small number of patients with oligometastatic disease. The goal of treatment of MBC should be the prolongation of life and improvement of symptoms and quality of life. The prognoses of patients with MBC, however, have been improved with the introduction of newer, more effective agents. Therefore, the clinical question arises whether MBC patients can be cured with these new therapeutic agents. However, there are a couple of problems in tackling this question, including the duration of follow-up and the presence of strong adjuvant therapy. Firstly, most trials in MBC have a relatively short follow-up; long-term surveillance (>3-5 years) is exceptional, so little is known about the definitive outcome and the exact proportion of long-term survivors. Secondly, most of the patients have received pre- or postoperative adjuvant therapy. The cancer cells at metastatic sites are considered to be relatively resistant to the agents used in metastatic settings. Promisingly, a number of novel therapeutic agents including antibody-drug conjugates, irreversible small molecule HER2-tyrosine inhibitors, and HER2 dimerization inhibitors show promise in the treatment of HER2-overexpressing MBC, as well as PARP-1 [poly(ADP-ribose) polymerase-1] inhibitors for triple-negative breast cancer.

Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000.

BACKGROUND: It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs) and trastuzumab. METHODS: A total of 407 patients who received first diagnosis of recurrent breast cancer and treatment at National Kyushu Cancer Center between 1992 and 2008 were retrospectively evaluated. As AIs and trastuzumab were approved for clinical use in Japan in 2001, the patients were divided into two time cohorts depending on whether the cancer recurred before or after 2001. Cohort A: 170 patients who were diagnosed between 1992 and 2000. Cohort B: 237 patients who were diagnosed between 2001 and 2008. Tumor characteristics, treatments, and outcome were compared. RESULTS: Fourteen percent of cohort A and 76% of cohort B received AIs and/or trastuzumab (P < 0.001). The median overall survival (OS) times after breast cancer recurrence were 1.7 years and 4.2 years for these respective cohorts (P < 0.001). Both the time period and treatment of AIs and/or trastuzumab for recurrent disease were significant prognostic factors in multivariate analysis (cohort B vs. cohort A: HR = 0.70, P = 0.01; AIs and/or trastuzumab for recurrent disease: yes vs. no: HR = 0.46, P < 0.001). When patients were categorized into 4 subgroups by the expression of hormone receptor (HR) and HER-2 status, the median OS times of the HR-positive/HER-2-negative, HR-positive/HER-2-positive, HR-negative/HER-2-positive, and HR-negative/HER-2-negative subtypes were 2.2, 2.4, 1.6, and 1.0 years in cohort A and 4.5, 5.1, 5.0, and 1.4 years in cohort B. CONCLUSIONS: The prognosis of patients with recurrent breast cancer was improved over time following the introduction of AIs and trastuzumab and the survival improvement was apparent in HR- and/or HER-2-positive tumors.