GnRH Agonist Therapy to Protect Ovarian Function in Young Korean Breast Cancer Patients

The increased survival of patients with breast cancer has given rise to other problems associated with the complications of chemotherapy. One major complication is premature ovarian failure, an especially harmful outcome for women of reproductive age. This study was performed to evaluate the efficacy of GnRH agonist (GnRHa) treatment on protecting ovarian function in young breast cancer patients (30.59±5.1 yr) receiving chemotherapy after surgery. Twenty-two women were enrolled and given subcutaneous injections of leuprolide acetate (3.75 mg) every 4 weeks during chemotherapy. Follow-up laboratory tests (luteinizing hormone [LH], follicle stimulating hormone [FSH], and estradiol) were performed 1, 3, and 6 months after chemotherapy. Menstruation patterns and clinical symptoms were followed up for a mean duration of 35.6±1.7 months. FSH and LH levels were normal in all patients 6 months after completing chemotherapy (8.0±5.3, 4.4±2.7 mIU/mL, respectively). During follow-up, none of the patients complained of menopausal symptoms and 81.8% experienced recovery of menstruation. This report is the first trial of GnRHa as a treatment modality to protect ovarian function during adjuvant chemotherapy in young Korean breast cancer patients.     

A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P= 2.87 × 10(-9)-9.41 × 10(-8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P= 2.02 × 10(-4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P= 1.26 × 10(-10)). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P= 6.29 × 10(-9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P= 2.28 × 10(-12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.     

Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer

Phosphorylation of oestrogen receptor alpha at serine 305 (ERalphaS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other endocrine agents, such as fulvestrant. We evaluated ERalphaS305-P using immunohistochemistry in 377 breast carcinomas from premenopausal participants of a randomized trial (n=248) and patients with advanced disease (n=129). Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ERalphaS305-P-negative tumours (multivariate HR=0.53, 95% CI 0.32-0.86, p=0.010), but not for ERalphaS305-P-positive tumours (multivariate HR=1.01, 95% CI 0.33-3.05, p=0.99) (interaction p=0.131). Notably, ERalphaS305-P was not significantly associated with RFS in patients not treated with tamoxifen (multivariate HR=0.64, 95% CI 0.30-1.37, p=0.248), indicating that ERalphaS305-P is a marker for treatment outcome rather than tumour progression. Given the direct experimental link between ERalphaS305-P and tamoxifen resistance and these first clinical data suggesting that premenopausal patients with ERalphaS305-P-positive breast cancer are resistant to adjuvant tamoxifen, further research is encouraged to study whether alternative endocrine treatment should be considered for this subgroup.     

Prognostic value of hormone receptor status conversion following neoadjuvant chemotherapy in a series of operable breast cancer patients

Background: To investigate the prognostic value of hormone receptor (HR) status conversion after neoadjuvant chemotherapy (NAC) in patients with primary breast cancer. Methods: 267 stage II-III breast cancer patients treated with NAC who had residual disease in the breast after NAC were retrospectively studied. The patients were divided into four groups based on the HR status: Group A, patients with HR-positive both before and after NAC; Group B, patients with HR status positive-to-negative change; Group C, patients with HR status negative-to-positive change; Group D, patients with HR-negative both before and after NAC. Patients with positive HR status (regardless of before or after NAC) were treated with adjuvant endocrine therapy, and a survival analysis was performed. Results: In total, 15.7% of patients had HR status change after NAC. progression-free survival (PFS) in Group A was similar to that in Group C (hazard ratio, 1.16; P = 0.652), but that in Group B was significantly lesser than that in Group A (hazard ratio, 6.88; P = 0.001), and that in Group C was significantly longer than that in Group D (hazard ratio, 6.88; P = 0.001). A similar pattern of results was obtained for overall survival (OS). Conclusions: The switch of HR status after NAC is remarkable for breast cancer. An HR switch may identify patients who would benefit from adjuvant endocrine therapy and impact the long-term outcome.     

Evaluation of oestrogen and progesterone receptor status in HER-2 positive breast carcinomas and correlation with outcome

AIM: HER-2/neu amplification occurs in 15-25% of breast carcinomas. This oncogene, also referred to as c-erbB-2, encodes a transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor family. HER-2 over-expression is reported to be associated with a poor prognosis in breast carcinoma patients and in some studies is associated with a poorer response to anti-oestrogen therapy. These patients are less likely to benefit from CMF (cyclophosphamide, methotrexate, fluorouracil)-based chemotherapy compared with anthracycline-based chemotherapy. The aim of this study was to evaluate breast carcinomas to determine hormone receptor status and if there is a difference in breast cancer specific survival for HER-2 positive patients. METHODS: A total of 591 breast carcinomas were evaluated using immunohistochemistry (IHC) for oestrogen receptor (ERp), progesterone receptor (PRp) and three different HER-2 antibodies (CB11, A0485 and TAB250). Percentage of tumour cells and intensity of staining for ERp were evaluated using a semiquantitative method. RESULTS: Of the 591 tumours, 91 (15.4%) showed 3+ membrane staining for HER-2 with one or more antibodies. Of these 91 tumours, 41 (45.1%) were ERp+/PRp+, seven (7.7%) were ERp+/PR-, six (6.6%) were ERp-/PRp+ and 37 (40.7%) were ERp-/PR-. Of HER-2 positive tumours, 5.5% showed >80% 3+ staining for ERp compared with 31.8% of 0-2+ HER-2 tumours; 24.2% of HER-2-positive tumours showed 60% or more cells with 2+ or 3+ staining for ERp. Treatment data were available for 209 patients and no difference was observed in breast cancer specific survival (BCSS) with HER-2 status and tamoxifen. CONCLUSION: Oestrogen receptor status cannot be used to select tumours for evaluation of HER-2 status, and oestrogen and progesterone receptor positivity does not preclude a positive HER-2 status. There is a higher proportion of ERp negative tumours associated with HER-2 positivity, however, more than 20% of HER-2 positive tumours show moderate or strong staining for ERp. HER-2 positive patients in this study did not show an adverse BCSS with tamoxifen treatment unlike some previous studies.     

Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response

ABSTRACT: BACKGROUND: This study was performed to determine if a chemotherapy-induced apoptosis assay (MiCK) could predict the best therapy for patients with ovarian cancer. METHODS: A prospective, multi-institutional and blinded trial of the assay was conducted in 104 evaluable ovarian cancer patients treated with chemotherapy. The MiCK assay was performed prior to therapy, but treating physicians were not told of the results and selected treatment only on clinical criteria. Outcomes (response, time to relapse, and survival) were compared to the drug-induced apoptosis observed in the assay. RESULTS: Overall survival in primary therapy, chemotherapy naive patients with Stage III or IV disease was longer if patients received a chemotherapy which was best in the MiCK assay, compared to shorter survival in patients who received a chemotherapy that was not the best. (p < 0.01, hazard ratio HR 0.23). Multivariate model risk ratio showed use of the best chemotherapy in the MiCK assay was the strongest predictor of overall survival (p < 0.01) in stage III or IV patients. Standard therapy with carboplatin plus paclitaxel (C + P) was not the best chemotherapy in the MiCK assay in 44 % of patients. If patients received C + P and it was the best chemotherapy in the MiCK assay, they had longer survival than those patients receiving C + P when it was not the best chemotherapy in the assay (p = 0.03). Relapse-free interval in primary therapy patients was longer if patients received the best chemotherapy from the MiCK assay (p = 0.03, HR 0.52). Response rates (CR + PR) were higher if physicians used an active chemotherapy based on the MiCK assay (p = 0.03). CONCLUSION: The MiCK assay can predict the chemotherapy associated with better outcomes in ovarian cancer patients. This study quantifies outcome benefits on which a prospective randomized trial can be developed.     

不同治疗方法对绝经后乳腺癌患者骨密度的影响

目的 探讨不同治疗方法 对绝经后乳腺癌患者骨密度(BMD)的影响.方法 研究分为健康对照组(50例)、肿瘤组[48例,其中24例再行他莫昔芬(TAM)组治疗].采用双能X线骨密度仪(DEXA)测定所有研究对象的基线BMD.肿瘤组术后均进行辅助化疗,其中24例(TAM组)化疗后继续使用TAM行内分泌治疗.用DEXA测量腰椎和左髋部位的BMD,比较肿瘤组化疗前、后以及TAM组行内分泌治疗8个月后BMD变化.结果 肿瘤组化疗后腰椎部位BMD(0.87±0.15)g/cm2比化疗前(0.93±0.15)g/cm2明显降低(P<0.05);TAM组行内分泌治疗8个月后腰椎BMD(0.90±0.04)g/cm2和股骨颈(0.74±0.05)g/cm2等左髋部位的BMD均有明显增加(P<0.05).结论 化疗可能导致绝经后乳腺癌患者BMD的下降,而TAM治疗能缓解化疗引起的BMD降低.     

Ovarian cyst formation in two pre-menopausal patients treated with tamoxifen for breast cancer

Pre-menopausal tamoxifen treatment causes hyperoestrogen productionand ovarian cyst formation. Two pre-menopausal breast cancerpatients who were treated with tamoxifen developed both permanentsupraphysiological oestrogen concentration and ovarian cysts.Serum oestrogen decreased to post-menopausal concentrationsand ovarian cysts completely resolved during and following simultaneoustreatment with tamoxifen and gonadotrophin-releasing hormoneagonist (GnRHa). In pre-menopausal breast cancer patients, GnRHamay prevent possible side-effects of tamoxifen, such as ovariancysts and supraphysiological oestrogen production.     

Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer

OBJECTIVE: Hormones have been implicated as modulators of cognitive functioning. For instance, results of our previous work in women with breast cancer showed that cognitive impairment was more severe and involved more memory domains in those who received adjuvant tamoxifen therapy compared with women who received chemotherapy alone or no adjuvant therapy. Recently aromatase inhibitors such as anastrozole have been used in lieu of tamoxifen for the adjuvant treatment of postmenopausal women with hormone receptor-positive, early-stage breast cancer. Plasma estrogen levels are significantly lower in women who receive anastrozole compared with those who receive tamoxifen. We hypothesized, therefore, that anastrozole would have a more profound effect on cognitive function than tamoxifen, a mixed estrogen agonist/antagonist. DESIGN: To test this hypothesis we compared cognitive function in women with early-stage breast cancer who received tamoxifen with those who received anastrozole therapy in a cross-sectional study. We evaluated cognitive function, depression, anxiety, and fatigue in 31 postmenopausal women with early-stage breast cancer who were between the ages of 21 and 65 years and treated with tamoxifen or anastrozole for a minimum of 3 months. RESULTS: The results showed that women who received anastrozole had poorer verbal and visual learning and memory than women who received tamoxifen. CONCLUSIONS: Additional, prospective studies are needed to validate and confirm the changes in cognitive function associated with hormone therapy for breast cancer.     

Assessment of hormone receptor status in breast cancer

The aim of the present paper was to investigate the most adequate method for the assessment of hormone receptor status in breast cancer in routine clinical settings. Subjects were 486 patients with primary breast cancer who underwent surgery and postoperative tamoxifen monotherapy in 1982-1993. Using representative sections of the primary lesion in each patient, estrogen receptors (ER) were immunohistochemically stained. Patients were divided into ER-positive and ER-negative groups using various methods, and then overall and 5 year recurrence-free survival rates were compared. The results of ER status, which are diagnosed on entire cancer area and invasive cancer area, matched in 98% of cases. When assessing prognosis based on the proportion of positive cells, a significant difference in 5 year recurrence-free survival was seen between ER-positive and ER-negative patients for a cut-off of 10%, and in overall and 5 year survival for a cut-off of 33%. Based on the proportion and the intensity of positive cells (Allred score), a significant difference was seen in overall and 5 year survival for a cut-off in total scores between 4 and 5 points. When assessing hormone receptors of breast cancer in routine clinical settings, it is sufficient to determine the proportion of positive cells in the entire cancer area.     

年轻早期子宫内膜癌患者保留卵巢的安全性及预后

目的探讨年轻的I期子宫内膜癌患者保留卵巢的安全性及预后。方法回顾性分析北京协和医院2005年1月至2011年12月间接受手术治疗的年龄≤45岁的I期子宫内膜癌患者的临床病理资料。根据术中是否保留卵巢分为保留卵巢组和切除卵巢组,比较分析两组的临床病理特征及预后。结果研究共纳入患者72例,其中保留卵巢组25例(34.7%),切除卵巢组47例(65.3%)。保留卵巢组患者与切除卵巢组患者相比更年轻(P=0.007),并且接受淋巴结切除的比例明显低于保留卵巢组患者(P0.001)。两组患者在分期、肿瘤分级、肌层浸润深度以及术后辅助治疗方面均无统计学差异(P0.05)。72例患者的中位随诊时间为89个月(7~131月),共有5例患者复发,没有患者死亡。Kaplan-Meier生存曲线及log rank检验显示两组的无复发生存时间无差异(P=0.194)。COX风险回归分析发现保留卵巢对无复发生存期无影响(HR=3.08,95%CI 0.54~18.44)。结论年轻的早期子宫内膜癌患者保留卵巢是安全的,对患者的无复发生存时间无显著影响。     

The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer

BACKGROUND: Reproductive function following cancer treatment is of increasing importance with improving survival rates. We therefore assessed the markers of the ovarian reserve in premenopausal women, to investigate and compare the effects of chemotherapy and long-term gonadotrophin withdrawal on ovarian function. METHODS: Fifty premenopausal (age range 28-52 years) women with early breast cancer were recruited. Serum hormone and ovarian ultrasound measurements were taken before treatment and at intervals up to 1 year during chemotherapy or gonadotrophin suppressive therapy. RESULTS: Pretreatment samples indicated a fall in anti-Müllerian hormone (AMH) concentration with age before changes in other hormone concentrations. AMH concentration showed a rapid and marked fall during chemotherapy, with undetectable concentrations in many women (P<0.0001). Inhibin B concentration showed a lesser fall (P<0.0001), whereas estradiol (E2) concentrations were maintained. Both antral follicle count (AFC) and ovarian volume fell (P<0.0001 and P<0.05 respectively). Regimens containing taxanes in addition to cyclophosphamide showed increased gonadotoxicity. Gonadotrophin suppression resulted in expected falls in E2 (P<0.05) and inhibin B (P<0.001) levels, but also resulted in a delayed fall in AMH level after 6 months (P<0.0001). CONCLUSIONS: These data confirm the value of AMH concentration as an early indicator of ovarian ageing including assessment of chemotherapy-induced ovarian follicle loss. FSH and AMH concentration measurements may be useful for the comparison of ovarian toxicity of different chemotherapy regimens.     

Contemporary treatment methods in primary breast carcinoma

Surgery for primary breast carcinoma is the method of choice. The use of the so-called conservative (sparing) techniques greatly improves late outcomes. Thus, five-year survival in patients with early cancer stages after radical resections followed by radiation therapy was 87.6% and relapse-free survival was 80.4%. Six courses of adjuvant chemotherapy in 400 patients with Stage IIb provided 5-year overall survival in 81.3% of cases and relapse-free survival in 73.7%. Neoadjuvant chemo- and radiation therapy followed by radical mastectomy preserving both breasts and adjuvant chemo- and hormone therapy increases five-year overall and relapse-free survival up to 71.6 and 41.6%, respectively. The promises of improving therapeutical outcomes are associated with early and, in some cases, preclinical diagnosis.     

伴有浸润性微乳头状癌结构乳腺癌的诊断和预后研究

目的探讨伴有浸润性微乳头状癌（IMPC）结构乳腺癌的临床病理特征和诊断标准及其与预后相关因素的关系。方法复习1989—2001年间乳腺癌存档切片,按2003年WHO乳腺病理学标准诊断含有IMPC结构的乳腺癌100例,98例获得随访结果。结果100例具有IMPC结构乳腺癌中,淋巴管侵犯率69％（69／100）,淋巴结转移率84．8％（84／99）;98例平均随访60．1个月。结果显示,11．2％（11／98）局部复发（术后平均存活26．4个月）,38．8％（38／98）远位转移（术后平均存活36．0个月）,36．7％（36／98）死于肿瘤,术后5年生存率59％,10年生存率48％;单因素及多因素生存分析均显示有肿瘤家族史及淋巴管侵犯的患者预后差,内分泌治疗可降低患者死亡的风险,单因素生存分析显示术后化疗可提高患者生存率。结论伴有IMPC结构的乳腺癌是一种预后极差的恶性肿瘤,无论肿瘤中IMPC结构比例占多少都应引起重视,预后与肿瘤家族史、淋巴管侵犯有关,内分泌治疗及个体性化疗可能是提高生存率的有效方法。     

Sertoli-Leydig cell tumour in an infertile patient after stimulated ovulation

A 36 year-old infertile female developed a stage IV (FIGO) ovarian carcinoma consisting of a poorly differentiated Sertoli-Leydig cell tumour after receiving one course of ovulation induction with follicle stimulating hormone (FSH), human menopausal gonadotrophin (HMG) and human chorionic gonadotrophin (HCG) followed by gonadotrophin-releasing hormone analogue (GnRHa). The patient died of liver metastasis and hepatic failure 4 1/2 months after first diagnosis, despite aggressive treatment consisting of debulking surgery and aggressive adjuvant chemotherapy.      

c-myc amplifications in primary breast carcinomas and their local recurrences

OBJECTIVE: To evaluate the role of c-myc oncogene amplifications in the progression of invasive breast carcinomas. METHODS: c-myc gene copy number was evaluated in a series of 49 primary breast carcinomas and the corresponding local recurrences using fluorescence in situ hybridisation. RESULTS: 11 of the primary carcinomas (22%) harboured c-myc amplifications; these tumours typically were hormone receptor negative and occurred in younger patients (43 v 53 years). At the time of relapse, six additional tumours had acquired a c-myc amplification. The mean recurrence-free survival was 24 months; c-myc amplified tumours relapsed significantly earlier than carcinomas without amplification (18 v 27 months). Univariate analysis showed a worse overall survival in these patients. CONCLUSIONS: While c-myc amplifications can be observed in early stage breast cancer, especially in younger patients, they often occur later in tumour development and appear to be associated with disease progression.     

The First Case of HER2+ Invasive Ductal Carcinoma Arising From a Breast Hamartoma and Literature Review

Carcinomas arising from breast hamartomas are exceedingly rare. We present the first reported case of an African-American female presenting with a right breast lump and a subsequent mammogram suggestive of a hamartoma. She later underwent lumpectomy and was found to have HER2+ invasive ductal carcinoma (IDC) arising from a hamartoma. She was amenable to HER2-targeted trastuzumab, hormone therapy and adjuvant radiation but declined chemotherapy. In a review of the literature, IDC is the predominant neoplastic type found in hamartomas. The average hamartoma size at time of neoplasm diagnosis is 6.0 cm. Patients with hamartomas greater than 6.0 cm, with changes in calcification pattern; new nodules or asymmetry should be considered for additional evaluation with ultrasound, MRI and/or biopsy. HER2 status is under-reported among cases and should be evaluated in any malignancy found within hamartomas as HER-2 therapy has improved overall survival and recurrence free survival in HER2+breast cancer patients.     

Survival in women with ovarian cancer before and after the introduction of adjuvant paclitaxel; a 25-year, single institution review

Adjuvant chemotherapy regime for ovarian cancer patients remains to be a contentious issue. The aim of this study was to compare the overall and progression-free survival of women with ovarian cancer before and after introduction of paclitaxel in our unit in 1992. A sample of 112 women who received adjuvant therapy following surgery for ovarian cancer was collected, 68 (61%) received platinum+alkylating agent before 1992 and later 44 (39%) received platinum+paclitaxel. Five-year survival was same in both treatment groups when there was no macroscopic disease after surgery (78% versus 70%) and when residual disease was <2 cm (50% versus 40%). Survival was greater in women with residual disease >2 cm in the platinum+paclitaxel group (50% versus 24%), (p = 0.04). However, progression-free survival was similar in both groups irrespective of stage or residual volume of disease. Therefore consideration to selective use of paclitaxel could reduce patient morbidity and costs significantly.     

De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype

Breast cancer molecular subtypes, categorized jointly by hormone receptors (HR) and human epidermal growth factor-2 (HER2), are utilized to guide systemic therapy. We hypothesized distinct patterns of de novo metastasis and overall survival by molecular subtype using a retrospective cohort of 399,772 women in the National Cancer Database diagnosed with first primary invasive breast cancer between 2010 and 2014, of whom 13,924 were diagnosed with de novo metastasis from 2010 to 2013 and had follow up data. The relationship of molecular subtype with patient and tumor characteristics, including site of de novo metastasis, were examined using Chi-squared tests. Kaplan–Meier and Cox proportional hazards analyses were used to examine overall survival by molecular subtype. Bone was the most frequent de novo metastatic site for all molecular subtypes. Compared to HR+/HER2?, patients with HR?/HER2+ experienced 4.5, 3.0, and 6.0 times the de novo brain, lung, and liver metastasis respectively. In survival analyses of women diagnosed with de novo metastasis, the mortality risk relative to HR+/HER2? was twice as high for triple-negative (hazard ratio?=?2.02, 95% CI 1.89–2.16) and modestly lower for HR+/HER2+ (hazard ratio?=?0.83, 95% CI 0.78–0.88). The median survival difference between metastatic patients with and without chemotherapy was 28.6 months in HR+/HER2+ and 28.2 months in HR?/HER2+, but only 10.9 months in triple-negative and 5.2 months in HR+/HER2?. In conclusion, despite unfavorable patterns of de novo metastasis, HER2+ breast cancers had relatively better survival in recent years, probably due to treatment differences. Utilizing molecular subtype and site of de novo metastasis may predict prognosis and guide treatment.