Erythema nodosum secondary to aromatase inhibitor use in breast cancer patients: case reports and review of the literature

Aromatase inhibitors (AI’s) are increasingly being incorporated in the treatment strategy for hormone receptor positive breast cancer either alone or in combination with chemotherapy, biologics in both the adjuvant and metastatic setting [1]. They markedly suppress plasma estrogen levels by inhibiting or inactivating aromatase, the enzyme responsible for the synthesis of estrogens from androgenic substrates [1]. Currently, the three selective aromatase inhibitors that are available are anastrozole, letrozole and exemestane which reduce circulating estrogen to 1 to 10% of pretreatment levels [2]. For advanced breast cancer, aromatase inhibitors appear to be at a minimum, equivalent and perhaps even better than tamoxifen in the first line setting [3, 4]. In primary breast cancer, adjuvant therapy with anastrozole or letrozole appears to be superior to tamoxifen in reducing the risk of relapse [5, 6]. Common adverse effects associated with AI’s include arthralgias (21%), myalgias (12%), other musculoskeletal disorders (28%) and an up to 60% increased risk of bone fracture [7, 8]. However, anastrozole, exemestane and letrozole are associated with significantly fewer endometrial cancers, as well as venous and arterial vascular events, when compared with tamoxifen [9, 10]. Very rarely letrozole and anastrozole can cause a skin rash; the frequency of its occurrence has not been quantified^. However, exemestane has not been reported to cause a skin rash [11]. To date, erythema nodosum (EN) has not been reported as a dermatologic side effect of AI’s. Here, we report three cases of EN which developed in postmenopausal breast cancer patients on AI’s.     

乳腺癌芳香化酶抑制剂耐药的研究进展

乳腺癌是女性常见的恶性肿瘤,约70％的患者为雌激素受体(estrogen receptor,ER)和(或)孕激素受体(progesterone receptor,PR)阳性,内分泌治疗是激素受体(hormone receptor,HR)阳性乳腺癌的主要治疗方式之一.近几十年来,内分泌治疗药物不断发展并应用于临床,乳腺癌...     

Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer

Purpose  Clinical trials have reported conflicting results as to whether pre-operative aromatase inhibitors (AIs) improve outcome over pre-operative tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. Methods  We performed a meta-analysis comparing primary and secondary end points of pre-operative AI and pre-operative tamoxifen. The event-based risk ratio (RR) with 95% confidence intervals (95% Cis) were derived, and a test of heterogeneity was applied. Results  Four studies (1,160 patients) met the inclusion criteria for the analysis. Meta-analysis showed that pre-operative AI was more effective than pre-operative tamoxifen. Pooled results of clinical efficacy were as follows: clinical objective response rate (RR, 1.29; 95% CI, 1.14–1.47; P < 0.001), ultrasound objective response rate (RR, 1.29; 95% CI, 1.10–1.51; P = 0.002), and breast conserving surgery (BCS) rate (RR, 1.36; 95% CI, 1.16–1.59; P < 0.001). Hot flashes, nausea, and fatigue were not different between the pre-operative AI and pre-operative tamoxifen groups. Although headache was more frequent in the pre-operative AI group (P = 0.011), it was a manageable toxicity and was not clinically relevant. Conclusion  Pre-operative AI has better BCS rate than tamoxifen and in terms of toxicities, is not inferior to tamoxifen; therefore, we could suggest pre-operative AI instead of tamoxifen for those postmenopausal patients with hormone receptor positive breast cancer, not eligible for chemotherapy.     

Erythema multiforme and dermatitis seborrhoides infantum as concomitant id-reactions to widespread candidosis in a suckling

The case of a young suckling is reported in whom widespread candidosis of the napkin area was followed by the clinical signs of both erythema multiforme and dermatitis seborrhoides infantum. Both these diseased states are considered as candidids.     

Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study

Background:

Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances.

Methods:

We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors.

Results:

Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5⁺). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies.

Conclusion:

Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy.     

Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy

: To present our clinical experience using intensity-modulated radiation therapy (IMRT) to improve dose uniformity and treatment efficacy in patients with early-stage breast cancer treated with breast-conserving therapy.

: A total of 281 patients with Stage 0, I, and II breast cancer treated with breast-conserving therapy received whole breast RT after lumpectomy using our static, multileaf collimator (sMLC) IMRT technique. The technical and practical aspects of implementing this technique on a large scale in the clinic were analyzed. The clinical outcome of patients treated with this technique was also reviewed.

: The median time required for three-dimensional alignment of the tangential fields and dosimetric IMRT planning was 40 and 45 min, respectively. The median number of sMLC segments required per patient to meet the predefined dose-volume constraints was 6 (range 3–12). The median percentage of the treatment given with open fields (no sMLC segments) was 83% (range 38–96%), and the median treatment time was <10 min. The median volume of breast receiving 105% of the prescribed dose was 11% (range 0–67.6%). The median breast volume receiving 110% of the prescribed dose was 0% (range 0–39%), and the median breast volume receiving 115% of the prescribed dose was also 0%. A total of 157 patients (56%) experienced Radiation Therapy Oncology Group Grade 0 or I acute skin toxicity; 102 patients (43%) developed Grade II acute skin toxicity and only 3 (1%) experienced Grade III toxicity. The cosmetic results at 12 months (95 patients analyzable) were rated as excellent/good in 94 patients (99%). No skin telengiectasias, significant fibrosis, or persistent breast pain was noted.

: The use of intensity modulation with our sMLC technique for tangential whole breast RT is an efficient method for achieving a uniform and standardized dose throughout the whole breast. Strict dose-volume constraints can be readily achieved resulting in both uniform coverage of breast tissue and a potential reduction in acute and chronic toxicities. Because the median number of sMLC segments required per patient is only 6, the treatment time is equivalent to conventional wedged-tangent treatment techniques. As a result, widespread implementation of this technology can be achieved with minimal imposition on clinic resources and time constraints.     

The role of aromatase inactivators in the treatment of breast cancer

 Third-generation aromatase inhibitors and inactivators have earned their place in the treatment of metastatic breast cancer. The third-generation aromatase inactivator exemestane was found to be superior to megestrol acetate as second-line endocrine therapy in postmenopausal women, with respect to time to progression as well as overall survival, and the results from an ongoing study comparing exemestane with tamoxifen in first-line treatment are promising. The finding that exemestane may also work in patients previously exposed to nonsteroidal aromatase inhibitors reveals lack of complete cross-resistance between the compounds. Currently, exemestane given as monotherapy, or in sequence with tamoxifen (2-3 + 3-2 years of tamoxifen-exemestane or 5 years of tamoxifen followed by 2 years of exemestane) is being compared with tamoxifen 5 years monotherapy in the adjuvant setting. In addition, we are currently addressing the toxicity of exemestane in a placebo-controlled trial in low-risk breast-cancer patients. The results from these studies will outline the potential role of exemestane in adjuvant treatment and, potentially, for breast-cancer prevention in postmenopausal women. Received: April 1, 2002     

The impact of comorbidities on outcomes for elderly women treated with breast-conservation treatment for early-stage breast cancer

PURPOSE: Breast cancer incidence increases with age and is a major cause of morbidity and mortality in elderly women, but is not well studied in this population. Comorbidities often impact on the management of breast cancer in elderly women. METHODS AND MATERIALS: From 1979 to 2002, a total of 238 women aged 70 years and older with Stage I or II invasive carcinoma of the breast underwent breast-conservation therapy. Outcomes were compared by age groups and comorbidities. Median age at presentation was 74 years (range, 70-89 years). Age distribution was 122 women (51%) aged 70-74 years, 71 women (30%) aged 75-79 years, and 45 women (19%) aged 80 years or older. Median follow-up was 6.2 years. RESULTS: On outcomes analysis by age groups, 10-year cause-specific survival rates for women aged 70-74, 75-79, and 80 years or older were 74%, 81%, and 82%, respectively (p = 0.87). Intercurrent deaths at 10 years were significantly higher in older patients: 20% in those aged 70-74 years, 36% in those aged 75-79 years, and 53% in those 80 years and older (p = 0.0005). Comorbidities were not significantly more common in the older age groups and did not correlate with cause-specific survival adjusted for age. Higher comorbidity scores were associated with intercurrent death. CONCLUSIONS: Older age itself is not a contraindication to standard breast-conservation therapy, including irradiation. Women of any age with low to moderate comorbidity indices should be offered standard breast-conservation treatment if otherwise clinically eligible.     

Current opinion of aromatase inhibitor-induced arthralgia in breast cancer in the UK

Aims

Aromatase inhibitors are now a standard of care in the management of hormone-responsive early breast cancer in postmenopausal women. The troublesome side-effect of arthralgia remains a distinct clinical problem, with limited data on its aetiology and management. The aim of this questionnaire study was to evaluate the opinion of UK breast cancer clinicians on the importance of this treatment side effect.

Materials and methods

In 2009, a questionnaire was sent to 772 breast surgeons and oncologists who manage breast cancer within the UK. The questionnaire evaluated the importance, investigation, management and the need for guidelines for aromatase inhibitor-induced arthralgia (AIA).

Results

Four hundred and sixteen (54%) returned questionnaires were suitable for analysis. By specialty, 234 (56%) were completed by breast surgeons, 134 (32%) by clinical oncologists, 45 (11%) by medical oncologists and one by a general surgeon. Three hundred and eighty-three (92%) specialists graded the importance of AIA as either very important or important; 211 (51%) did not know the aetiology of AIA; 280 (68%) did not perform bloods; 254 (61%) did not request radiology and 251 (60%) felt management was the responsibility of the oncologists. Three hundred and forty-nine (84%) considered that their practice would benefit from national guidelines.

Conclusion

This questionnaire has highlighted that AIA is a major patient concern. Further research, educational initiatives and guidance are needed to improve the management of this treatment complication.     

Recent perspectives of endocrine therapy for breast cancer

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.     

p53 accumulation is a strong predictor of recurrence in estrogen receptor‐positive breast cancer patients treated with aromatase inhibitors

Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)‐positive breast cancer in postmenopausal women. However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. Whole genome analysis identified that a TP53 gene mutation exists in ER‐positive breast cancers, although the frequency of TP53 gene mutation in luminal tumors is lower compared with basal‐like or human epidermal growth factor receptor type 2 (HER2)‐positive breast cancers. We examined expression of p53, as well as ER, progesterone receptor, HER2 and Ki‐67 using immunohistochemistry in postmenopausal ER‐positive breast cancer patients who were treated with aromatase inhibitors as adjuvant endocrine therapy. There were 53 (21%) tumors that contained 10% or more p53‐positive cells. High p53 expression was positively correlated with tumor grade, HER2 score and Ki‐67 expression. Significant association was observed between disease‐free survival and high p53 expression in multivariate analysis (P < 0.0001). Compared with women without recurrence, women with early recurrence had significantly higher p53 expression (P < 0.0001), as did women with late recurrence (P = 0.037). The present study demonstrates that p53 accumulation is a strong predictor of both early and late recurrence in ER‐positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy. TP53 gene alteration might be a key biological characteristic of ER‐positive breast cancer.     

Current topics and perspectives on the use of aromatase inhibitors in the treatment of breast cancer

Tamoxifen has played a central role in endocrine therapy for hormone-responsive breast cancer. Results of recent clinical trials have, however, clearly shown that third-generation aromatase inhibitors (AIs), such as anastrozole, letrozole and exemestane, are superior to tamoxifen in the treatment of postmenopausal patients with metastatic breast cancer, in an adjuvant setting and for early breast cancer. Many studies have been published that describe new results from clinical trials and how they fundamentally prove the efficacy of AIs. There are, however, still some unresolved issues concerning the applications of AIs, such as the optimal duration of the therapy, the optimal regimens (initial, adjuvant or switching from tamoxifen to AI), and combination with LH–RH agonists for premenopausal woman. These issues are discussed in this review. Additionally, further possibilities for the application of AIs, for example in combination therapy with pure antiestrogen aimed at complete estrogen blockade and in combination with new biological agents, as well as the pharmacogenomics of AIs will be discussed.     

Drug withdrawal in women with progressive metastatic breast cancer while on aromatase inhibitor therapy

Background:

Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients.

Methods:

A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression.

Results:

Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months.

Conclusions:

Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned.     

Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors

Purpose Aromatase inhibitors (AIs) are increasingly used as adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer. AIs are commonly associated with musculoskeletal symptoms. The primary objective of this study was to describe the musculoskeletal symptoms that developed in the first 100 subjects enrolled who had at least 6 months follow-up. Methods Women with early stage hormone receptor-positive breast cancer were recruited into a multicenter randomized clinical trial to study the pharmacogenomics of two AIs, exemestane, and letrozole. Patients completed the Health Assessment Questionnaire (HAQ) and Visual Analog Scale (VAS) at baseline, 1, 3, 6, and 12 months to assess changes in function and pain, respectively. Patients were referred for evaluation by a rheumatologist if their HAQ and/or VAS scores exceeded a predefined threshold. Results Forty-four of 97 eligible patients (45.4%) met criteria for rheumatologic referral. Three patients were ineligible because of elevated baseline HAQ (2) and failure to initiate AI therapy (1). No baseline characteristics were significantly associated with referral. Median time to onset of symptoms was 1.6 months (range 0.4-10 months). Clinical and laboratory evaluation of patients evaluated by rheumatology suggested that the majority developed either non-inflammatory musculoskeletal symptoms or inflammation localized to tenosynovial structures. Thirteen patients discontinued AI therapy because of musculoskeletal toxicity after a median 6.1 months (range 2.2-13 months). Conclusions Musculoskeletal side effects were common in AI-treated patients, resulting in therapy discontinuation in more than 10% of patients. There are no identifiable pre-therapy indicators of risk, and the etiology remains elusive.     

Aromatase inhibitor versus tamoxifen in postmenopausal woman with advanced breast cancer: a literature-based meta-analysis

Clinical trials have reported conflicting results as to whether Aromatase inhibitors (AIs) as first-line hormonal therapy improve outcome over tamoxifen in postmenopausal women with advanced breast cancer. We performed a meta-analysis comparing primary and secondary endpoints of AIs to tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. The event-based odds ratio (OR) with 95% confidence interval (95% CI) were derived, and a test of heterogeneity was applied. Six eligible trials (2560 patients) were selected from 488 studies that initially were identified. A significant difference in favoring AIs over tamoxifen was observed in overall response rate (ORR; OR, 1.56; 95% CI, 1.17-2.07; P = .002) and clinical benefit (CB; OR, 1.70; 95% CI, 1.24-2.33; P = .0009).Whereas the trend toward an improved overall survival (OS) rate was not significant (OR, 1.95; 95% CI, 0.88-4.30; P = .10).Toxicities did not differ significantly except vaginal bleeding (OR, 0.30; 95% CI, 0.16-0.56; P = .0002) and thromboembolic event (OR, 0.47; 95% CI, 0.28-0.77; P = .003). AIs appeared to be effective and feasible compared with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Further prospective, randomized, controlled trials will be necessary.     

乳腺癌芳香化酶抑制剂耐药分子机制研究进展

芳香化酶抑制剂（ aromatase inhibitors,AIs）在绝经后雌激素依赖性乳腺癌的治疗中取得了令人鼓舞的疗效。大型的临床试验ATAC和BIG 1-98均证明第三代芳香化酶抑制剂作为绝经后乳腺癌的辅助治疗可明显提高患者的无病生存期,疗效优于他莫昔芬。随着AIs在临床广泛应用及用药时间的延长,AIs耐药也成了临床医生不可回避的问题,至今国内尚没有对AIs耐药分子机制的详细报道,本文通过对国内外一些实验室和临床研究结果的综述,拟概述乳腺癌AIs耐药分子机制的研究进展。     

Efficacy of exemestane after nonsteroidal aromatase inhibitor use in metastatic breast cancer patients

Background: Previous studies have suggested a lack of complete cross-resistance between steroidal (exemestane) and non-steroidal aromatase inhibitors (nSAI). Methods: Eighty-eight metastatic breast cancer (MBC) patients who received 25 mg of exemestane orally once a day at the National Cancer Center, Korea, between 2003 and 2009, were reviewed retrospectively. All patients had received nSAI for metastatic disease prior to exemestane therapy. Results: The median age was 52 years (range, 33–79), and 13 (14.8%) patients were premenopausal who concomitantly received GnRH agonist. Exemestane was given as a second- (80.7%) or third-line (19.3%) hormone therapy. The clinical benefit (CB) rate (complete response + partial response + stable disease ≥ 24 weeks) was 30.7%, with a median CB duration of 10.0 months (range, 6.3–78.7). The median progression-free survival (PFS) was 3.0 months (95% confidence interval [CI], 1.99–4.01) and the overall survival (OS) 21.5 months (95% CI, 17.96–25.04), with a median follow-up of 50.3 months. Patients who achieved CB had longer OS than those patients who did not (29.6 vs 17.9 months; P = 0.002). On univariate analysis of predictive factors, patients who had achieved CB from previous nSAI tended to show lower CB rate (24.6% vs 44.4%, respectively; P = 0.063) and shorter PFS (2.8 vs 4.8 months, respectively; p = 0.233) than patients who had not. Achieving CB from previous nSAI became independent predictive factor for CBR to exemestane on multivariable analysis (Odds ratio = 2.852, P = 0.040). Conclusions: Exemestane after nSAI failure was effective in prolonging CB duration. The drug’s efficacy seemed to be inferior in patients who had benefit from previous nSAI use.