Changes in breast density and circulating estrogens in postmenopausal women receiving adjuvant anastrozole

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: -16%, 95% CI: -30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: -93%, 95% CI: -94 to -91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes.     

Use of dual mTOR inhibitor MLN0128 against everolimus-resistant breast cancer

Purpose

HR+/HER2? aromatase inhibitor-resistant metastatic breast cancer can be treated with everolimus and a second AI until the cancer recurs. Targeting these everolimus-resistant patients with the latest standard of care, CDK4/6 inhibitors, has not been clearly addressed. Understanding the signaling transduction pathways, which everolimus resistance activates, will elucidate the mechanisms and offer treatment strategies of everolimus resistance.

Methods

To mimic the clinical setting, letrozole-resistant cells were used to generate an everolimus-resistant model (RAD-R). Reverse phase protein array (RPPA) was performed to reveal changes in the signaling transduction pathways, and expression levels of key proteins were analyzed. Inhibitors targeting the major signaling pathways, a CDK4/6 inhibitor palbociclib and a mTORC1/2 inhibitor (MLN0128), were evaluated to establish resistance mechanisms of RAD-R.

Results

RPPA results from RAD-R indicated changes to significant regulatory pathways and upregulation of p-AKT expression level associating with everolimus resistance. MLN0128, that inhibits the AKT phosphorylation, effectively suppressed the proliferation of RAD-R cells while treatment with palbociclib had no effect.

Conclusion

Among the many signaling transduction pathways, which are altered post everolimus resistance, targeting dual mTORC1/2 is a possible option for patients who have recurrent disease from previous everolimus treatment.

     

213Bi (alpha-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model

Treatment failure in breast cancer is largely the failure to control metastatic dissemination. In this study, we investigated the efficacy of an antibody against the rat variant of HER-2/neu, labeled with the alpha-particle emitter (213)Bi to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination of tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 muCi of (213)Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 muCi (213)Bi-7.16.4, (b) 90 muCi (213)Bi-7.16.4, (c) 120 muCi (213)Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 muCi (213)Bi-7.16.4 increased median survival time to 41 days compared with 28 days for the untreated controls (P < 0.0001); corresponding median survival times for groups b, c, and d were 36 (P < 0.001), 31 (P < 0.01), and 33 (P = 0.05) days, respectively. Median survival relative to controls was not significantly improved in mice injected with 10-fold less cells or with multiple courses of treatment. We concluded that alpha-emitter (213)Bi-labeled monoclonal antibody targeting the HER-2/neu antigen was effective in treating early-stage HER-2/neu--expressing micrometastases. Analysis of the results suggests that further gains in efficacy may require higher specific activity constructs or target antigens that are more highly expressed on tumor cells.     

Ceftaroline for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus: a case series

Despite limited clinical data, ceftaroline is commonly used for treatment of complicated, invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). A retrospective chart review was conducted of adult patients receiving ceftaroline for MRSA osteomyelitis admitted between April 2011 and March 2016 at a five-hospital system. Twelve patients met the inclusion criteria. All patients received prior antimicrobial therapy with a median time to switch to ceftaroline of 45.5 days. Five of the 12 patients (41.7%) met criteria for ceftaroline failure. Patients with vertebral osteomyelitis (58%) had a longer length of stay, longer ceftaroline treatment, but similar success rates to those with non-vertebral osteomyelitis (57% vs. 60%). Ceftaroline is a viable alternative for a challenging patient population that has failed or are unable to receive other therapies.     

Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat)

Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.     

A dual-center randomized controlled double blind trial assessing the effect of acupuncture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors

Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85–274) at baseline, 35 pg/mL (12–64) at 6-weeks, 29 pg/mL (17–48) at 6 months and 25 pg/mL (8–46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.     

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.     

Comparison of breast cancer recurrence risk and cardiovascular disease incidence risk among postmenopausal women with breast cancer

The majority of breast cancers are diagnosed in postmenopausal women. Competing comorbidities, particularly cardiovascular disease (CVD), should be considered when individualizing adjuvant therapies for these women. We compared the 10-year predicted breast cancer recurrence risk with CVD risk among postmenopausal women with hormone receptor-positive (HR+), non-metastatic breast cancer. CVD risk factor data were prospectively collected from postmenopausal women with stage I-III, HR+?breast cancer initiating adjuvant aromatase inhibitor therapy. We compared predicted 10-year CVD risk, including the composite index heart age, computed from modified Framingham risk score, with predicted 10-year risk of breast cancer recurrence using Adjuvant! Online. We created multivariable logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (CI) for greater CVD risk than breast cancer recurrence risk. Among 415 women, mean age and heart age were 60 and 67?years, respectively. Overall, 43% of women had a predicted 10-year CVD risk equivalent to breast cancer recurrence risk and 37% had CVD risk higher than breast cancer recurrence risk. Predicted CVD risk was higher than breast cancer recurrence risk for stage I disease (OR: 6.1, 95% CI: 3.4-11.2) or heart age >65 (OR: 12.4, 95% CI: 7.0-22.6). The majority of postmenopausal women with HR+ early breast cancer had a predicted 10-year CVD risk that was equivalent to or higher than breast cancer recurrence risk. Physicians should weigh competing risks and offer early screening and cardiac prevention strategies for women at a greater risk for CVD.