Rinat Yerushalmi

Metastatic behavior of breast cancer subtypes.

PURPOSE Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected. METHODS Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression. RESULTS Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most common metastatic site in all subtypes except basal-like tumors. In multivariate analysis, compared with luminal A tumors, luminal/HER2 and HER2-enriched tumors were associated with a significantly higher rate of brain, liver, and lung metastases. Basal-like tumors had a higher rate of brain, lung, and distant nodal metastases but a significantly lower rate of liver and bone metastases. TN nonbasal tumors demonstrated a similar pattern but were not associated with fewer liver metastases. CONCLUSION Breast cancer subtypes are associated with distinct patterns of metastatic spread with notable differences in survival after relapse.

Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study

BACKGROUND Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. METHODS In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783. FINDINGS 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]). INTERPRETATION Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed. FUNDING AstraZeneca.

Ki67 in breast cancer: prognostic and predictive potential

The leading parameters that define treatment recommendations in early breast cancer are oestrogen-receptor, progesterone-receptor, and human epidermal growth-factor status. Although some pathologists report Ki67 in addition to other biological markers, the existing guidelines of the American Society of Clinical Oncology do not include Ki67 in the list of required routine biological markers. The advent of new genetic tests has emphasised the role of proliferative genes, including Ki67, as prognostic and predictive markers. Additionally, randomised studies have retrospectively reviewed data and reported on the role of Ki67 in breast cancer. In light of new data, we have re-assessed evidence that could change guidelines to include Ki67 in the standard pathological assessment of early breast cancers. This review provides an update on the current knowledge on Ki67 and of the evidence in the published work about the prognostic and predictive role of this marker, and provides information on the laboratory techniques used to determine Ki67.

A Case-Match Study Comparing Unilateral With Synchronous Bilateral Breast Cancer Outcomes

PURPOSE There is controversy about whether patients with synchronous bilateral breast cancer (SBBC) have similar or worse outcomes compared with patients with unilateral breast cancer. The purpose of this study was to determine whether survival outcomes for patients with SBBC can be estimated from the characteristics of their individual cancers. PATIENTS AND METHODS Patients had invasive breast cancer, without metastases or inflammatory disease, diagnosed in British Columbia between 1989 and 2000. There were 207 cases with SBBC (diagnosed ≤ 2 months apart) and 15,497 with unilateral breast cancer. By using 10-year breast cancer-specific survival (BCSS) estimates, the higher-risk cancer of each SBBC case was determined and matched with three breast cancers from the unilateral cohort to select 621 high-risk matches. The priority sequence of matching the prognostic and predictive variables was positive lymph node number, primary tumor size, age, grade, lymphovascular invasion, estrogen receptor status, local therapy used, margin status, treating clinic, diagnosis year, and type of systemic therapy used. RESULTS With a median follow-up of 10.2 years, the overall 10-year BCSS was significantly higher for the unilateral cohort (81%; 95% CI, 81% to 82%) than for the SBBC cases (71%; 95% CI, 63% to 77%). The SBBC cases had significantly higher mean age and stage at presentation. The 10-year BCSS was 74% (95% CI, 69% to 77%) for the high-risk matches. CONCLUSION BCSS was not significantly different between the SBBC cases and their high-risk matches.

Long-Term Follow-Up of Chemotherapy-Induced Ovarian Failure in Young Breast Cancer Patients: The Role of Vascular Toxicity

BACKGROUND We previously reported that chemotherapy-induced ovarian toxicity may result from acute vascular insult, demonstrated by decreased ovarian blood flow and diminished post-treatment anti-Müllerian hormone (AMH) levels. In the present study, we report the continuous prospective evaluation of ovarian function in that cohort. METHODS Patients (aged <43 years) with localized breast cancer were evaluated by transvaginal ultrasound prior to initiation of chemotherapy, immediately at treatment completion, and at 6 and 12 months after treatment cessation. Doppler flow velocity indices of the ovarian vasculature (resistance index [RI], pulsatility index [PI]) were visualized. Hormone markers of ovarian reserve were assessed at the same time points. RESULTS Twenty patients were enrolled in the study. Median age was 34 ± 5.24 years. Ovarian blood flow was significantly reduced immediately following chemotherapy (both RI and PI; p = .01). These parameters were partially recovered at later points of assessment (6 and 12 months after treatment); patients aged <35 years significantly regained ovarian blood flow compared with patients aged >35 years (p < .05). AMH dropped dramatically in all patients following treatment (p < .001) and recovered in only 10 patients. Hormone markers of ovarian reserve shortly after chemotherapy depicted a postmenopausal profile for most patients, accompanied by related symptoms. Follicle-stimulating hormone (FSH) levels recovered in 14 of 20 patients and significantly returned to the premenopausal range in patients aged <35 years (p = .04); 10 of 20 resumed menses at 12 months. The pattern of vascular impairment was lessened in patients treated with a trastuzumab-based protocol, although results did not reach statistical significance (p = .068). CONCLUSION Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Age may affect whether patients regain ovarian function, whereas recovery of blood flow and premenopausal FSH levels at later assessment was notable in patients aged <35 years. IMPLICATIONS FOR PRACTICE This study explored the role of vascular toxicity in mediating ovarian impairment and recovery following chemotherapy. Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Future studies are warranted to further characterize patterns of vascular toxicity of various chemotherapies in clinical practice and to assess the role of chemotherapy-induced vascular toxicity for specific end organs such as the ovary with systemic vascular effect. Elucidating the cause of impairment may facilitate development of measures to minimize vascular toxicity and consequences of acute vascular insult.

Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma

Purpose: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody–drug conjugate (ADC) being developed for the treatment of breast cancer. Experimental Design: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys. Results: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy. Conclusions: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552–62. ©2015 AACR.

Early Breast Cancer in the Elderly: Characteristics, Therapy, and Long-Term Outcome

Objective: The number of older adults diagnosed with breast cancer is increasing. However, data on breast cancer characteristics, treatment, and survival in elderly women are sparse. Methods: The database of a tertiary cancer center was searched for all women aged ≥65 years who were diagnosed with early breast cancer in 2004-2007. Patients were divided into 2 age groups: 65-75 years and >75 years. Data on tumor, treatment, and outcome parameters were compared. Results: The cohort included 390 patients. The older group underwent more mastectomies but less axillary surgery or adjuvant systemic therapy. Median overall survival (OS) was 9.5 years in the older group and not reached in the younger group; the 8-year disease-free survival rates were 85 and 88%, respectively (p = 0.27). Both age and tumor subtype had an effect on OS and recurrence rates (p < 0.001 for OS; p = 0.16 for recurrence). The worst outcome was noted in women aged >75 years with triple-negative (TN) disease. Conclusion: The treatment approach was different between both age groups, despite similar tumor characteristics. TN subtype presented as the most aggressive disease in both age groups. Physicians should be alert to these findings and select treatment on a case-by-case basis.

Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion

Secretory breast carcinoma (SBC) is a rare histologic subtype of breast cancer (BC) with distinct pathologic features that usually belongs to the triple-negative BC spectrum. SBC has been shown to express ETV6-NTRK3 gene fusion in over 90% of SBCs, with its chimeric product thought to be the driving oncoprotein. Larotrectinib (LOXO-101) is a highly selective and potent inhibitor of the tropomyosin-related kinases (TRKs), and it has shown evidence of antitumor activity in patients with TRK fusions expressed in various adult and pediatric tumor types. We report what is to our knowledge the first case of an adult with advanced triple-negative SBC with a demonstrated ETV6-NTRK3 fusion. The patient experienced a rapid clinical and radiographic response to first-line larotrectinib therapy. This report illustrates the potential of molecularly targeted therapy; specifically, it highlights the fact that TRK fusions are a valid target in BC. Practitioners should become familiar with its therapeutic significance.

Chemotherapy for oestrogen-receptor-negative breast cancer.

In today’s Lancet, the large (96 trials) and updated meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) highlights the important achievements of the past 30 years in chemotherapy for oestrogen-receptor-negative early breast cancer. The meta-analysis suggests a benefi cial eff ect with chemotherapy in both node-negative and node-positive women, with a 10-year breast-cancer mortality reduction of 6–8% due to adjuvant treatment. These data should be used as a reference to study future adjuvant gains, but what will the impact be in the clinic? The studies in today’s meta-analysis are from an era when eligibility for trials was based on anatomical criteria of tumour size and nodal involvement. Oestrogen-receptor status was recorded, but many early studies did not limit enrolment by this criterion. Current adjuvant studies, by contrast, defi ne breast cancers by hormonal status and the presence or absence of ERBB2 (also known as HER2) overexpression—responsiveness and not simply risk now defi nes eligibility. Thus the extrapolations that we can make from the meta-analysis are broad strokes compared with the fi ner classifi cations that we use today and hope to refi ne in the future. The defi nition of oestrogen negativity is a problem. The EBCTCG acknowledges that oestrogen testing was not well validated and quality controlled, and some of the res ponses reported in this analysis might be ex plained by misclassifi cations of hormonal status. The vague term “oestrogen poor” used by the EBCTCG does con form to the data available from these older studies, but is unsatisfac tory now that existence and strength of oestrogenreceptor expression seems to be predictive. How ever, in 2008 we still lack universal testing guidelines and agreement on defi ning a low level of hormone sensitivity. The EBCTCG’s meta-analysis suggests that if “the best of the drug combinations tested in these trials were to be given optimally then appreciably better results might be achieved”. But how large would the eff ect be in specifi c populations? To estimate this benefi t, we need data on how many oestrogen-receptor-negative cancers would be classifi ed as “triple negative” compared with those in this oestrogen-receptor-negative cohort with overexpression of ERBB2 (triple negative means no receptors for oestrogen, progesterone, or ERBB2). Assuming a typical distribution we would expect about a third of patients to be ERBB2-positive, and they should do substantially better with trastuzumab than patients with ERBB2-negative tumours. This benefi t would be in addition to the benefi t of chemotherapy shown in today’s report. The term triple negative is itself being replaced as more descriptive terms arise from further classifi cations such as the basal subtype defi ned by CK5/6 and EGFR expression and the BRCA mutation subtype. Although there are suggestions of preferential responses to specifi c therapies in the metastatic and neoadjuvant settings, we are still desperately seeking the optimum adjuvant regimen for the triple-negative subgroup and new targets for therapy are being identifi ed. There are variations in the genetic make-up and behav iour of tumours within the triple-negative group. Genetic assays, such as the 21-gene recurrence score (Oncotype DX) and 70-gene MammaPrint are insinuating themselves into clinicians’ work as a guide to prediction of response to chemotherapy as well as a further prognostic tool. New studies have recently provided prognostic data for disease-free survival with use of these tests in node-positive women, which adds to previous data on node-negative patients. Pros pective trials, including TAILORX and MINDACT, are now recruiting women who are node-negative and oestrogenreceptor-positive. We need a robust prognostic and predictive test for oestrogen-receptor-negative or triple-negative patients, but unfortunately prospective validation will take years. See Articles page 29

Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging?

Purpose Though former evidence implies a correlation of breast cancer susceptibility gene (BRCA) mutation with reduced ovarian reserve, the data is yet inconsistent. Our aim was to investigate biomarkers of ovarian aging in a cohort of young healthy carriers of the BRCA mutation. We hypothesized that the role played by BRCA genes in aging pathways is not exclusive to the ovary. Experimental Design Healthy female BRCA carriers, 40 years or younger and healthy male BRCA carriers, 50 years or younger, were enrolled in the study. Serum anti-mullerian Hormone (AMH), fibroblast growth factor-23 (FGF-23), Klotho and IL-1 were measured by enzyme-linked immunosorbent assay (ELISA). Ovarian AMH and protein kinase B (AKT) mRNA from BRCA carriers who underwent prophylactic oophorectomy and from age-matched, healthy, non-carriers who underwent partial oophorectomy due to benign conditions were analyzed by qPCR. Results Thirty-three female (median age 35y) and 20 male (44y) BRCA carriers were enrolled into the study and matched to control non-carriers (34y and 43y, respectively). Serum AMH level was significantly lower in BRCA female carriers than in both non-carrier controls and age-matched nomograms. The levels of ovarian AMH and AKT mRNA were significantly lower in carriers than in controls. The systemic aging cytokines FGF-23, klotho and IL-1 displayed a differential expression in carriers of both genders. FGF-23 level was higher in carriers (P=0.06). Conclusions Our results suggest a link between BRCA mutation, accelerated ovarian aging and systemic aging-related pathophysiology.