Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

Statistical methods in cancer research

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

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Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Purpose: To compare the clinical features, natural history, and outcomes for women with “triple-negative” breast cancer with women with other types of breast cancer. Experimental Design: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women9s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. Results: The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P P Conclusions: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.

https://clincancerres.aacrjournals.org/content/clincanres/13/15/4429.full.pdf

Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence

Triple-negative breast cancer, so called because it lacks expression of the estrogen receptor, progesterone receptor, and HER2, is often, but not always, a basal-like breast cancer. This review focuses on its origin, molecular and clinical characteristics, and treatment.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1001389

Triple-negative breast cancer.

PURPOSE: Insulin, a member of a family of growth factors that includes insulin-like growth factor (IGF)-I and IGF-II, exerts mitogenic effects on normal and malignant breast epithelial cells, acting via insulin and IGF-I receptors. Because of this and because of its recognized association with obesity, an adverse prognostic factor in breast cancer, we examined the prognostic associations of insulin in early-stage breast cancer. PATIENTS AND METHODS: A cohort of 512 women without known diabetes, who had early-stage (T1 to T3, N0 to N1, and M0) breast cancer, was assembled and observed prospectively. Information on traditional prognostic factors and body size was collected, and fasting blood was obtained. RESULTS: Fasting insulin was associated with distant recurrence and death; the hazard ratios and 95% confidence intervals (CI) for those in the highest (> 51.9 pmol/L) versus the lowest (< 27.0 pmol/L) insulin quartile were 2.0 (95% CI, 1.2 to 3.3) and 3.1 (95% CI, 1.7 to 5.7), respectively. There was some...

Fasting Insulin and Outcome in Early-Stage Breast Cancer: Results of a Prospective Cohort Study

BACKGROUND We determined the effect of breast irradiation plus tamoxifen on disease-free survival and local relapse in women 50 years of age or older who had T1 or T2 node-negative breast cancer. METHODS Between December 1992 and June 2000, 769 women with early breast cancer (tumor diameter, 5 cm or less) were randomly assigned to receive breast irradiation plus tamoxifen (386 women) or tamoxifen alone (383 women). The median follow-up was 5.6 years. RESULTS The rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation (hazard ratio, 8.3; 95 percent confidence interval, 3.3 to 21.2; P<0.001), with corresponding five-year disease-free survival rates of 84 percent and 91 percent (P=0.004). A planned subgroup analysis of 611 women with T1, receptor-positive tumors indicated a benefit from radiotherapy (five-year rates of local relapse, 0.4 percent with tamoxifen plus radiotherapy and 5.9 percent with tamoxifen alone; P<0.001). Overall, there was a significant difference in the rate of axillary relapse at five years (2.5 percent in the tamoxifen group and 0.5 percent in the group given tamoxifen plus irradiation, P=0.049), but no significant difference in the rates of distant relapse or overall survival. CONCLUSIONS As compared with tamoxifen alone, radiotherapy plus tamoxifen significantly reduces the risk of breast and axillary recurrence after lumpectomy in women with small, node-negative, hormone-receptor-positive breast cancers.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa040595

Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.

PURPOSE: Premenopausal women with breast cancer often enter a premature menopause during initial treatment of their malignancy, with resulting loss of childbearing capacity, onset of menopausal symptoms, and subsequent prolonged exposure to long-term risks of menopause. Adjuvant therapy is believed to contribute to this early menopause. PATIENTS AND METHODS: One hundred eighty-three premenopausal women with locoregional breast cancer (tumor-node-metastasis staging system classification, T1-3 N0-1 M0) who had undergone surgical treatment and provided information on menopausal status at diagnosis and 1 year later were enrolled. Systemic adjuvant therapy was recorded. Univariate and multivariate predictors of menopause were examined. RESULTS: Age, weight gain, tumor stage, nodal stage, and systemic adjuvant therapy (chemotherapy, tamoxifen) were all significant univariate correlates of menopause. In multivariate analysis, age, chemotherapy, and hormone therapy (tamoxifen) made significant independent contrib...

Risk of Menopause During the First Year After Breast Cancer Diagnosis

Purpose The prognosis of women with triple-negative breast cancers (defined as cancers that are estrogen receptor-negative, progesterone receptor-negative and HER2/neu negative) is poor, compared to women with other subtypes of breast cancer. It is proposed that the underlying difference in recurrence rates may be explained in part by different routes of metastatic spread. Experimental design We studied a cohort of 1608 patients diagnosed with breast cancer, diagnosed between January 1987 and December 1997 at Women’s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor-negative, progesterone receptor-negative and HER2/neu-negative. We compared the incidence rates of metastatic spread to bone and to other (non-bone) organs in women with triple-negative and other forms of breast cancer. Results Of the 1,608 patients, 180 (11.2%) had triple-negative breast cancer. The 1608 women were followed for a median of 9.0 years (range 0.1–19 years). Compared to other patients, those with triple-negative breast cancer had an increased likelihood of distant recurrence over the study period (adjusted hazard ratio (HR) 1.9; 95% CI: 1.5–2.5, P < 0.0001). The relatively poor prognosis was apparent in the five years after diagnosis (HR 2.9; 95% CI: 2.1–3.9; P = 0.0001) but not thereafter (HR 0.5; 95% CI: 0.2–1.1; P = 0.07). In particular, women with triple-negative breast cancer were four times more likely to experience a visceral metastasis within five years of diagnosis than those with other types of cancer (HR 4.0; 95% CI: 2.7–5.9; P < 0.0001). The rates of bone metastases were comparable for triple-negative and for other forms of cancer in this time period (HR 0.8; 95% CI: 0.4–1.6 P = 0.5). Conclusions The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.

Maureen E. Trudeau

Papers

Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence

Fasting Insulin and Outcome in Early-Stage Breast Cancer: Results of a Prospective Cohort Study

Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.

Risk of Menopause During the First Year After Breast Cancer Diagnosis

Pattern of metastatic spread in triple-negative breast cancer