Ductal carcinoma in situ of the breast: finding the balance between overtreatment and undertreatment.

Ductal carcinoma in situ (DCIS) accounts for 15-25% of all breast cancer diagnoses. Its prognosis is excellent overall, the main risk being the occurrence of local breast events, as most cases of DCIS do not progress to invasive cancer. Systematic screening has greatly increased the incidence of this non-obligate precursor of invasion, lending urgency to the need to identify DCIS that is prone to invasive progression and distinguish it from non-invasion-prone DCIS, as the latter can be overdiagnosed and therefore overtreated. Treatment strategies, including surgery, radiotherapy, and optional endocrine therapy, decrease the risk of local events, but have no effect on survival outcomes. Active surveillance is being evaluated as a possible new option for low-risk DCIS. Considerable efforts to decipher the biology of DCIS have led to a better understanding of the factors that determine its variable natural history. Given this variability, shared decision making regarding optimal, personalised treatment strategies is the most appropriate course of action. Well designed, risk-based de-escalation studies remain a major need in this field.

Primary-Site Local Therapy for Patients with De Novo Metastatic Breast Cancer: An Educational Review.

BACKGROUND: Until 2001, the paradigm guiding the management of women with de novo metastatic breast cancer (dnMBC) stipulated that primary-site locoregional therapy (PSLT) did not alter the course of metastatic disease and was necessary only for palliation of symptoms. Since 2002, retrospective data have begun questioning this paradigm. However, selection biases driving an observed survival advantage associated with PSLT in dnMBC were quickly recognized and led to several randomized clinical trials (RCTs) addressing this question. METHODS AND RESULTS: Four published RCTs have since tested the value of PSLT added to systemic therapy (ST) or not, with overall survival (OS) as the primary end point. The results of three published trials show no OS benefit for the addition of PSLT: Indian Tata Memorial, U.S./Canada E2108, and Austrian POSYTIVE (although POSYTIVE did not reach full accrual). The fourth RCT (Turkey, MF07-01) shows an OS benefit for PSLT at 5 years (42 % vs 24 % in the ST arm; hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.49-0.88). However, the 5-year survival in the PSLT arm of MF07-01 is similar to that in both arms of E2108, suggesting that the worse survival in the ST arm of MF07-01 is a result of biologically worse disease (from imbalanced randomization). Locoregional control was improved by PSLT in all trials, but without improvement in quality of life. CONCLUSIONS: The current evidence fails to refute the 20th century paradigm guiding management of de novo metastatic breast cancer. Discussion continues regarding the survival value of PSLT for patients with bone-only disease or oligometastases, but unbiased evidence is lacking.

Readdressing the Role of Surgery of the Primary Tumor in de Novo Stage IV Breast Cancer.

The impressive advances in breast cancer treatment observed in recent years also apply to the metastatic setting, where a subset of patients with favorable metastatic disease enjoy long-term survival with systemic therapy. In patients with distant disease, the primary tumor in the breast has not classically been though to merit specific locoregional therapy. However, about 6% of Stage IV patients in the USA and up to 20% in limited resource environments present with synchronous distant metastases at the time of initial diagnosis. For this group, who have an intact primary tumor, retrospective studies suggest that local therapy for the primary site may be beneficial. However, these retrospective analyses are biased in that women receiving local therapy to the primary site were younger and had biologically favorable tumors and lower volume metastatic disease. Two completed randomized clinical trials have shown conflicting results, and others are ongoing. In this chapter, we discuss the results of these studies through the present day and summarize their conclusions and their implications for clinical management.

Male Breast Cancer as a Second Primary Cancer: Increased Risk Following Lymphoma.

BACKGROUND: Male breast cancer (MBC) as a second primary cancer (SPC) has a known association with prior MBC. However, its association with non-breast index malignancies, relative to population risk, has not been previously reported. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results program (9 catchment area) data, we identified MBCs diagnosed from 1973-2012 as their SPC. Information regarding the index malignancy was also obtained. Standardized incidence ratios (SIR) of MBC as SPC were estimated, along with incidence rates and trends. Kaplan-Meier curves were used to estimate survival. RESULTS: Over a 38-year period, 464 MBCs were identified as SPC. The most common index malignancies were breast (SIR 30.86, 95% confidence interval [CI] 21.50-42.92, p < .001), lymphoma (SIR 1.58, 95% CI 1.08-2.22, p = .014), melanoma (SIR 1.26, 95% CI 0.80-1.89), urinary (SIR 1.05, 95% CI 0.74-1.43), colorectal (SIR 0.94, 95% CI 0.69-1.24), and prostate (SIR 0.93 95% CI 0.81-1.07). Apart from the known association with prior breast cancer, the only significant association was with lymphoma as an index cancer, although not significant with a Bonferroni correction. From 1975-2012, incidence of breast cancer as a first cancer increased at an annual percentage change of 1.3% while breast cancer as a SPC increased at 4.7% (both p values < .001). CONCLUSION: Male breast cancer as a SPC has increased markedly over 4 decades. Men with a history of lymphoma may experience higher-than-expected rates of breast SPC. These observations warrant further research, and suggest possible etiologic connections with disease biology, prior therapy, or genetics. IMPLICATIONS FOR PRACTICE: This study reports that men are presenting more frequently to the clinic with breast cancer, both as an initial cancer and as a second cancer following an earlier malignancy. We also report the novel observation that men who survive lymphoma are at increased risk of developing a subsequent breast cancer. Further work is needed to better understand possible treatment or biologic causes of this association. More immediately, these findings suggest the need for heightened vigilance for male breast cancer overall and, in particular, for male lymphoma survivors.

Surgical management of de novo stage IV breast cancer.

Management of the intact primary tumor in women presenting with stage IV breast cancer has classically been determined by the presence or absence of symptoms. However, multiple retrospective reviews completed over the past decade suggest a survival advantage with resection of the intact, asymptomatic primary tumor in these women. These reviews are not without bias, and recently completed randomized trials do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival. Until unbiased data are available, local therapy for the asymptomatic primary cannot be routinely recommended, but may be considered in selected individuals, with multidisciplinary input, when systemic disease is well controlled.

De novo Stage IV breast cancer: breast conserving resection of the primary tumor?

Multiple retrospective reviews completed over the past decade suggest a survival advantage with resection of the intact primary tumor in women with metastatic breast cancer. However, these reviews are not without bias, and recently completed randomized trials do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival.

Breast Cancer Risk Reduction: Current Status and Emerging Trends to Increase Efficacy and Reduce Toxicity of Preventive Medication.

The primary prevention of breast cancer is a worthwhile goal for which the efficacy of antiestrogens is well established. However, implementation has been problematic related to low prioritization by providers and the reluctance of high-risk women to experience medication side effects. Emerging solutions include improved risk estimation through the use of polygenic risk scores and the application of radiomics to screening mammograms; and optimization of medication dose to limit toxicity. The identification of agents to prevent estrogen receptor negative or HER2-positive tumors is being pursued, but personalization of medical risk reduction requires the prediction of tumor subtypes.

Towards the development of DCIS risk prediction models.

Ductal carcinoma in situ (DCIS) has a variable natural history, with a poorly understood biology. In this issue of Cancer Cell, Strand et. al. use two well-annotated DCIS repositories to identify an 812-gene classifier that associates with high risk of DCIS recurrence and define novel DCIS subtypes that informs future studies.

Lipid exposure activates gene expression changes associated with estrogen receptor negative breast cancer.

Improved understanding of local breast biology that favors the development of estrogen receptor negative (ER-) breast cancer (BC) would foster better prevention strategies. We have previously shown that overexpression of specific lipid metabolism genes is associated with the development of ER- BC. We now report results of exposure of MCF-10A and MCF-12A cells, and mammary organoids to representative medium- and long-chain polyunsaturated fatty acids. This exposure caused a dynamic and profound change in gene expression, accompanied by changes in chromatin packing density, chromatin accessibility, and histone posttranslational modifications (PTMs). We identified 38 metabolic reactions that showed significantly increased activity, including reactions related to one-carbon metabolism. Among these reactions are those that produce S-adenosyl-L-methionine for histone PTMs. Utilizing both an in-vitro model and samples from women at high risk for ER- BC, we show that lipid exposure engenders gene expression, signaling pathway activation, and histone marks associated with the development of ER- BC.

Surgical Management of de novo Stage IV Breast Cancer.

The natural history of stage IV breast cancer is changing, with diagnosis when the disease burden is lower and better drugs translating into longer survival. Nevertheless, a small but constant fraction of women present with de novo stage IV disease and an intact primary tumor. The management of the primary site in this setting has classically been determined by the presence of symptoms, but this approach has been questioned based on multiple retrospective reviews reported over the past decade that suggested a survival advantage for women whose intact primary tumor is resected. These reviews are necessarily biased, as younger women with lower disease burden and more favorable biological features were offered surgery, but they led to several randomized trials to test the value of local therapy for the primary tumor in the face of distant disease. Preliminary results from 2 of these do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival. Until unbiased data are available, local therapy for asymptomatic primary tumors cannot be recommended in the expectation of a survival benefit.