Rassegna della letteratura – febbraio 2019

Epidemiologia – Prevenzione Primaria – Diagnosi e Screening

Conant EF, Barlow WE, Herschorn SD et Al.- Association of Digital Breast Tomosynthesis vs Digital Mammography With Cancer Detection and Recall Rates by Age and Breast Density. JAMA Oncol. 2019 Feb 28

Purpose Breast cancer screening examinations using digital breast tomosynthesis (DBT) has been shown to be associated with decreased false-positive test results and increased breast cancer detection compared with digital mammography (DM). Little is known regarding the size and stage of breast cancer types detected and their association with age and breast density.

Methods To determine whether screening examinations using DBT detect breast cancers that are associated with an improved prognosis and to compare the detection rates by patient age and breast density. This retrospective analysis of prospective cohort data from 3 research centers in the Population-based Research Optimizing Screening Through Personalized Regimens (PROSPR) consortium included data of women aged 40 to 74 years who underwent screening examinations using DM and DBT from January 1, 2011, through September 30, 2014. Statistical analysis was performed from November 8, 2017, to August 14, 2018.

Results Among 96 269 women (mean [SD] patient age for all examinations, 55.9 [9.0] years), patient age was 56.4 (9.0) years for DM and 54.6 (8.9) years for DBT. Of 180 340 breast cancer screening examinations, 129 369 examinations (71.7%) used DM and 50 971 examinations (28.3%) used DBT. Screening examination with DBT (73 of 99 women [73.7%]) was associated with the detection of smaller, more often node-negative, HER2-negative, invasive cancers compared with DM (276 of 422 women [65.4%]). Screening examination with DBT was also associated with lower recall (odds ratio, 0.64; 95% CI, 0.57-0.72; P < .001) and higher cancer detection (odds ratio, 1.41; 95% CI, 1.05-1.89; P = .02) compared with DM for all age groups even when stratified by breast density. The largest increase in cancer detection rate and the greatest shift toward smaller, node-negative invasive cancers detected with DBT was for women aged 40 to 49 years. For women aged 40 to 49 years with nondense breasts, the cancer detection rate for examinations using DBT was 1.70 per 1000 women higher compared with the rate using DM; for women with dense breasts, the cancer detection rate was 2.27 per 1000 women higher for DBT. For these younger women, screening with DBT was associated with only 7 of 28 breast cancers (25.0%) categorized as poor prognosis compared with 19 of 47 breast cancers (40.4%) when screening with DM.

Conclusions The findings suggest that screening with DBT is associated with increased specificity and an increased proportion of breast cancers detected with better prognosis compared with DM. In the subgroup of women aged 40 to 49 years, routine DBT screening may have a favorable risk-benefit ratio.

Flanagan MR, Zabor EC, Stempel M et Al – Chemoprevention Uptake for Breast Cancer Risk Reduction Varies by Risk Factor – Ann Surg Oncol 2019 Feb 27.

Purpose The efficacy of chemoprevention for breast cancer risk reduction has been demonstrated in randomized controlled trials; however, use remains low. We sought to determine whether uptake differed by risk factors, and to identify reasons for refusal and termination.

Methods Women seen in a high-risk clinic from October 2014 to June 2017 considered eligible for chemoprevention (history of lobular carcinoma in situ, atypia, family history of breast/ovarian cancer, genetic mutation, or history of chest wall radiation) were retrospectively identified. Breast cancer risk factors were compared among those with and without chemoprevention use, and compliance was noted.

Results Overall, 1506 women were identified, 24% with prior/current chemoprevention use. Women ≥ 50 years of age were more likely to use chemoprevention than women < 50 years of age (28% vs. 11%, p < 0.001). Chemoprevention use by risk factor ranged from 7 to 40%. Having multiple risk factors did not increase use. Significant variation by risk factor was present among women ≥ 50 years of age (p < 0.001), but not among women < 50 years of age (p = 0.1). Among women with a documented discussion regarding chemoprevention (575/1141), fear of adverse effects was the most common refusal reason (57/156; 36%). The majority of women (61%) who initiated chemoprevention completed 5 years.

Conclusions Chemoprevention use among women at increased risk for breast cancer remains low, with more frequent use among women ≥ 50 years of age. These data highlight the need for ongoing educational efforts and counseling, as the majority who begin therapy complete 5 years of use. Given the fear of adverse effects as well as low uptake, particularly among women < 50 years of age, alternative risk-reducing strategies are needed.

Martínez MT, Oltra SS, Peña-Chilet M et Al. – Breast Cancer in Very Young Patients in a Spanish Cohort: Age as an Independent Bad Prognostic Indicator – Breast Cancer (Auckl). 2019 Feb 20;13

Purpose Breast cancer (BC) in very young women (BCVY) is more aggressive than in older women. The purpose of this study was to evaluate the relevance of a range of clinico-pathological factors in the prognosis of BCVY patients.

Methods We retrospectively analyzed 258 patients diagnosed with BCVY at our hospital from 1998 to 2014; the control group comprised 101 older patients with BC. We correlated clinicopathological factors, treatments, relapse and exitus with age and with previously published miRNA expression data.

Results We identified some significant differences in risk factors between BCVY and older patients. The age at menarche, number of pregnancies, and age at first pregnancy were lower in the BCVY group and had a greater probability of recurrence and death in all cases. Lymph node-positive patients in the BCVY group are associated with a worse prognosis (P= .02), an immunohistochemical HER2+ subtype, and disease relapse (P= .03). Moreover, there was a shorter time between diagnosis and first relapse in BCVY patients compared with controls, and they were more likely to die from the disease (P= .002). Finally, from our panel of miRNAs deregulated in BC, reduced miR-30c expression was associated with more aggressive BC in very young patients, lower overall survival, and with axillary lymph node metastases.

Conclusions Patient age and axillary lymph node status post-surgery are independent and significant predictors of distant disease-free survival, local recurrence-free survival, and overall survival. The HER2+ subtype and lower miR-30c expression are related to poor prognosis in lymph node-positive young BC patients.

Balleyguier C, Ceugnart L et Al. – Preoperative Breast Magnetic Resonance Imaging in Women With Local Ductal Carcinoma in Situ to Optimize Surgical Outcomes: Results From the Randomized Phase III Trial IRCIS – J Clin Oncol. 2019 Feb 27

Purpose We evaluated the addition of breast magnetic resonance imaging (MRI) to standard radiologic evaluation on the re-intervention rate in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery.

Methods Women with biopsy-proven DCIS corresponding to a unifocal microcalcification cluster or a mass less than 30 mm were randomly assigned to undergo MRI or standard evaluation. The primary end point was the re-intervention rate for positive or close margins (< 2 mm) in the 6 months after randomization

Results A total of 360 patients from 10 hospitals in France were included in the study. Of the 352 analyzable patients, 178 were randomly assigned to the MRI arm, and 174 were assigned to the control arm. In the intent-to-treat analysis, 82 of 345 patients with the assessable end point were reoperated for positive or close margins within 6 months, resulting in a re-intervention rate of 20% (35 of 173) in the MRI arm and 27% (47 of 172) in the control arm. The absolute difference of 7% (95% CI, -2% to 16%) corresponded to a relative reduction of 26% (stratified odds ratio, 0.68; 95% CI, 0.41 to 1.1; P = .13). When considering only the per-protocol population with an assessable end point, the difference was 9% (stratified odds ratio, 0.59; 95% CI, 0.35 to 1.0; P = .05). Total mastectomy rates were 18% (31 of 176) in the MRI arm and 17% (30 of 173) in the control arm (stratified P = .93). For 100 lesions seen on MRI, nonmass-like enhancement was more predominant (82%) than mass enhancement (20%). Nevertheless, no specific morphologic and kinetic parameters for DCIS were identified.

Conclusions The study did not show sufficient surgical improvement with the use of preoperative MRI to be clinically relevant in DCIS staging. However, this could be reconsidered with the improvement of new MRI sequences and new modalities in magnetic resonance techniques.

Barriga P, Vanhauwaert P, Porcile A – Hormonal contraception and risk of breast cancer: a critical look. Gynecol Endocrinol. 2019 Feb 26:1-3

Today health professionals are not only required to know medicine, but scientific reading, interpretation, and communication of new data. The new information about contraception and hormonal therapies must be analyzed by gynecologists to determine whether or not the new data are applicable to their patients and if it has an impact on their health. Recently a new study of hormonal contraceptives and the risk of breast cancer was published. In this study, the investigators found an elevation of the relative risk of breast cancers on the users versus the nonusers of hormonal contraception. After analyzing the publication and other data available, it is our opinion that it is a very low increase of the risk and its impact should be evaluated case by case, not forgetting to take into account the numerous beneficial effects that hormonal contraception have.

Blanks RG, Given-Wilson R, Alison R et Al. – An analysis of 11.3 million screening tests examining the association between needle biopsy rates and cancer detection rates in the English NHS Breast Cancer Screening Programme – Clin Radiol. 2019 Feb 21.

Purpose To examine the association between recall, needle biopsy, and cancer detection rates to inform the setting of target ranges to optimise the benefit to harm ratio of breast screening programmes.

Methods Annual screening programme information from 2009/10 to 2015/16 for the 80 screening units of the English National Health Service Breast Screening Programme (totalling 11.3 million screening tests) was obtained from annual (KC62) returns. Linear regression models were used to examine the association between needle biopsy rates and recall rates and non-linear regression models to examine the association between cancer detection rates and needle biopsy rates

Results The models show and quantify the diminishing returns for prevalent screens with increasing biopsy rates. A biopsy rate increase from 10 to 20 per 1,000 increases the cancer detection rate by 2.13 per 1,000 with four extra biopsies per extra cancer detected. Increasing the biopsy rate from 40 to 50 per 1,000, increases the cancer detection rate by only 0.25 per 1,000, with 40 extra biopsies per extra cancerdetected. Although diminishing returns are also seen at incident screens, screening is generally more efficient.

Conclusions Increasing needle biopsy rates leads to rapidly diminishing returns in cancer detection and a marked increase in non-malignant/benign needle biopsies. Much of the harms associated with screening in terms of false-positive recall rates and non-cancerbiopsies occur at prevalent screens with much lower rates at incident screens. Needle biopsy rate targets should be considered together with recall rate targets to maximise benefit and minimise harm.

Almerey T, Villacreses D, Li Z et Al – Value of Axillary Ultrasound after Negative Axillary MRI for Evaluating Nodal Status in High-Risk Breast Cancer – J Am Coll Surg. 2019 Feb 21. (19)30154-1.

Purpose It is assumed axillary ultrasound (AxUS) is the best method for axillary nodal evaluation in newly diagnosed breast cancerpatients. However, few have evaluated the efficacy of preoperative axillary MRI. Herein, we compare the statistical accuracy of AxUS and MRI in detecting nodal metastases among breast cancer patients who were selected for neoadjuvant chemotherapy.

Methods We retrospectively analyzed 219 breast cancer patients undergoing neoadjuvant chemotherapy from 2007-2015 all of whom had AxUS and breast MRI prior to-chemotherapy. Two breast radiologists blinded to clinical, pathological and AxUS findings re-reviewed all breast MRIs specifically focusing on axillary nodal characteristics. We correlated clinico-pathological characteristics, AxUS and MRI findings and quantified predictive values of both imaging modalities.

Results Overall, 101/219 (47%) patients had T2 tumors. The most common abnormal nodal finding was size >10mm. AxUS and MRI agreed on nodal status in 192/219 (87.6%). When correlated with prechemotherapy needle biopsy in 129 patients; AxUS and axillary MRI performed similarly (Sensitivity of 99.1% vs 97.4% and specificity 15.4% vs 15.4%, respectively). Only 4/129 (3.1%) patients had a negative MRI and positive AxUS of which 3/4 (75%) had a positive biopsy and 2/3 had positive lymph nodes on final pathology, therefore suggesting MRI missed clinically significant disease in only 2/129 (1.5%) patients.

Conclusions In a high risk patient population, AxUS and MRI have similar statistical profiles in evaluating axillary nodal status. Routine use of AxUS after a normal axillary MRI is not warranted.

Grimm L et Al. – Frequency of Breast Cancer Thoughts and Lifetime Risk Estimates: A Multi-Institutional Survey of Women Undergoing Screening Mammography – Am Coll Radiol. 2019 Feb 27. pii: S1546-1440(18)31597

Purpose: the aim of this study was to quantify women’s personal estimates of breast cancer risk and frequency of breast cancer thoughts.

Methods: Women from five medical centers were surveyed before their screening mammographic examinations. Participants were queried on their baseline anxiety and demographics, then asked how many times in the past month they had thought about developing breast cancer. Participants were then notified of the 12% lifetime average breast cancer risk and asked to estimate their personal risk both subjectively and objectively. Comparisons were made between responses and the demographic variables.

Results: There were 2,747 completed surveys for analysis. Women reported 2.5 ± 6.6 thoughts of cancer on average in the prior month. More frequent thoughts were associated with personal or family history of breast cancer, greater anxiety, and genetic testing (P < .001 for all). Among women without cancer risk factors (n = 1,412), there were 1.4 cancer thoughts per month, which was associated with baseline anxiety (P < .001). The median lifetime breast cancer risk was 12% among all women, with 37.4% high risk (>20%) estimates. Demographic variables associated with increased risk estimates were previous cancer diagnosis, higher education, genetic testing, white race, increased age, and greater anxiety (P < .01 for all). Among women with no risk factors, the median estimated risk was 10%, with 16.7% providing estimates greater than 20%, associated with baseline anxiety and white race (P < .001 for both).

Conclusions: Increased breast cancer thoughts and personal cancer estimates are associated with specific patient demographics. Improved understanding of patient perspectives could improve shared decision-making discussions and thus patient care.

Bitencourt AGV, Eugênio DSG, Souza JAPrognostic significance of preoperative MRI findings in young patients with breast cancer. Sci Rep. 2019 Feb 28;9(1):3106.

The objective is to evaluate the prognostic value of preoperative magnetic resonance imaging (MRI) findings in breast cancer patients aged less than 40 years. This retrospective, single-center study evaluated 92 women aged <40 years who received a diagnosis of invasive breastcarcinoma between 2008 and 2012. These patients underwent a breast MRI before treatment and follow-up at the same institution. Kaplan-Meier survival curves were used to analyze overall survival, with the log-rank test used to compare different groups. Cox regression analysis was used to estimate hazard ratios (HRs) with 95% confidence interval (95% CI) values. The mean age of the patients was 34 years (range: 25-39 years) and the mean tumor size was 3.9 cm in maximal dimension (range: 0.7-10.5 cm). Recurrence was observed in 21 (22.8%) patients and 15 (16.3%) patients did not survive during a mean follow-up period of 5.4 ± 1.9 years. MRI findings associated with worse overall survival included tumor size >5 cm (HR:5.404; 95% CI:1.922-15.198; p = 0.017), presence of non-mass enhancement (HR:3.730; 95% CI:1.274-10.922; p = 0.016) and multifocal tumor (HR:3.618; 95% CI:1.151-11.369; p = 0.028). Inconclusion, MRI findings that are suggestive of more extensive disease were associated with worse overall survival in young breast cancer patients.

Spei ME, Samoli E, Bravi FPhysical activity in breast cancer survivors: A systematic review and meta-analysis on overall and breast cancer survival – Breast. 2019 Feb 12;44:144-152.

Purpose To further quantify the association between physical activity (PA) after breast cancer diagnosis and all-cause mortality, breast cancermortality and/or breast cancer recurrence.

Results PubMed was searched until November 2017 for observational studies investigating any type of PA in association with total mortality, breast cancer mortality and/or breast cancer recurrence among women with breast cancer diagnosis. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using random-effects models for highest versus lowest categories of PA. Ten studies were included in the meta-analysis. During an average follow-up ranging from 3.5 to 12.7 years there were 23,041 breast cancersurvivors, 2,522 deaths from all causes, 841 deaths from breast cancer and 1,398 recurrences/remissions. Compared to women in the lowest recreational PA level (lowest quintile/quartile), women in the highest level had a lower risk of all-cause mortality (HR = 0.58, 95% CIs: 0.45-0.75; 8 studies), of death from breast cancer (HR = 0.60, 95% CIs 0.36-0.99; 5 studies) and a lower, albeit non-significant, risk of recurrence (HR = 0.79, 95% CIs 0.60-1.05; 5 studies). There was evidence of heterogeneity between the studies evaluating recreational PA and total mortality (Ι2 = 52.4%) and even higher for breast cancer mortality (Ι2 = 77.7%) or recurrence (Ι2 = 66.4%).

Conclusions Highest recreational PA after breast cancer diagnosis was associated with lower all-cause and breast cancer mortality. This finding probably reflects the favorable impact of PA on cardiovascular mortality, and a possible favorable role on breast cancer survival, though reverse causation cannot be excluded.

D’Andrea F, Ceccarelli M, Facciolà A et Al. – Breast cancer in women living with HIV. Eur Rev Med Pharmacol Sci. 2019 Feb;23(3):1158-1164.

With the introduction of HAART, the life expectancy of the patients infected with HIV almost approached that of the general population. The incidence of certain HIV-Associated cancers as Kaposi Sarcoma (KS) and Non-Hodgkin Lymphoma (NHL) decreased, while an increase in Non-AIDS-Defining cancers (NADCs) has been documented. HIV infection is a risk factor for numerous cancers in PLWH. Breast cancer is the most common cancer worldwide among all women. The association between HIV infection and breast cancer has not been thoroughly investigated: when compared to the general population, people living with HIV/AIDS (PLWHA) have a similar or slightly lower risk of breast cancer. Screening tests are essential weapons to fight cancer burden and more effective therapeutic and preventive strategies are needed, especially among PLWHA. Further and more comprehensive studies are needed to better characterize breast cancer among PLWH.