Coping Mechanisms, Psychological Distress, and Quality of Life Prior to Cancer Genetic Counseling

Background: Breast Cancer susceptibility genes 1 and 2 are implicated in hereditary breast and ovarian cancer and women can test for the presence of these genes prior to developing cancer. The goal of this study is to examine psychological distress, quality of life, and active coping mechanisms in a sample of women during the pre-test stage of the genetic counseling process, considering that pre-test distress can be an indicator of post-test distress. We also wanted to identify if subgroups of women, defined based on their health status, were more vulnerable to developing distress during the genetic counseling process.Methods: This study included 181 female participants who accessed a Cancer Genetic Counseling Clinic. The participants were subdivided into three groups on the basis of the presence of a cancer diagnosis: Affected patients, Ex-patients, and Unaffected participants. Following a self-report questionnaire, a battery of tests was administered to examine psychological symptomatology, quality of life, and coping mechanisms.Results: The results confirm that the genetic counseling procedure is not a source of psychological distress. Certain participants were identified as being more vulnerable than others; in the pre-test phase, they reported on average higher levels of distress and lower quality of life. These participants were predominantly Ex-patients and Affected patients, who may be at risk of distress during the counseling process.Conclusions: These findings highlight that individuals who take part in the genetic counseling process are not all the same regarding pre-test psychological distress. Attention should be paid particularly to Ex-patients and Affected patients by the multidisciplinary treating team

Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy

30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study

Objective To assess the long term effectiveness of adjuvant treatment with cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of relapse, on the basis of three successive randomised trials and one observational study conducted from June 1973 to December 1980. Design Cohort study. Setting Istituto Nazionale Tumori in Milan, Italy. Main outcome measures Relapse free and overall survival, measured by univariate and multivariate analyses. Results After a median follow up of 28.5 years for the initial study, adjuvant CMF was found to reduce the relative risk of relapse significantly (hazard ratio 0.71, 95% confidence interval 0.56 to 0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04). Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In the node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P = 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow up of 20 years. Conclusions When delivered optimally, CMF benefits patients at risk of relapse of distant disease without evidence of detrimental effects in any of the examined subgroups

Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): An exploratory, open-label, phase 2 study

Background: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer. Methods: NA-PHER2 is a multicohort, open-label, exploratory, phase 2 study done at seven sites in Italy. Patients were eligible for the first cohort if they had previously untreated, histologically confirmed, unilateral, invasive, HER2-positive, ER-positive breast cancer and were suitable for neoadjuvant therapy. Patients were treated every 3 weeks with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and intravenous pertuzumab (840 mg loading dose in the first cycle and then at 420 mg) for six cycles plus oral palbociclib (125 mg once a day for 21 days in a 4-week cycle) and intramuscular fulvestrant (500 mg) every 4 weeks for five cycles. The coprimary endpoints were change from baseline in Ki67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment) and changes in apoptosis from baseline to surgery. Secondary endpoints were clinical objective response (according to modified Response Evaluation Criteria in Solid Tumors) and pathological complete response. All patients who met eligibility criteria were assessed for the primary and secondary endpoints. All patients who received at least one cycle of therapy were assessed for safety. This trial is registered with ClinicalTrials.gov, number NCT02530424. The trial is ongoing and two further cohorts are being enrolled. Findings: Between May 20, 2015, and Feb 8, 2016, we enrolled 36 patients, of whom one was deemed ineligible for the study and five were found to be HER2-negative on retrospective analysis. Thus, 35 patients were included in safety analyses and 30 were assessed for the primary and secondary endpoints. At baseline, geometric mean Ki67 expression was 31·9 (SD 15·7), versus 4·3 (15·0) at week 2 (n=25; p&lt;0·0001) and 12·1 (20·0) at time of surgery (n=22; p=0·013). The geometric mean for apoptosis was 1·2 (SD 0·3) at baseline versus 0·4 (0·4; p=0·019) at surgery. A clinical objective response immediately before surgery was achieved by 29 (97%; 95% CI 83-100) of 30 patients. At surgery, eight (27%; 95% CI 12-46) patients had a pathological complete response in breast and axillary nodes. The most frequent grade 3 adverse events were neutropenia (ten [29%]), diarrhoea (five [14%]), and stomatitis, increased alanine aminotransferase, and hypersensitivity reactions (one [3%] of each event). No grade 4 or serious adverse events were recorded in the study and there were no deaths. Interpretation: The combination of palbociclib, fulvestrant, trastuzumab, and pertuzumab had a significant effect on the expression of Ki67 at 2 weeks and at surgery. Triple targeting of ER, HER2, and RB1 in HER2-positive and ER-positive breast cancer could be an effective chemotherapy-free treatment strategy. Further clinical testing and additional molecular characterisation is necessary, not only in hormone receptor-positive tumours but also in tumours without HER2 amplification. Funding: Pfizer and Roche