Revisión bibliográfica 4º trimestre de 2017 Diciembre de 2017 Revisión bibliográfica 4º trimestre de 2017 Yann Izarzugaza Peron Fundación Jiménez Díaz

METODOLOGÍA

METODOLOGÍA

Índice Un metaanálisis de NEJM Un artículo de JCO por las implicaciones del metaanálisis previo.. 3 fases III publicados Una busqueda de biomarcador

Importance of the study: The absolute benefits of continuing endocrine therapy after 5 years depend on the absolute risk of later recurrence if no further therapy is given Study the influence of various characteristics of the original tumor on the 20-year incidence of breast-cancer outcomes in women with ER-positive, early-stage breast cancer who were scheduled to receive adjuvant endocrine therapy for 5 years.

Meta-analysis that combines individual patient data from 88 trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database Women who had: ER positive breast cancer Diagnosed before the age of 75 years T1 disease (tumor diameter, ≤2.0 cm) or T2 disease (tumor diameter, >2.0 to 5.0 cm) Fewer than 10 involved nodes (stratified according to a pathological nodal status of no nodes [N0], 1 to 3 nodes [N1–3], or 4 to 9 nodes [N4–9]) No distant metastases. All the patients were scheduled to receive endocrine therapy for 5 years then stop, regardless of actual adherence Total of 62923 patients

Tumores T1 Tumores T2

Tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence The status regarding the progesterone receptor (in 54,115 patients) and HER2 (in 15,418 patients in trials with no use of trastuzumab) was not predictive

Conclusions Breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status Patients at risk even with T1-2N0 tumors

Background Approximately half of patients develop AI-associated musculoskeletal symptoms (AIMSS) and 20% to 30% discontinue treatment early because of intolerance. Results of phase III trials only support use of acupuncture and exercise for improvement of AIMSS. Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) indicated for depression and anxiety. Also approved for treatment of multiple chronic pain conditions, including fibromyalgia, diabetic peripheral neuropathic pain, and chronic musculoskeletal pain Hypothesized that treatment with duloxetine for 12 weeks would result in a greater reduction in average joint pain in postmenopausal women with AIMSS compared with placebo treatment. Secondary endopoints: patient-reported outcomes, including depression and overall quality of life.

Randomized, double-blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of 4 out of 10 that developed or worsened since AI therapy initiation

By 12 weeks, the average joint pain score was 0 By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, -1.24 to -0.40; P = .0002)

Secondary endpoints Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning

Safety Rates of adverse events of any grade were higher in the duloxetine treated group (78% v 50%); rates of grade 3 adverse events were similar

Conclusions Results of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer Although it resulted in more frequent low-grade toxicities In addition, duloxetine treatment resulted in a statistically significant improvement in functional quality of life.

Background Abemaciclib, an oral, selective small-molecule inhibitor of CDK 4 and CDK 6, is dosed twice daily on a continuous schedule and is 14 times more potent against CDK 4/cyclin D1 than CDK 6/cyclin D3 in enzymatic assays In patients with HR-positive, HER2-negative advanced breast cancer: Refractory to endocrine therapy, abemaciclib demonstrated clinical activity as monotherapy (MONARCH 1) Who progressed while receiving endocrine therapy, abemaciclib plus fulvestrant resulted in a 7.2-month extension in median progression- free survival compared with the placebo arm (hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P , .001). (MONARCH 2)

Efficacy Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm (P = .004)

Subgroup analysis: lesser benefit >36 months free interval Bone only disease

Abemaciclib dose reductions as the result of adverse events occurred in 142 (43.4%) patients versus 10 (6.2%) receiving placebo. Interruption of abemaciclib as the result of an adverse event occurred in 184 (56.3%) patients versus 31 (19.3%) receiving placebo. A total of 64 (19.6%) patients in the abemaciclib arm versus four (2.5%) in the placebo arm discontinued treatment as the result of adverse events

Conclusions 3rd CDK 4-6 inhibitor to prove efficacy in first line with similar HR Slightly different in toxicity profile. Lesser benefit for good profile patients?

This report summarises efficacy, safety, and patient-reported outcome data from the neoadjuvant phase of the trial. Adjuvant treatment ended in November, 2016, and follow-up in the adjuvant phase is ongoing

A pathological complete response was achieved by 99 (44 A pathological complete response was achieved by 99 (44.4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55.7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference −11.3 percentage points, 95% CI −20.5 to −2.0; p=0.016)

SAFETY Fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3–4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3–4 adverse events in the trastuzumab emtansine plus pertuzumab group were: -Decreased platelet count (3 [1%] of 223 patients vs 11 [5%] of 219 with PTCH -fatigue (3 [1%] vs 7 [3%]) -Alanine aminotransferase increase (3 [1%] vs 4 [2%]) -hypokalaemia (three [1%] vs five [2%]). The most common grade 3–4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were: -Neutropenia (55 [25%] of 219 vs 1 [<1%] of 223 with P-TDM1 -Diarrhoea (33 [15%] vs 2 [<1%]) -Febrile neutropenia (33 [15%] vs 0).

Conclusions Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade resulted in significantly more pathological complete responses than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab) However, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group

Background Three randomised trials of systemic adjuvant therapy in patients with early-stage HER2-positive breast cancer aimed to improve outcomes beyond current standard of care (ie, 1 year of trastuzumab) 1) In HERA, 2 years of trastuzumab did not significantly improve disease-free survival compared with 1 year of trastuzumab after 8 years of follow-up. 2) In ALTTO, lapatinib given concurrently with trastuzumab for 1 year, or sequentially for 8,5 months after 3 months of trastuzumab, did not significantly improve disease-free survival after a median follow-up of 4,5 years. 3) In APHINITY, the addition of pertuzumab to trastuzumab for 1 year improved 3-year invasive disease-free survival (hazard ratio 0.81, 95% CI 0.66–1.00, p=0.045) compared with trastuzumab alone, after a median follow-up of 45,4 months.

Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420).

After a median follow-up of 5,2 years, patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0.73, 95% CI 0.57–0.92, p=0.0083) Invasive disease free survival. ITT population Hormone receptor positive Hormone receptor negative

Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo

Conclusions 1 year of neratinib after chemotherapy and trastuzumab adjuvant therapy significantly reduces the likelihood of clinically relevant breast cancer relapse in women with early-stage HER2-positive breast cancer No significant risk of long-term toxicity. Extended adjuvant neratinib after chemotherapy and trastuzumab should be considered a new therapeutic option for this patient population. An analysis of overall survival is planned after 248 events

Background The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) patient level meta-analysis of adjuvant bisphosphonates, which included 18 776 women with breast cancer, showed a reduction in breast-cancer-associated death among postmenopausal women (hazard ratio [HR] 0.82, 95% CI 0.73–0.93). This outcome was mainly due to the reduction in bone recurrence. Thus, several guidelines have included zoledronic acid and clodronic acid as adjuvant treatments for breast cancer in postmenopausal women

MAF, a transcription factor implicated in control of expression of several genes associated with bone metastasis from breast cancer HYPOTHESIS: MAF amplification status, indicated by copy number on fluorescence in-situ hybridisation (FISH), could predict treatment effects with adjuvant zoledronic acid compared with standard care alone Of 1739 patients who contributed primary tumour samples, 865 (50%) had enough tissue to create two cores assessable by FISH. 184 (21%) had MAF-positive tumours (copy number ≥2.5).

In patients with MAF-negative tumours, zoledronic acid was associated with higher invasive-disease-free survival than was control treatment (HR 0·74, 95% CI 0·56–0·98) But not in patients who had MAF-positive tumours MAF positivity seemed to predict harm with adjuvant zoledronic acid in non-postmenopausal women, particularly for extraskeletal recurrence (zoledronic acid vs control HR 6.92, 95% CI 2.44–19.60).

Conclusions Testing for MAF amplification in tumours is a potential companion diagnostic on which to base the decision of whether to use adjuvant zoledronic acid in patients with early breast cancer. Prospective validation of these findings in another randomised trial is warranted