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

2. METODOLOGÍA

3. METODOLOGÍA

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

6. 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.

7. 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 patients

8. Tumores T1
Tumores T2

9. 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

10. 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

12. 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.

13. 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

14. 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, to -0.40; P = .0002)

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

16. 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

17. 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.

19. 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, to 0.681; P , .001). (MONARCH 2)

22. Efficacy
Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = ; 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)

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

24. 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

25. 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?

27. 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

28. 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)

29. 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).

30. 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

32. 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.

33. 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).

34. 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

35. 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

36. 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

38. Background
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) patient level meta-analysis of adjuvant bisphosphonates, which included 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

40. 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).

41. 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).

42. 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