1. USS Oncologia Geriatrica
THBT neoadjuvant endocrine therapy is to be used in post-menopausal breast cancer woman
Antonino Grassadonia
Università «G. D’Annunzio» – Chieti-Pescara
Silvana LEO
USS Oncologia Geriatrica
Lecce

2. Neoadjuvant endocrine therapy in the management of breast cancer is woefully underutilized by U.S. clinicians
Judy C. Boughey, MB, BChir, Professor and Research Chair in the Department of Surgery at the Mayo Clinic, Rochester.
Matthew Ellis, MD, PhD, Director of the Lester and Sue Smith Breast Cancer and Professor of Medicine and Cellular and Molecular Biology at Baylor College of Medicine, Houston

3. greatest benefit in patients with strongly HR positive disease
Judy C. Boughey, MB, BChir, Professor and Research Chair in the Department of Surgery at the Mayo Clinic, Rochester.
In postmenopausal women with estrogen receptor–rich tumors, neoadjuvant endocrine therapy is often a better choice than neoadjuvant chemotherapy, for a number of reasons
greatest benefit in patients with strongly HR positive disease
Low toxicity
Can significantly dowstage the extent of disease
Increase breast conservation rates
Miami BC conference 2016

4. Matthew Ellis, MD, PhD, Director of the Lester and Sue Smith Breast Cancer and Professor of Medicine and Cellular and Molecular Biology at Baylor College of Medicine, Houston
Low percent of elegible patients :
3.2% (National Cancer data Base 2012)
2.9% (Surgical Oncology annual Cancer Symposium 2016)
Over 50 y, HR+, T2-T4
11% (T4) (Surgical Oncology annual Cancer Symposium 2016)
HR +,large tumors
One-fourth of patients with T3 and T4 tumors treated with neoadjuvant endocrine therapy were able to have breast-conserving surgery
Response Indicators ?

5. Neoadjuvant endocrine therapy versus neoadjuvant chemotherapy:
Neoadjuvant endocrine therapy in the management of breast cancer is underutilized by Italian clinicians?
Antonino Grassadonia
Università «G. D’Annunzio» – Chieti-Pescara
Neoadjuvant endocrine therapy versus neoadjuvant chemotherapy:
what is the evidence?
The NEOCENT trial which was designed to compare NCT (FEC100) to NET (letrozole) in postmenopausal women with strongly HR+ primary BC, was unfortunately prema-turely closed because of slow accrual, and it is therefore unlikely to contribute in clarifying this critically important question
Restricted to elderly or frail patients who were felt to be unsuitable for chemotherapy or ineligible for surgery ?

6. which is the best choice?
Randomised clinical trials comparing different endocrine agents in the neoadjuvant setting.
study prospectively
These results, suggest that the effectiveness of the three commercially available AIs are largely equivalent.
Barroso-Sousa R et al.ecancer 2016

7. What is the optimum duration of neoadjuvant endocrine treatment?
Randomised clinical trials comparing different endocrine agents in the neoadjuvant setting.
is there a theoretical risk that genomic events such deleterious resistance-inducing mutations would start to arise during the treatment?
Barroso-Sousa R et al.ecancer 2016

8. BCS was performed in 121 (84 %) of 144 patients
45%
46%
43%
The grade G1 is a tumor biological characteristic
strongly associated with longer DFS and OS
85 % of patients receiving NET for more than 5 months.

9. (preoperative endocrine prognostic index)
Are there any validated biomarkers to predict short (response) and/or long-term (recurrence/death) outcome?
Ki-67
PEPI score
(preoperative endocrine prognostic index)

10. a surrogate of response to endocrine therapy ?
Ki-67
a surrogate of response to endocrine therapy ?
Clinical utility of on-treatment Ki67 level measured in NET trials at different time-points.
Surgery
Which the best time point to assess Ki-67?
One potential limitation of the early assessment of Ki-67 is the development of delayed or acquired resistance
Barroso-Sousa R et al.ecancer 2016

11. In the United States, we are routinely giving neoadjuvant CHT, but based on our PEPI model, one-third of pts did not even need CHT since endocrine therapy alone was sufficient to control their disease long term
PEPI score
The preoperative endocrine prognostic index PEPI score
was developed
Ellis M et al J Natl Cancer 2008,Barroso-Sousa R et al ecancer 2016

12. The FUTURE? ALTERNATE trial (Alliance A011106 ) PEPI score Ki-67
the advantage of measuring two-week Ki67 instead of pretreatment Ki67 is being prospectively investigated in the large (n = 4.000) peri-operative endocrine therapy for individualising care window-of-opportunity trial.(to predict response from adjuvant endocrine therapy
POETIC TRIAL
Anziche
Valutare il Ki67 a due settimane anziche prima del trattamento
ALTERNATE trial
(Alliance A )
2280 postmenopausal women with clinical stage II or III HR+, HER-2-negative BC to receive NET with anastrozole, fulvestrant, or the combination of these two drugs for 24 weeks.
Ki-67 is >10%, pts are recommended to switch to 12 weeks of weekly paclitaxel for the determination of the pCR in this population.
Ki-67 <10% will continue their assigned regimen to complete 24 weeks of NET followed by surgery and PEPI score calculation

13. The FUTURE?
Ki-67
Study that aims to evaluate the role of Ki-67 as an early predictive surrogate marker for therapy response under a short induction treatment
German ADAPT
HR+,HER-2 negative
postmenopausal women will receive a three week induction with AI, HC evaluation of Ki-67 will be determined by central pathology and the measurements will be performed from the diagnostic core biopsy tumour sample and the repeat core biopsy after induction therapy . Optimal therapy response is defined as a drop of Ki-67 to or below 10%
Anziche
Valutare il Ki67 a due settimane anziche prima del trattamento
the Ki-67 value after the induction therapy, treatment decision will be based on pretreatment risk assessment (recurrence score (RS) by the OncotypeDx® and nodal status
Non responders (post-therapeutic Ki-67 >10%) and patients initially identified as high-risk for recurrence (N2-3 or N0-1 and RS ≥ 26) will be randomised to a chemotherapy protocol optimising dose-dense taxane-based chemotherapy.

15. Network diagram of studies comparing clinical objective response (COR) of different neoadjuvant endocrine therapy (NET) therapies for HR-positive breast cancer.
CONCLUSION: our study proved that letrozole plus everolimus is the most effective treatment for postmeno- pausal, HR-positive breast cancer in the neoadjuvant setting. In addition, when patients have hot flushes during the period of NET, NSAIDs, such as celecoxib, are recommended.

16. Importantly, one should keep in mind that the decision to prescribe NET to a given patient is not necessarily an irreversible one; in case of poor clinical response, the treatment can be switched to immediate surgery or chemotherapy.

17. Antonino Grassadonia
Università «G. D’Annunzio» – Chieti-Pescara