Unit of Investigative Clinical Oncology (INCO) Fondazione del Piemonte per l’Oncologia
Candiolo Cancer Institute (IRCCs)
Aggiornamenti tra ricerca e clinica: il carcinoma della mammella
Filippo Montemurro
Investigative Clinical Oncology
De-escalate breast cancer therapies in early breast cancer without sacrificing outcomes
Explore optimal adjuvant treatment durations
Develop better tools to identify patients with genetic predisposition
Improve care in young patients with breast cancer
Develop tools to speed up drug development in biomarker- defined populations
Identify and validate targets that mediate resistance to chemotherapy, endocrine therapy or anti-HER2 therapies
Research Needs in Breast Cancer
Cardoso et al, Ann Oncol, Epub 9
thNov 2016
Evaluate the efficacy of local-regional treatments for metastatic disease
Better define the optimal sequence of treatments in the metastatic setting
Evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity)
Better understand the biology and identify new targets in triple- negative breast cancer
Better understand immune surveillance in breast cancer and further develop immunotherapies
Increase survivorship research efforts including supportive care and quality of life
Research Needs in Breast Cancer: 2016
Cardoso et al, Ann Oncol, Epub 9
thNov 2016
Investigative Clinical Oncology
Altough many of these aims are being pursued by innovative clinical trial designing, most of the recent practice changing treatments come from
"traditional" randomized phase III trials, where meeting the "primary end-point" provides
evidence for registration (almost always)
My problem….
Not always a problem:
CLEOPATRA trial
First-line
HER2 positive
MBC
Investigative Clinical Oncology
PALOMA 2: Study Design
Slamon R, et al. ASCO 2016. Abstract 507.
CDK 4/6 inhibitors added to endocrine therapy Paloma 2: primary end-point analysis
First-line HR+ HER2- MBC
Finn et al, NEJM 375;1925, 2016
Investigative Clinical Oncology
CDK 4/6 inhibitors added to endocrine therapy Monnaleesa 2: primary end-point analysis
Hortobagyi et al. NEJM, epub Oct 2016 First-line
HR+ HER2-
MBC
Cyclin Dependent Kinase (CDK) 4/6 Inhibitors
Investigative Clinical Oncology
Palbocliclib: CDK 4/6 Inhibitor – Breast Panel
Finn RS. Breast Cancer Res 2009
Potential biomarkers of palbociclib
activity
Investigative Clinical Oncology
Clinical evaluation of biomarkers of Palbociclib Activity
Rb Protein CCDN1
P16 ER status (central review)
Finn et al, ESMO 2016
Two-component tumor growth model
Cytotoxic model: fast response and
highly resistance tumor burden model Cytostatic model: slow response and highly resistance tumor burden model
Filleron et al, Ann Oncol 27; 1981, 2016
Investigative Clinical Oncology
How frequency of restaging influences TTP
Cytotoxic Citostatic
Filleron et al, Ann Oncol 27; 1981, 2016
Different estimates of TTP according to assessment schedule
Filleron et al, Ann Oncol 27; 1981, 2016
Investigative Clinical Oncology
Paloma 2: primary end-point analysis
Finn et al, NEJM 375;1925, 2016
BOLERO-2 (NCT00863655) Study design and results
Baselga J, NEYM 2012
Yardley DA, Adv Ther. 2013
Assessment Arms Events/N PFS (mo) HR (95% CI) P-value
Local EVE+EXE 310/485 7.8 0.45 (0.38-
0.54) P<0.0001
PBO+EXE 3200/239 3.2
Investigative Clinical Oncology
BOLERO-2 (NCT00863655)
Efficacy and safety according to visceral vs non-visceral metastases
Campone M. EJC 2013
Visceral
Non-visceral
BOLERO-2 (NCT00863655)
39 months follow-up: OS analysis
Investigative Clinical Oncology
Should we abandon single agent endocrine therapy?
Tiurner et al, NEJM 375;1925, 2016 Hortobagyi et al, NEJM 375;1738, 2016 Finn et al, Lancet Oncol 16; 25, 2015 Turner et al, NEJM 373; 209, 2015 Piccart et al, Ann Oncol 25; 2357, 2014 Bachelot et al, JClin Oncol 30;2718, 2012 Dickler et al, ASCO 2015
Martin et al, J Clin Oncol, epub feb 2015
Author (Year) Setting ET
alone ET+ biologic ∆RR (∆CBR)
aMonths ∆PFS
aMonths ∆OS
aMonths Turner (2016) 1st Line metastatic Letroz. Letroz.+Palbo 10.9% (14.6%)* 10.3* N.R.
Hortobagyi (2016) 1st Line metastatic Letroz. Letroz.+Palbo 15.6% (9.3%)* >10* N.R.
Finn (2015) 1st Line metastatic Letroz. Letroz.+Palbo 9% (21%)* 10* 4.2
Turner (2015) Failing prior ET Fulv. Fulv+Palbo. 4.1% (15%)* 5.4* -
Piccart (2015) Failing prior NSAIs Exem. Exem.+ Everolimus 9.1%* (25%)* 4.1* 4.4 Bachelot (2012) Failing prior AIs Tam. Tam.+Everolimus 1% (19%)* 4.1* 0.45 (HR)*
Dickler 2015 1st line metastatic Letroz. Letroz.+ Bevacizumab 20%* b (18%)* b 4* 3 Martin 2015 1st line metastatic Letroz. Letroz.+Bevacizumab 18.9%* (9.4%)* 4.9* N.S.
aIncrease in response rate (RR), clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS) of combined therapy vs endocrine therapy alone.
bCalculated in patients with measurable disease.
*Increase is statistically significant
Abbreviations: ET, endocrine therapy; NSAIs, non-steroidal aromatase inhibitors; AIs, aromatase inhibitors; HR, hazard ratio. Fulv, fulvestrant; Letroz., letrozole;
Exem., exemestane; Tam., tamoxifen.
