management of breast cancer: past, present and future · early breast cancer (ebc) patients (n =...
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Angelo Di Leo
“Sandro Pitigliani” Medical Oncology Department Hospital of Prato
Istituto Toscano Tumori, Prato, Italy
Management of breast cancer:
past, present and future
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Adjuvant chemotherapy:
Which patient?
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Luminal A-like patients do not seem to derive benefit from adjuvant chemotherapy
N- ER+ pre- and post-menopausal TAM vs CMF/MF + TAM
Paik S et al, J Clin Oncol 2006 Albain K et al, Lancet Oncol 2010
N+ ER+ post-menopausal TAM vs CAF + TAM
high
intermediate
low
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Main limitations of the presented studies
Modest sample size potential risk of false positive/negative results
Retrospective design mainly hypothesis-generating studies
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Contrasting evidence on the role of adjuvant chemotherapy in ER+ tumors is provided by the
EBCTCG overview
The most recent results provided by the EBCTCG overview are based on ± 100.000 women and 123 randomised trials
The overview results suggest that adjuvant chemotherapy proportional benefits are independent of patient’s age, nodal status, ER status, and histology grade
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by the EBCTCG, The Lancet 379: 432-44, 2012
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Issues limiting the use of the overview results on adjuvant chemotherapy in clinical practice in 2015
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ER + tumors are clinically heterogeneous
Results for the ER + patients aged < 55 may at least in part be related to ovarian function suppression due to chemotherapy, and they may tend to over-estimate benefits deriving from chemotherapy cytotoxicity
The population evaluated in the overview does not seem to represent the majority of the population seen in today’s practice
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Conclusions: can we avoid the use of adjuvant chemotherapy in Luminal A breast cancer?
Lack of strong evidence in favour of, or against, adjuvant chemotherapy in Luminal A breast cancer
Prospectively-designed trials are ongoing (Rx-Ponder, Mindact, TailorX)
In the meantime
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• N neg. N + 1-3 N + ≥ 4
No Maybe Yes
Consider the patient’s wishes and expectations
Adjuvant chemotherapy
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Adjuvant chemotherapy in 2015: What regimen?
Once the decision is made to give adjuvant chemotherapy, should an anthracycline-taxane regimen be the
standard of care for all patients?
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Chemotherapy regimens by intrinsic subtype (My personal opinion)
Considering the lack of bio-markers with proven predictive value for the activity of individual regimens, risk (pT, pN) may still be an important factor to select the most appropriate regimen
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Luminal A Luminal B HER-2 + Triple negative*
Low risk
High risk
No chemo TC CMF
TCH TC+H T+H TC
CMF
TC CMF
A T A T+H A T
TC=Docetaxel-Cyclophosphamide, A T=Sequential antracycline-taxane, TCH=Docetaxel-Carboplatin-Herceptin, TC+H=Docetaxel-Cyclophosphamide-Herceptin, T+H=Weekly paclitaxel-Herceptin, A T+H=Sequential anthracycline-taxane+herceptin
* Consider platinum compounds if BRCA mutation
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Challenges for the future
Intra-tumor heterogeneity: should we target adjuvant therapy on
the most prevalent tumor cell type identified
the most biologically-aggressive tumor cell type identified
Improving the definition of risk of disease relapse
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?
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A considerable proportion of early breast cancer patients not receiving adjuvant systemic therapy do not relapse
surgery
CMF
no adjuvant systemic therapy
N+ Median f-up 28.5 yrs.
N- ER- Median f-up 20 yrs.
RFS
%
CMF
Surgery
Bonadonna G et al, BMJ 2005
CMF
Surgery
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A considerable proportion of ER+ “high risk” patients treated with tamoxifen as the only adjuvant therapy do not relapse
N- ER+* N+ ER+**
R Tamoxifen
Chemo tamoxifen R
Tamoxifen
Chemo tamoxifen
* Paik S et al, J Clin Oncol 2006; ** Albain K et al, Lancet Oncol 2010
High risk cohort High risk cohort
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Present and Future
Year 2015 Year 20…
to define risk of disease relapse
to define responsiveness to adjuvant therapies
to define responsiveness to
adjuvant therapies (The Predictor)
to define risk of disease relapse (The Detector)
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Can metabolomics predict the risk of disease relapse?
To explore the value of metabolomic spectra from serum samples of early breast cancer patients in predicting disease relapse
Potential advantage of metabolomics: data are collected from peripheral sites and are host- and tumor- derived
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Key-message from our pilot study: early and advanced breast cancer patients
have different metabolomic profiles
Oakman C et al, Ann Oncol 22: 1295-1301, 2011
Green : pre-operative Red : advanced stage
• Of 48 pre-operative cases, 36 are correctly classified • Of 51 advanced cases, 35 are correctly classified
(accuracy 71.7%)
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The second study
Breast Medicine Service Memorial Sloan-Kettering Cancer Center New York
“Sandro Pitigliani” Dept. of Medical Oncology, Prato, Istituto Toscano Tumori
clinical data Data-analysis
and study reports
Magnetic Resonance Center (CERM) University of Florence
Serum samples from breast cancer patients
Metabolomic data
Tenori L et al, Mol Oncol 9:128-39, 2015
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Study design
Early breast cancer (EBC) patients (N = 80)
breast surgery serum samples 1H-NMR-based metabolomic spectra*
Metastatic breast cancer (MBC) patients (N = 95)
Serum samples (before a new line of therapy)
1H-NMR-based metabolomic spectra*
* by a Bruker 600 MHZ metabolic profiler
EBC pts. split to form a training set (N = 40 pts.)
a validation set (N = 40 pts.)
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Methods
First step: to establish if metabolomic spectra could distinguish between EBC and MBC pts.
Second step: to assign a metabolomic score (MS) of relapse to each EBC pt. from the training set using a Random Forest classifier
Third step: to correlate the MS with actual clinical outcome (performance of the MS evaluated by ROC curves)
Fourth step: to replicate the analysis using the spectra from the validation set
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Metabolomic spectra from MBC and EBC patients
Discrimination between metastatic (green) N = 95 and early (red) N = 40
Accuracy: 83.7%
Tenori L et al, Mol Oncol 9:128-39, 2015
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Methods
First step: to establish if metabolomic spectra could distinguish between EBC and MBC pts.
Second step: to assign a metabolomic score (MS) of relapse to each EBC pt. from the training set using a Random Forest classifier
Third step: to correlate the MS with actual clinical outcome (performance of the MS evaluated by ROC curves)
Fourth step: to replicate the analysis using the spectra from the validation set
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Random forest: steps
1) Each sample from EBC patients evaluated through 100 decisional algorythms
2) Each algorythm made of different metabolites
3) Each sample from EBC pts. classified by each algorythm as “early” or “advanced”, based on metabolites level of expression
4) The number of times a given sample from EBC pts. is miss-classified as “advanced” indicates the “Metabolomic score”
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Methods
First step: to establish if metabolomic spectra could distinguish between EBC and MBC pts.
Second step: to assign a metabolomic score (MS) of relapse to each EBC pt. from the training set using a Random Forest classifier
Third step: to correlate the MS with actual clinical outcome (performance of the MS evaluated by ROC curves)
Fourth step: to replicate the analysis using the spectra from the validation set
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ROC curve for the Metabolomic Score from EBC patients (training set)
AUC = 0.863
Tenori L et al, Mol Oncol 9:128-39, 2015
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Methods
First step: to establish if metabolomic spectra could distinguish between EBC and MBC pts.
Second step: to assign a metabolomic score (MS) of relapse to each EBC pt. from the training set using a Random Forest classifier
Third step: to correlate the MS with actual clinical outcome (performance of the MS evaluated by ROC curves)
Fourth step: to replicate the analysis using the spectra from the validation set
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ROC curve for the Metabolomic Score from EBC patients (validation set)
AUC = 0.824
Tenori L et al, Mol Oncol 9:128-39, 2015
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Next steps
Repeat the study in a series of EBC patients treated at a different center and, possibly not treated with adjuvant systemic therapies
Use the MS information to stratify patients classified as low score or high score by Oncotype Dx® (ongoing in collaboration with the Memorial Sloan-Kettering Cancer Center)
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A new challenge for clinicians: the biopsy of a metastatic site
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Size of the problem Analysis of 29 studies comparing ER and HER-2 status between
matched primary and metastatic tumor samples
Turner NH and Di Leo A, Cancer Treat Rev 39:947-57, 2013
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Pitfalls for most of the reported studies
• Most of the studies have a retrospective design and a limited sample size
• Importantly, in most of these studies ER and
HER-2 status from the primary and the metastatic sites has not been re-assessed at the same time using the same technical procedures
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Impact of a change in ER or HER-2 status in physician’s treatment decisions
ER loss ER gain HER-2 loss HER-2 gain
37 cases 30 cases 69 cases 80 cases
stop hormonotherapy start hormonotherapy stop anti-HER-2 start anti-HER-2
22/37 (59%)
13/30 (43%)
41/69 (59%)
61/80 (76%)
Turner NH and Di Leo A, Cancer Treat Rev 39:947-57, 2013
Evaluated in 14 studies
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Is the rate of change in physician’s treatment decisions the most clinically
relevant parameter?
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Impact on clinical outcome derived from treatment change (HER-2 negative HER-2 positive treated
with anti-HER-2 based therapy)
Chang et al.
• +/+ vs. -/+
• Median OS 32 vs. 11 mos. • ORR 69 vs. 40%
Chang HJ et al, Jpn J Clin Oncol 2011; Fabi A et al, Clin Cancer Res 2011
Fabi et al.
• +/+ vs. -/+
• Median TTP 10.3 vs. 5.2 mos.
Evaluated in 2 of the 14 studies assessing the impact on physician’s treatment decisions
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Conclusions • Despite the evidence of a shift in ER and/or
HER-2 status between the primary and the metastatic sites is well documented,
• Despite the change in physician’s treatment decisions due to the shift in receptors status is also well documented,
We are lacking good evidence on the clinical activity of the treatment given because of a documented receptors shift
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Current indications in clinical practice: my opinion
• Doubts on the presence of metastatic disease (single lesion)
• No (reliable) data on HRs and HER-2 status at the primary tumor site
• HER-2 negative (primary tumor) patient heavily pre-treated, still fit for additional therapies and lack of valid options (???)
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The future: free-tumor DNA (ft DNA) and circulating tumor cells (CTC)
In favour of ft DNA
• reduced cost
• ft DNA found in the
majority of pts.
In favour of CTC
• comprehensive evaluation
of DNA and RNA
• assessment of tumor
clonality
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900 µl
14 µl
DEPArray™ system: CTCs count and sorting: single CTCs or a poll of pure CTCs, putative
CTCs and WBC
Whole blood
CellSearch CTCs enrichment EpCAM EpCAM + CD146
Analyser CTCs count
Cut off CTC ≥ 5
Whole genome amplification Ampli1 WGA Kit
Ion Torrent (Ion AmpliSeq technology) to detect
mutations in a panel of 50 target genes and/or in other genes
(customised probes)
MBC patients untreated for a least 3 weeks
DNA extraction from circulating tumor cells and gene sequencing is feasible
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A pilot study from our group testing the feasibility of detecting PIK3CA gene mutations from CTC of advanced breast cancer patients
21 ER+ pts. with ≥ 5 CTC/7.5 ml blood sample (by CellSearch® )
15 pts. 6 pts. with PIK3CA mutations
No PIK3CA mutations
4 pts. with mutations at exons 9 or 20 (confirmed
in all recovered CTC, range 1-4)
1 pt. with LOH (8 CTC)
1 pt. with heterogeneity
between CTC (19 CTC)
•
Pestrin M et al, Mol Oncol 2015, e-pub ahead of print 9 Dec 2014; doi:10.1016/j.molonc.2014.12.001
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Next Generation Sequencing
Load Chip and Sequence
• 10 ng of DNA obtained from primary tumor tissue, plasma and single CTCs • Ion Torrent platform • The Ion AmpliSeqTM Cancer Panel targets 50 cancer related genes
• The presence and frequency of a variant were interpreted through the dbSNP, 1000genomi, esp6500 and COSMIC systems
• The pathogeneity of the mutation was analysed with PolyPhen and SNPeff
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NGS Analysis of single CTCs, plasma and primary tumor tissue from pt 11; pt 12 and pt 18
Pt11
Pt12
Pt18
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Our current Phase II randomized study comparing DNA damaging vs. DNA non-damaging cytotoxics
in advanced breast cancer patients
Eligible pts
• advanced disease
• pre-treated or not (0-2 lines)
• CTC + blood sample
• access to primary tumor sample
Treatment arms DNA non-damaging regimen
(capecitabine + oral vinorelbine)
DNA damaging regimen
(Cisplatin + cyclophosphamide)
R
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Acknowledgments