Malattia HER-2 positiva

(1)

Malattia HER-2 positiva

Patrizia Vici

Novità sul trattamento del

carcinoma mammario

(2)

Neoadjuvant - Adjuvant - Advanced

Prognostic/Predictive factors

……..Her-2 heterogeneity……..

(3)

«Trend»

advantage from adding

pertuzumab

Neoadjuvant

Pre-planned

Phase II

(4)

Despite identical adjuvant therapy (Trast):

Association between pCR and long term outcomes

(5)

NeoSphere

Gianni L et al, SABCS 2012

(6)

(7)

pCR prognostic of good long- term outcomes

n.s.

DFS OS

(8)

DFS n.s.

OS: lapatinib better in HR+?

DFS OS

(9)

pCR: strongly prognostic (better OS) for Trastuzumab (pCR vs no pCR), not for Lapat

no pCR: OS trend better Lapat

(10)

(11)

(12)

PIK3CA… and pCR/DFS/OS in HER-2 +

(13)

(14)

(15)

(16)

n.s.

p.s.

By intrinsic subtype (all arms)

T H L T

H No advant.

dual block

(17)

(18)

HR-/wt : better pCR

Double-block-mutated: low pCR

(19)

(20)

from NeoALTTO

53%

28%

(21)

Guarneri V Oncologist 2015

Biomarkers Cher-lob

PIK3CA mutation exon 9 or 20

(20% of the pts)

Overall, no differences in wt or mutated in pCR (33%vs23% p ns) Trast+Lap: pCR wt 48.4% vs mutated 12.5%, p 0.06

PIK3CA mutations seem to identify pts

less sensitive to dual-block Trast/Lap

(22)

(23)

NEOPHOEBE (CBKM120F2203)

A phase II, randomized, parallel cohort, two stage, open-label study of neoadjuvant trastuzumab (T control) versus T + BKM120 in combination with weekly paclitaxel in HER2- positive, PI3KCA wild-type (WT) and PIK3CA mutant (mt) primary breast cancer

(24)

TILs in Her-2 + BC

(25)

(26)

(27)

Geparsixto HER2 + LPBC epithelial

stromal No LPBC

(28)

(29)

(30)

EFS

Predictive for pCR

Prognostic for EFS

(31)

(32)

BEYOND BIOMARKERS….

(33)

Residual Disease After Neoadjuvant Therapy for HER2-Positive Early BC

• Questions remain on optimal approach for patients with residual disease following neoadjuvant therapy, and various trials are currently ongoing in this setting

1. ClinicalTrials.gov. NCT01772472. 2. ClinicalTrials.gov. NCT00925652. 3. ClinicalTrials.gov. NCT01401959.

4. ClinicalTrials.gov. NCT01618357. 5. ClinicalTrials.gov. NCT02061423. 6. ClinicalTrials.gov. NCT02110199.

Study Phase Treatment Setting

KATHERINE^[1] III T-DM1 vs trastuzumab Adj tx in pts with HER2+ BC and residual disease after neoadj tx

ABCDE

(TBCRC 012)^[2] II

Dietary intervention ± exercise intervention

± bevacizumab and metronomic chemotherapy

Adj tx in pts with HER2+ BC and residual disease after neoadj tx

SCRI BRE 186^[3] II Eribulin + trastuzumab Adj tx in pts not achieving pCR after neoadj tx NCT01618357^[4] I Preoperative radiation and veliparib Pts with residual disease after neoadj tx NCT02061423^[5]

NCT02110199^[6] I HER2 pulsed DC vaccines Pts with ER- residual disease after neoadj tx

(34)

Key Ongoing Phase III Neoadjuvant Studies in HER2+ Early Breast Cancer

ClinicalTrials.gov.

Study Planned

N

Treatment Primary Endpoint Notes

B327-04

(NCT02187744) 220 Docetaxel/carboplatin + PF-05280014 or H

% with steady drug conc >

20 µg/mL

PF-05280014, CT-P6, ABP 980 are H

biosimilars

NCT02162667 532 CT-P6 vs H pCR

Lilac

(NCT01901146) 808 Epirubicin/cyclophosphamide/

paclitaxel + ABP 980 or H pCR

NCT01785420 1100 Trastuzumab vs placebo DFS Stage I, preop Tx

GeparOcto

(NCT02125344) 950 ETC + HP vs

PM(Cb) + HP pCR

Comparison of 2 dose-dense approaches +

dual HER2 targeting

NSABP B-52

(NCT02003209) 212

Docetaxel/carboplatin/HP, surgery, RT ± estrogen

deprivation

pCR in breast and

posttherapy LN Dual HER2 targeting

KRISTINE

(NCT02131064) 432 Docetaxel/carboplatin/HP vs

T-DM1/pertuzumab Local pCR

Adj therapy:

H + pertuzumab or T-DM1 + pertuzumab

(35)

Adjuvant

Trastuzumab

benefit confirmed

(36)

(37)

After adjuvant….

(38)

(39)

Small HER2 positive tumors

What systemic adjuvant therapy, if any, should be recommended for small, HER2-positive cancers (10% of all early-stage breast cancers)?

O'Sullivan C, et al. JCO.2015.60.8620

A total of 4220 patients with small (2 cm) HER2-positive BC treated in randomized trials were included in this analysis

(40)

Small HER2 positive tumors

Pts with HR+ disease and tumors < 2 cm

• ↑ DFS (17.3% vs. 24.3%, p < 0.001)

• ↑ OS (7.8% vs. 11.6%, p < 0.005)

Pts with HR- disease and tumors < 2 cm

• ↑ DFS (24% vs. 33.4% p < 0.0001)

• ↑ OS (12.4% vs. 21.2% p < 0.0001)

(41)

Investigation of the association between tumor PTEN protein expression and Disease Free Survival

Prognostic/Predictive biomarkers

Tissue microarrays

(42)

Intermediate-levels ERBB2, High levels ESR1 mRNA expression

Low trastuzumab benefit

(43)

Arm A n.s.

ArmB/C enriched p.s .(not enriched n.s).

Enriched: high RFS trastuz, no CT

Not enriched: n.s.

Not from chemo

«Immune enriched»

if >9 of 14 immune genes were expressed

Predictive in arms B and C (trastuz.), not

A (chemo)

(44)

Her2-enriched Other Her2+ subtypes

All PAM50 intrinsic

subtypes benefit from

trastuzumab

(45)

CT+trast

CT

(46)

TILs and FinHER

(Loi S Ann Oncol 2014)

209 Her-2 + pts

Each 10% increase in TILs significantly associated with decrease recurrence in the trastuzumab arm (p 0.025)

High TILs -> high trastuzumab benefit

(47)

High TIL=lack trast efficacy

TIL prognostic (high TIL -->good RFS (Arm A: CT alone)

TIL not prognostic for CT/trast

???

But 94 pts and 8 recurrences!

90%

64%

80%

(48)

Advanced

(49)

PIK3CA represented the greatest prognostic factor, with longer PFS in patients with wild-type vs mutated PIK3CA tumors in both the control (13.8m vs 8.8m) and pertuzumab (21.8m vs 12.5m) groups

(50)

[TITLE]

Presented By Martine J. Piccart-Gebhart, MD, PhD at 2013 ASCO Annual Meeting

PFS

M Piccart ASCO 3013…

T-DM1 and PIK3CA mutation

(51)

BEYOND BIOMARKERS

(52)

1°

line

(53)

Prespecified specific threshold not crossed

(54)

Not better…?

(55)

(56)

T-DM1 expanded access

215 US Her2 positive, pretreated advanced BC pts

Median n of cycles 8 (3-23)

Median T-DM1 treatment duration: 5 mo (0-29)

ORR 25.6%

Toxicity and activity comparable with that reported in clinical trials

Yardley DA Cancer J 2015

TH3ERESA: OR, PFS, OS advantage

(57)

Eribuline + Trastuzumab

I° line MBC trial Phase II

Wilks S, Puhalla S, O'Shaughnessy J et al: Phase 2, multicenter, single-arm study of Eribulin Mesylate with Trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. Clin Breast Cancer 2014,

(58)

1° line: Trast >>> Lapat

PFS OS

652 pts

In pts centrally confirmed Her2+ OS p.s.

(59)

PFS

OS

t. to symptom PD Pts with treated asymptom CNS met

and pts developing CNS met during Emilia

Brain met

(60)

Brain met

No difference in CNS met incidence : 3% vs 5%

PFS OS

Lap/cape vs Trast/cape

(61)

No prior trast Prior trast

1° line Advanced line

(62)

Focusing on Her-2 heterogeneity

(63)

(64)

(65)

Prat et al JNCI 2014

Her-2 heterogeneity

IHC

Cancer Genome Atlas + Metabric datasets

Subtype is more informative than HER2-status on

breast cancer specific DFS

(66)

Reciprocal crosstalk between estrogen receptor (ER) α and growth factor receptor signaling pathways.

Miller T W et al. JCO 2011;29:4452-4461

Caratterizzazione biologica: crosstalk

Triple positive BC

(ER+/PgR+/Her2+)

(67)

67

Breast Cancer Subtypes: 21% Her-2 positive

67

Breakdown of the 21%

HER2+

Bauer K., Cancer. 2010;10:228.

ER+/PR+/HER2+

ER+/PR-/HER2+

ER-/PR+/HER2+

ER-/PR-/HER2+

10.8%

7.1%

3.3%

0.5%

N=114,786

~21% HER2+

~79% HER2-

Triple positive

(68)

[TITLE]

Trastuzumab benefit less impressive ?

Even double-block works less in ER+

???

Less pCR

Her-2+/HR+

(69)

Less pCR

(70)

[TITLE]

pCR: less predictive value (EFS) Her2+/ER+ tumors

(71)

Prognostic impact of pCR on DFS according to breast cancer intrinsic subtype

von Minckwitz G et al J Clin Oncol 2012

Luminal A

Luminal B HER2 neg

Luminal B HER2 pos

HER2 positive Triple neg

no

yes yes

yes no

(72)

3,394 Her-2 positive pts

2000-2007(44% treated with neoad/adj trastuz)

Recurrence : 45% HR+, 55% HR- Recurrence beyond 5yrs: 66%

HR+ vs 34% HR neg

Timing of recurrence

HR+

HR-

Curves tend to converge (late

recurrences?)

OS by HR status

(73)

Metastatic Behavior of Breast Cancer Subtypes

Brain Liver Lung Bone Distant Nodes

Pleura

/peritoneum

Luminal A 7.6 28.6 23.8 66.6 15.9 28.2

Luminal B 10.8 32.0 30.4 71.4 23.3 35.2

Luminal/HER2 15.4 44.4 36.8 65.0 22.2 34.2

HER2 enriched 28.7 45.6 47.1 59.6 25.0 31.6

Basal Like 25.2 21.4 42.8 39.0 39.6 29.6

TN non basal 22.0 32.1 35.8 43.1 35.8 28.4

H Kennecke, JCO 2010 Frequency among pts who developed mts(%)

Pearson’s Chi-square test showed p <0.001 in all cases

(74)

Quantitative expression of HRs may influence response rate to trastuzumab and chemotherapy

Receptor positivity Number

(%)

CR + PR (%)

SD+PD (%)

P value*

ER

0-29% 140 (66) 95 (68) 45 (32) 0.032

30-100% 72 (34) 38 (53) 34 (47)

PgR

0-49% 195 (92) 126 (65) 69 (35) 0.055

50-100% 17 (8) 7 (41) 10 (59)

Multivariate Odds Ratio of response in tumors expressing ER in ≥30% of cells 0.422, 95% C.I. 0.222-0.803, p = 0.009

Montemurro, Cancer 2012

(75)

• Different staging ? ( more bone and less brain recurrences?)

• Different f up ^? (timing and type of follow up, since

luminal B Her 2+ may recur after 10-15 years….)

(76)

08.11.2014

Carcinoma mammario triplo positivo. Una nuova entità? 76

n.s.

Innovative

predictive factors

????

(77)

Ongoing studies without chemo in HR+/Her2+ tumors

PER ELISA (neoadjuvant) ADAPT (neoadjuvant) HERLAPAC 2 (advanced)

PERTAIN (advanced)

(78)

Triple positive

Concurrent endocrine neoadjuvant

Ph. II random

Without chemo, but

only 12wks….

ONGOING

(79)

RFS OS

925 pts Her2 +

925 Her2+

pts

5yr RFS 5yr OS

(80)

RFS

OS OS

(81)

(82)

Triple positive early breast cancer

• Retrospective analysis:

872 TP early BC from 19 italian oncologic centres

• Cohort A: chemotherapy (-> endocrine therapy)

• Cohort B: chemotherapy + trastuzumab (-> endocrine therapy

(Vici et al, under rev)

(83)

3 and 5 year RFS and BCSS in the two cohorts

(84)

Multivariate logistic regression model of factors impacting

survival outcomes in the study population.

(85)

RFS (1) and BCSS (2) in the overall study population (N=872) according to cohort

(m f up 78mo).

Overall: trastuzumab benefit, but….

(86)

Hazard rate of recurrence for the overall study population (panel A) and in pts with ER and PgR staining >50% of tumour cells (TP50, panel B) and other pts (noTP50,

panel C).

overall . TP50

No TP50

More relapses in the first 5 yrs, constant effect of

trastuz.

Late recurrence, less trastuz effect

(87)

Stepp analysis of the effect on ER (Panel A) and PgR (Panel B) expression on the hazard of relapse in the two cohorts

ER

PgR

(88)

BluePrint 80-gene assay: two distint TP subtypes

Whitworth PW, Breast Cancer Symposium 2015

Neoadjuvant Breast Symphony Trial

Compare multigene classifiers to conventional IHC/FISH to predict pCR to standard CT+Her2-block

80-gene assay re-classified more than 1/5 tumors pCR 54% in BP-Her2 pts vs 40% in the IHC/FISH-Her2+ pts (p 0.02)

The group with biggest change was the TP group

(48% pts are re-

assigned in the low-responsive-BP Luminal vs 44% assigned to responsive-BP Her2 +)

137 IHC/FISH TP: BP reclassified -> BP Luminal (66, pCR 11%) BP Her2 (60, pCR 45%)

In the TP luminal group pCR ,low with trastuzumab, was higher with CT+trastuzumab/pertuzumab

(89)