Valentina GuarneriDiSCOG, Università di Padova

Istituto Oncologico Veneto IRCCS

J Clin Oncol. 2014 Apr 1;32(10):1050-7.

Primary systemic therapy in breast cancer

• Tumor biology, rather than stage, is the driver of treatment selection

• Most patients with HR+/HER2- disease are offered adjuvant hormonal

therapy alone, even in case of node + disease

• In the tamoxifen era, neoadjuvant hormonal therapy has been

traditionally limited to elderly, unfit patients with large, inoperable

disease

• Aromatase inhibitors have opened new options

Let Tam p value

Clinical OR % 55 36 < 0.001

USG response % 35 25 0.042

Mammographic response % 34 16 < 0.001

BCS % 45 35 0.022

Breast pCR # 2 3

Eiermann W et al. Ann Oncol 2001

P024: a double blind randomised trial of

preoperative letrozole versus tamoxifen

A T A+T

Clinical OR % 37 36 39

USG response % 24 20 28

Improvement in BCS % 46* 22 26

* p 0.03

Smith IE et al , JCO 2005

IMPACT Trial: results

Neoadjuvant endocrine therapy vs CT in

postmenopausal women with HR+ BC

Doxo60+TXL200 q3w X 4 (118 pts)

ET for 3 mos (121 pts) Exemestane or Anastrozole

R Surgery

ChemoRx Endocrine Rx

Clinical OR % 63.6 64.5

USG response % 46 40

Mammography % 63 60

BCS % 24 33

pCR % 6 3

LRF at 3y % 2.3 3.3

Semiglazov VF, Cancer 2007

Alba et al, Ann Oncol 2012

CT arm HT arm p-value

ORR 66% 48% 0.075

BCS 47% 56% 0.23

pCR 2% - 0.6

pN0 36% 29% 0.47

95 ER+/ PgR +/HER2- patients randomized to:

EC x 4 → Docetaxel 100 x 4

Exemestane x 24 weeks (+ goserelin if pre-menopausal)

The Mechanism of Endocrine Resistance

De novo

ER lossER loss

CoA/CoR expressionCoA/CoR expression

Acquired

Growth factor signaling

pathway activation：

PI3K/AKT/mTOR

MAPK/ERK

Growth factor signaling

pathway activation：

PI3K/AKT/mTOR

MAPK/ERK

Tumor microenvironment

changes

Tumor microenvironment

changes

Image from Osborne CK, et al. Annu Rev Med. 2011;62:233-247.

Bianco S and Gévry N, Transcription. 2012;3(4):165-70; Zill M, et al. Biochim Biophys Acta. 2009;1795:62-81. 9

The mechanisms of Endocrine resistance

PI3K

AKT

PTEN

mTOR

RAS

RAF

MEK

MAPK

ER target gene transcription

P P

EGFRHER2

E

E

ER

E

ER

E

ER

E

TKI

Aromatase InhibitorNonsteroidal AIs

Anastrozole Letrozole

Steroidal AIsExemestane

Aromatase InhibitorNonsteroidal AIs

Anastrozole Letrozole

Steroidal AIsExemestane

Selective Estrogen Receptor ModulatorsTamoxifen Toremifene

Selective Estrogen Receptor ModulatorsTamoxifen Toremifene

ER DownregulatorFulvestrant

ER DownregulatorFulvestrant

Cell

Cycle

Combining targeted and antiestrogen therapies

in HR positive BC

Combining targeted and antiestrogen therapies

in HR positive BC

EGFR/HER2 inhibitorsEGFR/HER2 inhibitors

• Blocks signaling through

ErbB1 and ErbB2 homodimers

and heterodimers

• Might also prevent signaling

through heterodimers between

these receptors and other

ErbB family members

• Potentially blocks multiple

ErbB signaling pathways

Downstream Signaling Cascade

1 + 1 2 + 2 1 + 2

Lapatinib: HER1-2 TKI

S

U

R

G

E

R

Y

R

Letrozole 2.5 mg daily for 6 months

Sample size: 91 pts

HR+/HER2 -,

postmenopausal

operable BC

(Stage II-IIIA)Lapatinib 1500 mg daily for 6 months

Letrozole 2.5 mg daily for 6 months

Placebo daily for 6 months

♥ ♥ ♥

Study Design

Study Aims

Primary Aim

• Rate of breast clinical objective responses (cOR) (completeplus partial, measured by USG)

Secondary Aims

• Breast and axillary pCR rate

• Rate of breast conservative surgery and conversion from

mastectomy to BCS

• Safety profile

• Biomarkers analyses

• Gene expression profiling

• Time to treatment failure from start of primary therapy

Key inclusion criteria

• Previously untreated, infiltrating primary breast cancer of

more than 2.0 cm in largest clinical diameter

• Estrogen and/or progesterone receptor positivity (10% of

positive cancer cells by immunohistochemistry)

• HER2 negativity

• ECOG PS 0-1

• Normal LVEF

• Normal organ and marrow function

• Written informed consent

Enrollment

0

5

10

15

20

25

30

35

40

Cremona Modena Carpi Piacenza ReggioEmilia

Rimini

Patient and tumor characteristics

Letrozole-Lapatinib

(Arm A) n= 43

Letrozole-placebo

(Arm B) n=49

n (%) n (%)

Median age, yrs (range) 70 (49-88) 70 (47-88)

ECOG PS 0 41 (95.35) 45 (91.8)

1

NA

2 (4.65)

0

3 (6.12)

1 (2)

Clinical stage: IIA 21 (48.8) 26 (53)

IIB 17 (39.5) 21 (42.9)

IIIA 5 (11.6) 2 (4.1)

Histology: Ductal 29 (67.4) 38 (77.6)

Lobular 8 (18.6) 7 (14.3)

Other/not specified 6 (14) 4 (8.12)

Histologic Grade: 1/2 17 (39.5) 19 (38.8)

3 13 (30.2) 19 (38.8)

NA 13 (30.2) 11 (22.4)

Mean ER expression (range) 89% (40-100) 90% (30-100)

Mean PgR expression (range) 56% (0-100) 52% (0-100)ER: Estrogen Receptor; PgR: Progesterone Receptor; NA: Not Available

Adverse Events (AEs) occurring in at least 10% of

the study population and AEs Grade 3 to 4

Letrozole-Lapatinib (n=43)

N (%)

Letrozole-placebo (n=49)

N (%)

AE description overall Grade 2 Grade 3 Grade 4 overallGrade

2

Grade

3

Grade

4

Skin disorders 25 (58.1) 10 (23.2) 4 (9.3) 1 (2.3) 3 (6.1) 1 (2.0) 0 0

Nail toxicity 5 (11.6) 1 (2.3) 2 (4.6) 0 0 0 0 0

Diarrhea 26 (60.5) 4 (9.3) 6 (13.9) 0 5 (10.2) 2 (4.1) 0 0

Increased

transaminases8 (18.6) 2 (4.6) 2 (4.6) 0 2 (4.1) 0 1 (2.0) 0

Increased GGT 3 (6.9) 0 2 (4.6) 0 0 0 0 0

Mucositis 7 (16.3) 5 (11.6) 0 0 1 (2.0) 0 0 0

Fatigue 7 (16.3) 1 (2.3) 1 (2.3) 0 6 (12.2) 1 (2.0) 0 0

Muscoloskeleta

l disorders6 (13.9) 1 (2.3) 1 (2.3) 0 9 (18.4) 3 (6.1) 0 0

Dispepsia 5 (11.6) 2 (4.6) 0 0 5 (10.2) 0 0 0

Nausea 2 (4.6) 0 0 0 6 (12.2) 0 0 0

Congestive

heart failure1 (2.3) 0 1 (2.3) 0 0 0 0 0

Response rate per treatment arm

Surgical outcomes

0

10

20

30

40

50

60

70Conversion from

mastectomy

BCS

ARM A Letrozole-Lapatinib ARM B Letrozole-placebo

Treatment effect on tumor biomarkers

Guarneri V, et al. J Clin Oncol 2014

Baselga J, The Oncologist 2011

Cancer Genome Atlas Network. Nature 2012, 490:61-70

PIK3 pathway deregulation in breast cancer

• The prognostic role of PIK3CA mutation in HR-positive BC

has been controversial

• PIK3CA mutations emerge as a non-independent prognostic

factor probably because of the positive association with HR

positivity and good prognostic features.

• In the TEAM study, PIK3CA mutated patients (39.8 %)

experienced a significant better 5-yr DDFS vs wild-type

patients (91 vs 88 %; HR 0.76 95 % CI 0.63–0.91, p=0.003)

• PIK3CA mutation did not maintain an independent prognostic effect in multivariate analysis

PIK3CA mutations in HR+ BC

Responses according to PIK3CA status in

the LET-LOB study

ORR 63% in WT vs 93% in PIK3CA

mutated tumors, p=0.037ORR 66% in WT vs 63% in PIK3CA

mutated tumors, p=0.79

Mean Ki67 suppression overall, by clinical

response and by PI3KCA status

Heatmap of differentially expressed genes

Conclusions

• The combination of letrozole-lapatinib in early breast cancer

was feasible, with expected and manageable toxicities.

• In unselected ER+/HER2- patients, letrozole-lapatinib and

letrozole-placebo resulted in a similar overall clinical response

rate

• A significant decrease in Ki67 and pAKT was observed in

both treatment arms.

• A significant correlation between PIK3CA mutation and

response to letrozole-lapatinib in hormone receptor

positive/HER2 negative early breast cancer was observed

• These data warrant independent confirmation