Adjuvant and NeoadjuvantChemotherapy

2014 Situation

Dr Alexandre BodmerCentre du SeinHUG Genève

Encouraging….

Kaplan-Meier Survival Curves

Breast Cancer - Survival

2014 challenge

• We need to:

• Identify which patientswould benefit fromchemotherapy.

Identify which patient

Which Breast Cancers Return?

• Identify which patientwould not.

• Have reliable prognosticfactors

• Have clinically applicablepredictive factors

Risk assessmentPrognostic and predictive factors

• Tumor size

• Lymph node involvement

• Grade

• Proliferation Markers : Ki 67• Proliferation Markers : Ki 67

• Hormone receptors

• HER2 status

• Gene expression profiles

91% at5 years

80 %at5 years

98% at 5years

84% at 5years

Stage : prognostic factor

63% at5 years

5 years years

58% at 5years

Molecular subtypes and prognosis

How can we do better?

• Better selection of patients for adjuvantchemotherapy

• Treat only those patients who are most likely to recur• Treat only those patients who are most likely to recurand who will therefore benefit most from theaddition of chemotherapy

• Take advantage of genomics

ATAC trial1ABCSG-8 trial2

The PAM 50 risk of recurrence scorerisk of recurrence score (ROR)

1Dowsett M et al. Comparison of PAM50 risk recurrence (ROR) with Oncotype DX and IHC4 for predicting riskof distant recurrence after endocrine therapy JCO 2013;31:2783

2Chia SK et al. A 50 gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvanttamoxifen. Clin Caner Res 2012M18:4465

21 gene recurrence scoreOncotype DX®

• N = 675 patients ER+, N0, ttt Tamoxifen (NASBP-B14)

• Risk of distant recurrence at 10yr, according to recurrence-score categories.

7%

14%

31%

HR 3.21 p <0.001

Paik et al, NEJM 2004

31%

21 gene recurrence scorepredictive factor

NSABP B20N= 651, ER+ N0227 : TAM424 : CT + TAM

All RS :< 18

Outcome : time to

91%

90%

RS : 18-30RS > 30

Outcome : time todistant recurrence

Paik et al. JCO 2006

88%

60%

21 gene recurrence scorepredictive factor

• Retrospective analysis, 1447 patients, menopausal , N+ (1-3/>4) , RE+

• Tamoxifen vs CAF-Tamoxifen

60%64%

P=0.97P=0.97HR 1.02

55%43%P=0.033HR 0.59

Albain K et al. Lancet oncol 2010

21 gene recurrence scoreissues unresolved in 2014

• Not clear at which RS cut off chemotherapy should or shouldnot be administrated ?– Recently completed TAILORx trial will provide better data

– In this trial women with RS between 11 et 25 were randomly assignedtreatment either endocrin therapy vs chemotherapy followed byendocrine therapyendocrine therapy

• Data from SWOG study suggest role for RS in patients withinvolved lymph nodes?– We wait results from prospective study RxPONDER.

Adjvuant chemotherapy for HR+/- & HER2- BC

Adjvuant chemotherapy for HR+/-,HER2- BCAnthracycline better than CMF

EBCTCG Comparison between different polychimiotherapy regimens for early breast cancer: meta-analysis of long term outcome among 100.000 women in 123 randomised trial. Lancet 2012;379:432

Adjvuant chemotherapy for HR+ /-,HER2- BCAnthracycline + taxane better than anthracycline alone

EBCTCG Comparison between different polychimiotherapy regimens for early breast cancer: meta-analysis of long term outcome among 100.000 women in 123 randomised trial. Lancet 2012;379:432

Adjvuant chemotherapy for HR+/-, HER2- BCNo single standard regimen

• Intermediate risk– ER+/PR- or low ER/PR or T>2cm or Grade 2-3 orKi67% >20%– TC x 4 ( docetaxel 75mg/2 + Cyclophosphamide 600mg/m2)

• High risk– N+– 3xFEC – 3x docetaxel– 3xFEC – 3x docetaxel

• Alternative chemotherapy– AC /EC x 4– AC/EC x 4 –docetaxel x 4– AC / EC x 4-paclitaxel weekly x 12 weeks– 4x AC( every 14 days) -paclitaxel dose dense– FEC 100 x 6– CMF x6

Adjvuant chemotherapy for HR+/-, HER2- BCschedule / every 2 weeks treatment

Bonilla L et al. Dose dense chemotherapy in non metastatic breast cancer: a systematic review andmeta-analysis of randomized controlled trials: J Natl Cancer Inst 2010;102:1845)

Improvement of DFS and OS mainly seen for ER/ PR negative BC

Adjvuant therapy for HR+/- & HER2+ BC

Adjvuant chemotherapy for HER2+ BCbenefit of adjuvant trastuzumab

• All trials establishing the benefit (DFS and OS) of adjuvant trastuzumab1

• pT1a ?

• Trastuzumab is, still in 2014, the only HER2 directed agent to result insurvival benefit when administered with chemotherapy in the adjuvantsetting

• Subcutaneous formulation?• Subcutaneous formulation?

• On the basis of pertuzumab in neoadjuvant and metastatic setting, NCCNguidelines added: pertuzumab can be incorporated into adjuvanttreatment of HER2+, alongside trastuzumab and chemotherapy.

• However the benefit of this strategy for overall survival is not known

• Randomized trial evaluating th role of pertuzumab are ongoing.

• Other HER directed agent including trastuzumab-emtansine and lapatinibremain area of clinical investigation.

1Moja L et al. Trastuzumab containing regimens for early breastcancer Cochrane Database Syst Rev 2012;4:CD006243

Adjvuant therapy for HER2+ BCtrastuzumab duration, HERA study

Women with locally determined HER2-positive invasive early breast cancer

Surgery + (neo)adjuvant CT ± RT

Centrally confirmed IHC 3+ or FISH+

OBSERVATIONn=1698

Centrally confirmed IHC 3+ or FISH+and LVEF ≥ 55%

Randomization

1 year Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1703

2 years Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1701

After ASCO 2005,option of switchto Trastuzumab

HERA trialDFS for 2 years vs 1 year trastuzumab at 8 yrs FU

urv

iva

l(%

)

89.1%

86.7%81.0%

81.6%

75.8%

76.0%

100

80

60

Dis

ea

se

-fre

es

u

Years from randomization

60

40

20

0

0 1 2 3 4 5 6 7 8 9

No. at risk

Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194

Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205

Trastuzumab 1 year

Trastuzumab 2 years

Pts Events HR (2 vs 1) 95% CI p-value

2 years 1553 367 0.99 (0.85-1.14) 0.86

1 year 1552 367

DFS

Adjuvant therapy for HER2+ BCChoice of chemotherapy

• Several chimiotherapy regimens have been evaluated withtrastuzumab

• Anthracycline followd by taxane&trastuzumab regimen isprefered: greater experience and limited data to suggestgreater efficacy for non-anthracycline based regimengreater efficacy for non-anthracycline based regimen

• No anthracycline based regimen: docetaxel+ carboplatine+trastuzumab (TCH)(D. Slamon) = appropriate and effectivealternative

• Lower congestive heart failure (0.4% vs 2%)

Adjuvant therapy for HER2+ BCLapatinib ?

• Should not be administered in adjuvant setting

• Lack of benefit for the combined HER2 directed therapytrastuzumab + lapatinib

• ALTTO study, 4.5 years follow up: combination lapatinib +trastuzumab non impact on DFStrastuzumab non impact on DFS

Piccart-Gebhart MJ et al. First results from the phase III ALTTO trial (BIG 2-06;NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy withlapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their

combination (T+L) in the adjuvant treatment of HER2-positive early breastcancer (EBC). 2014 American Society of Clinical Oncology Annual Meeting;

Abstract LBA4.

Role of Neoadjuvant chemotherapy

Role of Neoadjuvant Chemotherapy

• Originally neoadjuvant chemotherapy was considered forwomen with large toumors or inflammatory disease

• Actually commonly used for high risk (ER-/PR-) (HER2+),operable, stage II and III, primary breast cancer.

• Associated with identical DFS and OS compared to same• Associated with identical DFS and OS compared to sametreatment in the adjuvant setting1

• Additionnal benefit:– Improvement surgical options

– Enhancement of breast conservation

• Attractive model for new drug investigation

1Mauri D et al. Neoadjuvant verus adjuvant systemic treatment inbreast cancer: meta-analysis. J Natl Cancer Inst 2005;97:188-94

Role of Neoadjuvant ChemotherapyImpact of pCR

• Assess clinical response of the primary tumor.

• Minimal response to pathological complet response (pCR)

• Definition of pCR/FDA1

– Absence of any residual invasive cancer– Absence of any residual invasive cancer

– Absence of invasive and non invasive cancer on hematoxylin and eosinevaluation on the resected breast specimen, and all sampledipsilateral lymph nodes following completion of Neoadjuvantchemotherapy

• pCR correlated with improved survival2

1Cortazar P et al. Pathological complete response and long term clinical benefit in breastcancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13

2Von Minckwitz G et al. Impact of treatment charachterisitcs on response of different breastcancer phenotypes:pooled analysis of the German neoadjuvant chemotherapy trials Breast

cencer Treat 2011;125: 145-56

Prognostic value of pCR

Cortazar P et al. Pathological complete response and long term clinicalbenefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13

Prognostic value of pCRby breast subtypes

Cortazar P et al. Pathological complete response and long term clinicalbenefit in breast cancer : the CTNeoBC pooled analysis. Lancet 2014, feb 13

Factors associated with pCR

• Adequate cumulative dose of anthracycline and taxane

• Concurrent use of trastuzumab

• ER-/PR-, G3, HER2+ : pCR rate up to 40%

Von Minckwitz G et al. Impact of treatment charachterisitcs on response of different breast cancerphenotypes:pooled analysis of the German neoadjuvant chemotherapy trials Breast cencer Treat 2011;125:

145-56

Patients selection

• Locally advanced breast cancer, stage 2-3

• Inflammatory breast cancer

• Large operable tumor (> 5cm)1

• According tumor biology, likelihood of achieving a pCR• According tumor biology, likelihood of achieving a pCR– HER2+/non luminal

– TNBC

– Luminal B

1Fisher B et al. Effect of preoperative chemotherapy on loco-regional disease in women with operable breast cancer:

findings from the NSABP B18. JCO 1997:15:2483

Patients selection

• Invasive lobular carcinoma:

– Better clinical behaviour compared with other histological types

– Lower pCR rates after neoadjuvant chemotherapy

• Offer neoadjuvant chemotherapy mainly to ILC patients with ER/PRnegative and high grade tumor

Loibl S et al. Response and prognosis after neoadjuvant chemotherapy in 1051 patientswith infiltrating lobular breast carcinoma. Berast Cancer Res Treat,2014;144:153-162

Systemic therapy

• Optimal regimen and duration of neoadjuvant chemotherapyhave not been established.

• General concensus: third generation regimen that containanthracycline and taxanes.

• NSABP B267 trial: AC x4 followed by docetaxel x4 was• NSABP B267 trial: AC x4 followed by docetaxel x4 wasassociated with a higher clinical complete response rate (63%vs 40.1% p< 0.001) compare to AC alone, and a higher pCRrate (26.1% vs 13.7%p< 0.0001)

Bear HD et al. JCO 2003;21:4165

What we have learned?

• Early switch to a non-cross resistant regimen: GeparTrio study

– Specific treatment strategies for patients with or without response to2 cycles of TAC ( docetaxel, doxorubicine, cyclophosphamide)

– Response guided ( switch to another chemotherapy in case of no earlyresponse)response)

– Patient with response guided chemotherapy had a signigificant longerDFS and OS.

– Regimen: TAC x 6 vs TAC x 8 /responder vs TAC-NX ( navelbine, xeloda)

Von Minckwitz G et al. Neoadjuvant chemotherapy adapted by interim response improvesoverall survival of primary breast cancer patients: result of the Gepar Trio trial. Cancer Res

2011;72 (24suppl)53-2

What we have learned?

• NSABP B-40 : addition of bevacizumab to neoadjuvantchemotherapy

Addition of capecitabin and gemictabine to docetaxiel .

What we have learned?

• EC (90/600mg/m2) with or without use bevacizumab 15mg/kgGeparQuinto trial

• pCR rate breast and axilla 15.9%in chimiotherapie alone vs 18.4% inbevacizumab group.

• With bevacizumab improvement of pCR rates but higher incidence oftoxicitytoxicity

• Until results of other study ( biomarkers of response), bevacizumab is notrecommended to use in neoadjuvant setting

• Incorporation of additional cytotoxic agent or anti-angiogenic agent to anthracycline-taxane basedregimens:

What we have learned?Conclusion-I

– Has not offered significant additional benefit to breastconservation or pCR rate

• Dual blockade of the HER2 receptor with trastuzumab andlapatinib

• NeoALTTO study

What we have learned?Dual blockade of HER2 signaling

• pCR :

• Combination of trastuzumab and lapatinib increase pCR rateand pCR is associated with improved survival.

• Not confirmed in adjuvant ALTTO trial1 1Piccart-Gebhart M et al. JCO 2014Abstract LBA4

• Pertuzumab, monoclonal antibody inhibiting dimerization of HER2 withother HER receptors

• NeoSPHERE phase II trial: evaluated efficacy of trastuzumab + pertuzumab+ docetaxel

What we have learned?Dual blockade of HER2 signaling

• FDA granted accelerated approval to pertuzumab for the use incombination with deocetaxel for neoadjuvant treatment of patientsHER2+, locally advanced, inflammatory, early stage greater than2cm, orwith N+

Gianni L et al. Lancet Oncol 2012,13:25

• Evaluate efficacy of carboplatin in combination with paclitaxel for HER2+ andTNBC

What we have learned?Gepar Sixto

• Results : increase of the pCR rate (37.2 to 46.7%) by addition to carboplatin

• Absolute increase by > 20% oberved in patients with TNBC (37.9% vs 58.7%)but not increase in HER2+

• Large biomarker program, including BRCA mutation in aim to identifysubgroup of TNBC that derive higher benefit from carboplatin

• We have to wait until result of correlative studies before to decide carboplatinas part of standard neoadjuvant therapy for stage 2-3 TNBC

Future perspective

• Patients who have no achieving pCR, currently no clear rolefor adjuvant chemotherapy.

• Novel compounds are being investigated in post neoadjuvant

Future perspective

• Trastuzumab-emtansine (T-DM1)– Post neoadjuvant without pCR: treatment with T-DM1 compared with

continuation of trastuzumab in HER2+ patients (Katherine Study)

• Novel cyclin D kinase 4/6 inhibitor: palbociclib– Cyclin D kinase inhibitor explored in addition to endocrine therapy in– Cyclin D kinase inhibitor explored in addition to endocrine therapy in

patients without pCR after neoadjuvant treatment (PENELOPE study)

• Olaparib:– Phase III evaluating efficacy and safety of PARP ihibitors as adjuvant

treatment in patients with germline BRCA1/2 mutations and high riskHER2- primary breast cancer.Have completed surgery and(neo)adjuvant chemotherapy

CONCLUSIONS

• Current consensus opinion for use of neoadjuvant chemotherapyrecommends anthracycline and taxane based therapy

• Several data suggest that neoadjuvant anthracycline and taxane basedtherapy is associated with the highest response rate.

• As similar survival benefits have been demonstrated for the administrationof chemotherapy before or after surgery. More frequently recommendedof chemotherapy before or after surgery. More frequently recommendedfor women with primary operable stage 2-3 disease

• Neoadjuvant chemotherapy is an attractive area for research byidentifying new effective treatment strategies

• As we enter in an era of « personalized » therapy, the identification ofsurrogate predictive and prognostic biomarkers are essential in order toaid treatment decisions.

Thank you for your attention