Adjuvant chemotherapy of breast cancer

Presenter: Dr. Gita BhatModerator: Dr. Linu Jacob

• Why adjuvant CT? (Rationale)

• What is the evidence for the benefit of adjuvant CT?

• Do all patients require adjuvant CT?

• How to select adjuvant systemic treatment?

• What adjuvant CT?

• When to start adjuvant CT?

• How many cycles of adjuvant CT?

• Toxicity of adjuvant CT?

• Special clinical situations

Why adjuvant CT?

• Fisher hypothesis• Gompertzian model

• William S. Halsted• Halsted radical mastectomy• Breast cancer arose in one location and spread

to nearby lymph nodes and then throughout the body

• So, removal of breast, chest wall muscle, and lymph nodes was the logical treatment.

• Bernard Fisher - alternative hypothesis• “Breast cancer is a systemic disease in

that, tumor cells were likely to have been disseminated throughout the body by the time of diagnosis and that more expansive locoregional therapy was unlikely to improve survival”

• In 1967, chairman of NSABP – multicentre RCT

Fisher hypothesis : “Breast cancer is considered a systemic disease at

time of diagnosis, a condition requiring treatment of the entire patient rather than just the source organ”

Gompertzian model

• Benjamin Gompertz• 18th century mathematician

“Law of mortality”• Growth rate of populations are exponential at

early stages of development and slower at later stages

150 years later….

Dr. Larry Norton

Norton and Simon hypothesis

• Tumors follow Gompertzian growth functions• Smaller tumors grow faster than larger ones• Rate of cell-killing by many drugs is proportional to

tumor growth rates• Tumors given less time to regrow between

treatments are more likely to be destroyed• Shorten the interval between chemotherapy

treatments from 3 weeks to 2• High-density dosing – Improved survival

Dose dense chemotherapy

What is the evidence for benefit of adjuvant CT?

EBCTCG meta-analysis

EBCTCG Meta-analysis

EBCTCG 2011

• Is there a benefit to adjuvant chemotherapy compared with no treatment?

• Is there a benefit to anthracycline-based regimens compared with CMF?

EBCTCG 2012

• Role of taxanes in adjuvant chemotherapy of early breast cancer

EBCTCG 2011Compared with no treatment, the use of anthracycline-containing regimen

was associated with the following outcomes at 10 years:

Risk of recurrence Significant improvement

RR 0.73 Absolute gain of 8%

Breast cancer mortality

Significant reduction RR 0.79 Absolute gain of 6.5%

Overall mortality Significant reduction RR 0.84 Absolute gain of 5%

Compared with no treatment, the use of CMF was associated with these outcomes at 10 years:

Risk of recurrence Significant improvement

RR 0.7 Absolute gain of 10.2%

Breast cancer mortality Significant reduction RR 0.76 Absolute gain of 6.2%

Overall mortality Significant reduction RR 0.84 Absolute gain of 4.7%

Anthracycline-based therapy vs. CMF

The use of “standard” doses of anthracyclines was associated with the following outcomes at 10 years compared with CMF (n=5122 women)

The use of higher cumulative doses of anthracyclines (> 4 cycles, to cumulative dose of >240 mg/m2) compared with CMF was associated with the following outcomes at 10 years (n=9572)

No improvement in the risk of recurrence (RR 0.99)

No improvement in breast cancer mortality (RR 0.98)

No improvement in overall mortality (RR 0.97)

Reduction in risk of recurrence

RR 0.89 Absolute gain of 2.6%

Reduction in breast cancer mortality

RR 0.80 Absolute gain of 4.1%

Reduction of overall mortality

RR 0.84 Absolute gain of 3.9%

• Preference of anthracycline-containing regimen as adjuvant chemotherapy

• Standard dosing of anthracycline-based therapy is equivalent to CMF, though less effective than more anthracycline-intensive regimens

• However, the data did not take into account the use of taxanes.

EBCTCG 2012 meta-analysisTrials where the same control regimen was used in both arms (n=11,167

women) (8 year outcome):

Trials where the number of cycles in the control anthracycline regimen was doubled to mirror the addition of cycles of taxanes to anthracyclines (n=33,084) (5 year outcome):

Reduction in risk of recurrence

RR 0.84 Absolute gain of 4.6% in RFS

Reduction in breast cancer mortality

RR 0.86 2.8% improvement in breast cancer-specific OS

Reduction in overall mortality RR 0.86 3.2% improvement in OS

Reduction in risk of recurrence

RR 0.86 Absolute gain of 2.9%

Reduction in breast cancer mortality

RR 0.88 Absolute improvement of 1.4%

Reduction in overall mortality

RR 0.9 Absolute improvement of 1.2%

• Affirms the benefit of taxanes when incorporated into the adjuvant setting for women with newly-diagnosed breast cancer

• The benefits were seen independent of age, nodal status, tumor size, tumor grade and ER status

How to select adjuvant systemic treatment?

Do all patients require adjuvant CT?

St. Gallen Consensus Conference 2013

National Comprehensive Cancer Network 2013

HER2 positive tumors Adjuvant chemotherapy (no specific size threshold) and trastuzumab

Adjuvant chemotherapy and trastuzumab for tumors >0.5 cm and/or node-positive

HER2 negative tumors ER negative:Adjuvant chemotherapy (no specific size threshold)

ER negative:Adjuvant chemotherapy for tumors ≥ 1.0 cm and/or node positiveConsider for tumors 0.5 to 1.0 cm if adverse prognostic factors are present (lymphovascular invasion, high-grade features)

HER2 negative tumors ER positive:Adjuvant chemotherapy if 4 or ore lymph nodes are positiveConsider if tumor >2 cm, or grade 2-3, or age <35, or lymphovascular invasion is present.Risk stratify by ER/PR/Ki67/Oncotype Dx/ Intrinsic subtype

ER positive:Adjuvant chemotherapy if node-positiveRisk stratify by Oncotype Dx if node negative (and in select patients with 1-3 involved ipsilateral axillary LN – NCCN 2015)Consider if tumor >1 cm, or if tumor 0.6 to 1.0 cm and lymphovascular invasion or grade 2-3 features are present.

Systemic treatment for early breast cancer subtypes

Subtype Recommended therapy

Luminal A-like ET alone in the majority of casesConsider CT ifi) High tumor burden (four or more

positive lymph nodes, T3, or higher)

ii) Grade III

Luminal B-like (HER 2-negative) ET+CT for the majority of the cases

Luminal B-like (HER2-positive) CT+ anti-HER2+ ET for all the patients

HER2-positive (non-luminal) CT+ anti-HER2

Triple-negative (ductal) CT

• * For special histological subtypes:• St. Gallen 2013 recommendations

ET for endocrine responsive CT for endocrine non-responsive

Cribriform Apocrine

Tubular Medullary

Mucinous Adenoid cystic

Metaplastic

Do all patients require adjuvant chemotherapy?

• Previously: Based on T size and N status• Now: Tumor biology (Prognosis and variable response

to chemotherapy)• IBCSG and CALGB:• Some HR+ breast cancers do not benefit from adjuvant

CT and are relatively chemo resistant. They have excellent prognosis with endocrine treatment alone.

• * Post menopausal ER+, LN-• Therefore, role of genomics to help us select patients

for CT

Tools to select patients

• Oncotype Dx• Mammaprint• Adjuvant! Online• NPI • Predict score

Oncotype Dx or RS assay for patients with ER+, LN- disease:• 16 cancer and 5 reference genes from 3 studies:

Category RS 0-100

Low risk RS <18

Intermediate risk RS ≥18 to ≤31

High risk RS ≥ 31

• Clinical validation – B14 results• Patients with tumors that have low RS derive minimal if any benefit from CT• Patients with tumors that have high RS have a large absolute benefit from CT

NCI Cooperative Groups TAILORx

Node-Negative, ER-Positive Breast Cancer

Recurrence Score <10HormoneTherapyRegistry

RS 11-25Randomize

Hormone Rxvs

Chemotherapy + Hormone Rx

RS >25Chemotherapy

+Hormone Rx

21-Gene Recurrence Score Assay

RegisterSpecimen banking

Primary study group

• Primary study group: Those with RS between 11 and 25 will be randomized to either hormonal therapy alone or hormonal therapy + chemotherapy.

• This corresponds approximately to a risk of recurrence at 10 years of 10%-20%.

• Dealer’s choice–type design: Individual investigators can select the type of hormonal therapy and chemotherapy from a list included in the protocol.

• The groups do not correspond to the low-, intermediate and high-risk cutoffs found on the Oncotype DX™ report.

• The cutoffs in the study were selected to correspond with specific risk levels.

• It was felt that it was not ethical to deprive a women of chemotherapy if she had a risk level above 20%.

RxPONDER

• Rx for Positive node, Endocrine Responsive Breast Cancer trial

• Use of 21-gene RS in node positive population

Other molecular tools for deciding chemotherapy in node negative patients:

• 70-gene signature (Mammaprint): It uses fresh tissue for microarray analysis US FDA approval in February 2007 LN negative patients of all ages, ER negative or positive, with tumor size <5 cm MINDACT trial: phase III RCT Mammaprint vs. Adjuvant!Online Selecting patients who are LN negative or 1-3 LN+ for adjuvant chemotherapy in

breast cancer

• PAM50 intrinsic subtype classifier • GGI- Gene Expression Grade Index ( 97-gene measure of histologic grade. High GGI

is associated with a lower relapse-free survival)

• NPI: Nottingham Prognostic Index• Prognostic scoring system for EBC• Divides patients into 6 prognostic groups

based on tumor size, grade and lymph node status

• PREDICT: UK prognostic model that predicts survival following surgery for invasive breast cancer

• Adjuvant! Online: Web based tool to estimate the net benefit of adjuvant treatment for an individual patient

• Estimates prognosis based on tumor size, number of involved LN, grading, ER status

• Source: SEER database• Assessment of treatment effect is mainly

based on: EBCTCG overview meta-analysis

What adjuvant CT?

• EBCTCG meta-analysis: benefit of polychemotherapy, anthracyclines and taxanes

• Evolution through CMF, AC, FAC and FEC-D• Concurrent anthracycline-taxane vs sequential• Weekly vs 3 weekly taxane• Role of dose dense CT• Role of HDCT

History (NSABP trials)• B-01 (1958-61)

– Thiotepa vs placebo. Short course perioperative. Advantage in premenopausal, >4 nodes positive

• B-05 (1972-75)– L-PAM (L-phenylalanine mustard, Melphalan) for node-positive orally for 2 year. 8% DFS and

5% OS advantage in < 50 years at 10 year follow up

• B-10 (1977-81)- immunotherapy– Combination chemotherapy (L-PAM + 5FU) +/- C.parvum and hydrocortisone: no adv

• B-11 (1981-84)– {L-PAM + 5-FU} +/- Adriamycin for node-positive and ER-negative tumors

• B-13 (1981-88)– chemotherapy (sequential MTX and 5-FU) for node-negative, ER-negative tumors– Benefit at 8 yr in overall DFS (74% v 59%; P < .001) was seen

Adjuvant treatment and survival improvement over the past 40 years

CMF• Cyclophosphamide, methotrexate and 5-FU• 1st regimen to show improved DFS and OS in adjuvant

treatment of breast cancer• Well tolerated ADR: Fatigue, nausea and diarrhea• Use has diminished with data showing benefit of

anthracyclines

CMF PO (Classic CMF)Cyclophosphamide 100mg/m2 po d1-d14Methotrexate 40 mg/m2 iv d1 and d85-FU 600mg/m2 iv d1 and d8

CMF ivC 600mg/m2 iv d1M 40mg/m2 iv d1 and d8F 600mg/m2 iv d1

Epirubicin---CMFEpirubicin 100 mg/m2 iv q3w* 4 cyclesFollowed by CMF* 4 cyclesN=2391, N+ and N-RFS of ECMF 83% vs 77% OS 88% vs 82%

AC• NSABP-B-15 (1984-88)• AC*4=CMF*6

• Findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups

• AC seems preferable since: AC was completed on day 63 versus day 154 for conventional CMF

• patients visited health professionals three times as often for conventional CMF as for AC

• nausea-control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC.

FACSECSG Trial in Node-Positive Breast Cancer:

Median follow-up of 5 years (n = 528):

• No significant difference in overall survival rates (74% vs 68%, P = .415) between CAF and CMF

• Major toxicities similar

SWOG BREAST INTERGROUP INT0102 TRIAL: CMF vs FAC, in node negative EBC• 10-year estimates indicated that CAF was not significantly better than CMF

for DFS (77% v 75%; HR 1.09; 95% CI, 0.94 to 1.27).

• CAF had slightly better OS than CMF (85% v 82%, HR 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43)

• Toxicity was greater with CAF

Role of anthracyclines (contd…)• EBCTCG 2011 meta-analysis• What is the optimal dose?• CALGB 9344: compared 60/75/90 mg/m2 of Adriamycin – no benefit of

dose escalation

• CALGB 8541: Evaluated 3 doses of anthracyclines – low (30mg/m2), moderate (40 mg/m2) and high (60 mg/m2). Benefit with high dose in OS and RFS in HER2 positive patients.

Epirubicin – What is the optimal dose?

• 1996: ICCG• Showed that FEC 50 and CMF had similar efficacy in pre-

menopausal, node-positive patients

• 1998: Dose of Epirubicin (FASG)• FEC-100 vs FEC-50 as adjuvant treatment for patients with

Node-positive breast cancer• 5-yr RFS 65% vs 52% (Relative risk reduction 32% P= 0.007)• 5-yr OS 76% vs 65% (Relative risk reduction 31% P=0.007)• CHF/AML/ALL – (1.1%, 0.4%, 0) vs (0.4%, 0, 0.4%)

Role of taxanes

CALGB 9344N >3,000 patientsA: 60=75=90 mg/m2 P 175 mg/m2

C:600 mg/m2

EBCTCG 2012

5-year DFS65% vs 70%

P= 0.0023

5-year OS77% vs 80%P= 0.0064

PACS 01 trial: FEC-D

SURGERY

R

6 * FEC100: Arm A5-FU 500mg/m2 on day 1Epirubicin 100mg/m2 on day 1Cyclophosphamide 500mg/m2 on day 1

6 cycles (q3w)

FEC-D: Arm B3 cycles of FEC 100 q21 days

followed by3 cycles of Docetaxel 100 mg/m2 on day 1

Every 21 days

Stratified on:Centre

Age: < or ≥ 50yNodes: 1-3; ≥4

Key outcomes of PACS-01• FEC-D • Superior DFS and OS irrespective of number of nodes or

hormonal status• 18% reduction in risk of relapse• 23% reduction in risk of death• Significant DFS benefit with FEC-D in ≥ 50 years age group (P=

0.001)• Incidence of FN with FEC-D: 11.2% (vs 24.7% with TAC)• Reduced risks of acute and delayed cardiac events because of

50% less exposure to anthracyclines• FEC-D is a reasonable alternative in patients ≥ 50 years of age.

Role of Taxane-based combinations as adjuvant chemotherapy of early breast cancer

Concurrent vs sequential

BCIRG 005NSABP-B-30

BCIRG 005

• Phase III RCT• TAC (6) vs. AC (4) ---T (4)• EBC – HER2 normal and

axillary LN positive

BCIRG 005 study design

Major eligibility criteria:•HER2 normal by central FISH•Histologically proven node-positive•Stage T1-3, N1, M0•Age ≤ 70 years, KPS ≥ 80%

Primary EP: DFS

Secondary EP:OS, safety

BCIRG 005

BCIRG 005

Non-hematological adverse events (Grade 3 or 4 with incidence >1%)TACN= 1635

AC-TN= 1634

% % P-valueArthralgia 0.9 2.4 0.001Sensory neuropathy

0.3 1.5 0.0004

Fluid retention 1.3 2.8 0.011HFS 0 1.8 <0.0001Myalgia 0.9 4.9 <0.0001

Key findings of BCIRG 005• For the primary endpoint, DFS, adjuvant TAC is equivalent to

AC-T in patients with HER2 normal, node positive breast cancer• Despite AC-T delivering higher dose intensity for each of the

three agents and requiring 8 cycles, AC-T was not more effective than TAC

• Compared to AC-T, TAC is associated with: More febrile neutropenia and GCSF use. Less sensory neuropathy, nail change, myalgia and shorter

duration of therapy

NSABP-B-30

• 1999-2004• Role of sequential vs concurrent taxanes• 3 arms (AC*4—T*4) vs (AT*4) vs (TAC*4)

“Sequential better than concurrent and AT non-inferior to TAC”

AC-T AT TAC

8 yr DFS 74% 68% 69%

8 yr OS 83% 79% 79%

BCIRG 001

• TAC vs FAC• 1491 patients, Node+• Median follow up: 124 months• DFS: 62% (TAC) vs 55% (FAC) (P=0.0043)• 10Y OS: 76% (TAC) vs 69% (FAC) (p=0.0002)

CALGB-9741 (contd..)

Key findings of CALGB 9741

• At 4 yr: 26% reduction in risk of recurrence and 31% improvement in OS with dose-dense administration.

• There was a significant improvement in DFS for dose dense regimen 82 vs 75%

• OS also improved(92 vs 90)• Dose density improved DFS and OS, no

difference was seen between sequential or concurrent schedule

10-year follow up of Intense Dose-dense chemotherapy vs. Conventional chemotherapy in

high-risk patients with ≥4 positive LNs (SABCS 2012)

• Rationale: There are no published reports of long-term survival and toxicity data with dose-sense regimens.

• Objective: Confirm the Norton Simon hypothesis of dose density and evaluate the safety of epoietin alfa as primary prophylaxis

• Study population: High-risk patients having atleast 4 positive LN

• All patients in the dose-dense arm received G-CSF

RANDOMIZE

N=1284

Cyclophosphamide 2500 mg/m2

q2w*3

Paclitaxel 225 mg/m2q2w*3

Epirubicin 150mg/m2

q2w*3

Paclitaxel 175 mg/m2 q3w*4

EC 90/600 mg/m2q3w*4

+TAM

+TAM

Primary EP: RFSSecondary EP: OS,

QOL, toxicity

G-CSF ± epoietin alfa

• Efficacy results:

• No therapy-related death or long-term toxicity was observed with iddETC

• Transfusion results:• Negative impacts of epoietin alfa on RFS and OS were not observed

• ;

Outcome IDD-ETC EC→T HR (95% CI) P-value10-yr RFS 56% 47% 0.74 (0.63-0.87) .0001410-yr OS 4-9 positive LNs 10+ positive LNs

69%74%62%

59%66%48%

0.72 (0.60-0.87)0.77 (0.59-1.01)0.66 (0.51-0.86)

.0007.06

.0016

Transfusion-related outcomesIDD-ETC(n=324)

IDD-ETC + EPO

(n=319)P-value

Median hemoglobin (g/dL) -- -- < .001 (favoring +EPO arm)

Need for ≥1 transfusion 28% 13% < .0001

Patients with venous thrombotic event

7% 13% .029

Node-negative breast cancer

• GEICAM 9805 (FAC vs. TAC)

significant toxicity

• GEICAM/2003-02 (FAC vs. FAC—wP)

GEICAM 9805 (FAC vs TAC)

• High-risk, node-negative breast cancer defined according to St. Gallen criteria

•18-70 years•Post primary surgery for unilateral operable breast cancer (T1-T3, N0)•≥1 of St. Gallen 1998 high risk criteria:

T size > 2cmER and PR negativeTumor Grade II or IIIAge <35 y

Randomized

TAC q3w*6 cycles

FAC q3w*6 cycles

Primary EP: DFSSec EP: OS

Results of GEICAM 9805 • At a median follow-up of 77 months:• TAC group had 32% reduction in the risk of having an event• Fewer local and distant relapses• Estimated DFS at 5 years: 90.1% in TAC group vs. 85.3% in FAC

group• 24% reduction in the risk of death among those who received TAC• Safety: Grade 3 or 4 ADR (TAC> FAC) – asthenia, neutropenia and

leucopenia• All grades (TAC> FAC) – Peripheral motor neuropathy, sensory

neuropathy, one pain, pyrexia, skin changes, peripheral edema, arthralgia, amenorrhea and myalgia

Key findings of GEICAM 9805• In women with high risk, node negative breast

cancer:• TAC significantly improved DFS (32% reduction

in risk of recurrence at 77 months)• Benefit from TAC maybe due to hormonal effect

in pre-menopausal women (Chemotherapy induced amenorrhea: TAC> FAC)

• Post menopausal women also derived benefit from TAC

GEICAM/2003-02 study

• Node negative breast cancer with high risk of recurrence as per St. Gallen criteria

• FAC (6) vs. FAC (4)---wP(8)• Primary EP: DFS• Secondary P: OS

GEICAM/2003-02 (contd…)• Results:• At a median follow-up of 63.3 months:• 5Y-DFS: 93% in FAC-wP vs 90.3% in FAC• FAC-wP reduces the risk of relapse by 26.7% compared with FAC (statistically sig.)

FAC-wP FAC

Grade 3-4 neutropenia 21.8% 25.4%

Febrile neutropenia 2.7% 3.6%

Fatigue 7.9% 3.4%

Sensory neuropathy 5.5% 0

Vomiting 4.3% 4.1%

Persistent amenorrhea 15.9% 10.6%

Higher incidence of thrombosis with FAC-wP (due to use of steroids)

AC vs AC--P

• CALGB 9344: 5y DFS 65% vs 70%• OS: 77% vs 80%• NSABP-B-28: 5y DFS:72% vs 76%• OS: 85% vs 85%

Which regimen?

• As of today, there are no recommendations for choosing the regimen based on Histopathology or Intrinsic subtypes.

• Choice of chemotherapy is based on comorbidities, side effects and patient preference.

• Endocrine-responsive breast cancer

• HER2 positive breast cancer

• TNBC

* Adjuvant chemotherapy: Which patient? What regimen? (ASCO 2013 Educational book)

Endocrine-responsive breast cancer

• Luminal A: Node negative- no benefit from adjuvant CT

• Node positive:• ? Absolute benefit of CT• Addition of CT to be discussed with the

patient

• Luminal B: High Ki67 index, aggressive, risk of relapse• Hence, chemotherapy and endocrine therapy are

indicated• Choice of CT is based on risk of relapse

Luminal B with additional risk factors: pT>1 &/or pN>0

Luminal B without additional high risk factors

Sequential anthracyclines- Taxanes

Docetaxel/cyclophosphamide

Adriamycin/cyclophosphamide

CMF

Spares toxicityDoes not compromise efficacy

HER-2 positive breast cancer:

• Trastuzumab + Chemotherapy• Major consideration: Whether or not to add

an anthracycline• Observed increased sensitivity of HER2+

tumors to anthracyclines is due to TOP2A amplification

BCIRG 006

• Phase III trial comparing AC → T with AC → TH and with TCH in the adjuvant treatment of HER2-amplified early breast cancer patients: Third planned efficacy analysis

• (Slamon et al, SABCS 2009)

BCIRG 006 (contd..)

• Trastuzumab provides a similar and significant advantage for both DFS and OS when used with either ACTH or TCH.

• The acute and chronic toxicity profiles of TCH are better than those of ACTH

• No statistically significant advantage of ACTH over TCH

• CHF was 5* more in ACTH than in TCH

• Plan treatment based on risk of relapse:

HER2 positive EBC with high risk features (pT >1 and/or pN>0)

HER2 positive EBC with low risk features

AC-TH TCH

TNBC

• TNBC with good prognosis:• Adenoid cystic and medullary

N- N+

Avoid adjuvant CT

Give adjuvant CT even with good prognosis

subtype

• Other TNBC:• Eg: Metaplastic• Adjuvant CT: Sequential anthracyclines –

taxane regimen

• TNBC and BRCA-associated breast cancer:• Use of platinum

When to start adjuvant CT?• Preferably within 2 to 6 weeks• Significant decrease in the efficacy of

chemotherapy is observed when administered more than 12 weeks from surgery

How many cycles of adjuvant CT?• 6-8 cycles

Early and late long-term effects of adjuvant chemotherapy in breast cancer

*Breast cancer - ASCO 2013 educational book

• Adjuvant CT can lead to early and late long-term side effects for breast cancer survivors.

• Effects of CT can vary in severity, but can often negatively affect the QOL and overall health status.

• Screening for symptoms, use of supportive medication, referral for specialty consultation as needed

• Ongoing research: Evaluate the etiology of toxicity as well as effective interventions

Ovarian failure: premature menopause, infertility, sexual dysfunction

Hot flashesAtrophic vaginitisLoss of pelvic muscle toneLoss of libido

Pretherapy referral to a fertility specialistAssisted reproduction (Ovarian stimulation with AI in the setting of HR+ cancer)

Weight gain Reasons: changes in activity level, menopausal status, endocrine manipulation, diet, metabolism and moodNurses’ Health Study: Weight gain may increase the risk of recurrence

Diet ExerciseActive lifestyle

Bone loss Premature menopauseEffect of AIWHI study: increased risk of fracture in post menopausal breast cancer survivors

Screen at risk individuals: DEXA q1-2yTimely initiation of bisphosphonates Adequate calcium and Vitamin DWeight bearing exercise

Neuropathy:• Peripheral sensory and motor neuropathy –

affect QOL• Microtubule inhibitors: Taxanes• Rate and severity of taxane-related

neuropathy: agent selection, dose, schedule, comorbidities

• Supportive management:• Dose modification and treatment delay• Glutathione, acetyl-l-carnitine, alpha-lipoic acid• Gabapentin, venlafaxine• CALGB 170601: Duloxetine for painful chemotherapy-induced

neuropathy• Best management: Avoid toxicity by identification of individuals at

highest risk Higher P-APS scores with first dose of CT may correlate with

peripheral neuropathy Identification of SNPs associated with development of moderate to

severe peripheral neuropathy after paclitaxel exposure

• * Taxol package insert• Severity is dose dependent• Those with pre-existing neuropathy should be

carefully monitored• In severe cases, all subsequent doses of

paclitaxel should be reduced by 20%

• Cardiac dysfunction:• Left ventricular dysfunction (Anthracyclines and

trastuzumab > cyclophosphamide and taxanes)• Prechemotherapy identification of individuals at

high risk of toxicity: Older age, pre-existing hypertension, low baseline LVEF, elevated BMI

• Cardiac risk score (Age and LVEF) to predict the risk of a cardiac event (NSABP-B-31)

• ECHO

• Anthracycline mediated cardiotoxicity:• Late-onset (atleast I year after completion of

CT) > acute or sub-acute• Permanent cardiomyocyte apoptosis and

necrosis• Late onset: irreversible, related to cumulative

anthracycline dose, due to free radical formation

• Rates of symptomatic or severe cardiac dysfunction in the major trials of adjuvant trastuzumab + anthracycline: maximum of 4.1%

• Trastuzumab without chemotherapy/ T without anthracyclines: 0.6% to 1.87%

• Rates of asymptomatic drop in cardiac function after anthracycline exposure: 17% to 19%

• Neurocognitive dysfunction:• “Chemo brain”• 75% of women: change in cognitive function 2y after

treatment (attention, memory and concentration)• Multifactorial: exposure to CT, other modalities of

treatment, supportive care medications, menopausal symptoms, anxiety, depression, fatigue, comorbidities

• Role of genetic polymorphisms: APOE and COMT• ? Prophylactic or therapeutic modafinil, fluoxetine, CBT

• Secondary malignancy:• Rare yet most feared complication – MDS or AML• <1% ( reflect increased cumulative dose)• Concurrent use of growth factors, RT

Alkylators Topoisomerase-II targeted agents

Examples Cyclophosphamide Anthracyclines

Induction period 5-8 y after start of therapy 2-3 y

Preceded by MDS yes No

Type of translocation Unbalanced Balanced

Chromosomes involved Long arm del or monosomy of chr 5 and 7

MLL, RARA, RUNX1 loci of 11q23, 17q21, 21q22

Special situations

• Very young patient (< 35 years)• Older patients (≥ 65 years)• Isolated local and regional recurrence

Very young patient (<35 years)• Young age is an independent risk factor for poor prognosis• Aggressive disease: high incidence of Hormone insensitive Undifferentiated HER2+ tumors

• Combination chemotherapy with anthracyclines and taxanes: Luminal B, HER2+, TNBC; even for N-

• Gonadal toxicity• Early referral to reproductive specialist

Chemotherapy in older patients (≥ 65 years)

• Comprehensive geriatric assessment• Balance against:• Risk of toxicity• Poor QOL• Functional decline

• Combination CT preferred in Node+, HR- EBC HR+, Luminal B HR-, Node-

Polychemotherapy in older patient?CALGB 49907

Age > 65y60% ≥ 70

RANDOMIZE

Oral CMF * 6AC * 4

Capecitabine (X) * 6 cycles

Both arms were tolerated well but more toxicity in AC/CMF

Median follow-up: 2-4 yearsCMF/AC vs single agent Capecitabine: Better RFS (p=0.00009)

Difference particularly marked in ER negativePolychemotherapy is relevant in the elderly population

RFS

CALOR: Adjuvant CT for ILRR (SABCS 2012)

• Rationale: isolated local or regional recurrence (ILRR) of breast cancer has poor prognosis

• No randomized studies of adjuvant chemotherapy for ILRR have been published in the last 30 years

• Objective: Evaluate the effect of adjuvant chemotherapy on patients with ILRR

• Sample size: Original 977• Due to slow accrual, only 162 patients were

randomized

• Chemotherapy chosen by investigators• At least 2 drugs, 3-6 months of therapy

RANDOMIZE

+Endocrine therapy for HR-positive disease

+ HER2-directed therapy (optional)

+ RT (mandatory for those with positive margins)

Adjuvant chemotherapy

No chemotherapy

Eligibility criteria:•First ILRR•Complete gross excision of recurrence•No evidence of positive SCLN•No evidence of distant metastasis

CALOR trial (contd..)

CALOR trial (contd..)

• Results:

Site of first failure (after ILRR)Chemotherap

y*(n=85)

No chemotherapy*

(n=77)Total failures 24 34

Local/regional 6 (25%) 9 (26%)

Distant Soft tissue Bone Viscera

15 (63%)087

22 (65%)25

15

Contralateral breast 1 (4%) 1 (3%)

Secondary non-breast malignancy

1 (4%) 0

Deaths without failure 1 (4%) 2 (6%)

CALOR trial (contd…)

• Efficacy results:• Multivariate analysis showed treatment

(chemo/ no chemo) to have significant impact on both DFS and OS

Survival ChemotherapyNo

chemotherapy HR (95% CI) P-value

5-yr DFS ER-positive ER-negative

69%70%67%

57%69%35%

0.59 (0.35-0.99)0.94 (0.47-1.89)0.32 (0.14-0.73)

.046.87

.007

5-yr OS ER-positive ER-negative

88%94%79%

76%80%69%

0.41 (0.19-0.89)0.40 (0.12-1.28)0.43 (0.15-1.24)

.02

.12

.12

Considerations for the future

• These need further validation in large cohorts:

Disseminated tumor cells (DTC) on BMA assessment

•Prognostic in EBC•Marker of recurrence

Circulating tumor cells (CTC) Poor survival after NACT or primary breast cancer surgery

cf-DNA (cell free-DNA)Plasma miRNA

Markers of relapse in EBC

Debate about anthracyclines in HER2 +Does HER2 over-expression confer a unique and/or inherent

sensitivity to anthracyclines?

• The Topoisomerase IIα Protein 1s a major target of the anthracyclines

• Current data indicate that it is the TOP2A gene amplification and not HER2 that is responsible for improved anthracycline sensitivity

• TOP2A amplification occurs ONLY in 35% of the 25% of breast cancer patients with HER2 amplification

“only 8% of breast cancer patients”• Moreover, for HER2-positive breast cancers, trastuzumab appears

to replace the gained efficacy of anthracyclines in the one third of patients with co-amplification of HER2 and TOP2A

Predicting anthracycline benefit: TOP2A and CEP17

• Meta-analysis of adjuvant trials that compared anthracycline-based regimen with CMF – HER2 amplification and combined TOP2A amplification or deletion may have some value in the prediction of response to anthracycline-based CT, findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A aberrated tumors.

questions

• Concept of adjuvant CT in ca breast?• Which subtype of pt as per ebctcg do not

require CT?• Subgroup analysis of dose dense CT??

Thank you