The Association of Breast Cancer Subtypes, Guideline-Concordant Adjuvant Systemic Therapy and Survival among Women with Stage I-III Disease

MEICHIN HSIEH, PHD, MSPH, CTR

LOUISIANA TUMOR REGISTRY EPIDEMIOLOGY PROGRAM, SCHOOL OF PUBLIC HEALTH, LSU HEALTH SCIENCES CENTER– NEW ORLEANS

NAACCR 2018 Annual Conference, June 13, 2018, Pittsburg, PA

Co-Authors Lu Zheng, PhD1

Xiao-Cheng Wu, MD, MPH, CTR1

Mary Davidson, MN, CTR1

Michelle Loch, MD2

Vivien W Chen, PhD1

1. Louisiana Tumor Registry, Epidemiology Program, School of Public Health, LSU Health – New Orleans

2. Hematology & Oncology, School of Medicine, LSU Health – New Orleans

Introduction▪ Since four main subtypes of breast cancer have been

distinguished by gene-expression profiling in 2000, breast cancer is no longer a single disease. ▪ Breast cancer subtype becomes one of key indicators in

determining what type of adjuvant systemic therapies (ASTs) would ultimately benefit patients. ▪HR+ (ER+ and/or PR+) benefit from Tamoxifen

▪HR- (ER- & PR-) patients benefit from the adjuvant chemotherapy ▪HER2+ patients benefit from trastuzumab (Herceptin)

HR = Hormone receptor; ER = Estrogen receptor; PR = progesterone receptor; and human epidermal growth factor receptor 2 (HER2)

Introduction▪ In 2007, the American Society of Clinical Oncology (ASCO) recommended

measuring the ER/PR and HER2 expression and/or amplification in every primary invasive breast cancer. ▪ The National Comprehensive Cancer Network (NCCN) recommended to

take the ER/PR and HER2 status into account to guide the clinical care for breast cancer patients.

▪ Limited population-based studies that examined the association of breast cancer subtype on guideline-concordant adjuvant systemic therapy (AST) and survival outcome. ▪ Focused on adjuvant hormone and chemotherapy which was based on the hormone receptor (ER and

PR) status

▪ Examined the use of trastuzumab only ▪ None of them examined AST that jointly considered hormone, chemotherapy and trastuzumab

together.

Study Objectives▪To investigate whether receipt of guideline-concordant

adjuvant systemic therapy varied by breast cancer subtype after adjusting for patients’ sociodemographic and tumor characteristics ▪To examine the impact of guideline-concordant treatment

status and cancer subtype on survival outcome.

Data Source and Study Cohort▪ Female breast cancer data were obtained from the Louisiana

Tumor Registry (LTR) ▪LTR participated in the Enhancing Cancer Registry Data for

Comparative Effectiveness Research (CER) and the Patient Centered Outcomes Research (PCOR) projects funded by CDC

▪Collect detailed and complete first-course treatment & cancer patients had been followed at least 60 months

▪Women having unknown ER/PR or HER2 or that died within 30 days after surgery or identified through autopsy or death certificate were excluded.

Define Breast Cancer Subtype▪ ER, PR, and HER2 collected based on immunohistochemistry

(IHC) are used as surrogates to divide breast cancer into four molecular subtypes: ▪HR+/HER2+, HR+/HER2-, HR-/HER2+, and HR-/HER2- ▪When ER+ or borderline and/or PR + or borderline then HR status was

categorized to positive (HR+)

▪HER2+ only when IHC test for HER2 was positive, negative or borderline results was grouped to negative.

Define Guideline-Concordant AST▪The systemic therapy included in this study were hormone,

chemotherapy, and trastuzumab. ▪Receipt of guideline-concordant AST ▪ Patients received the AST based on the NCCN Clinical Practice

Guidelines 2011 which took into account the cancer subtype, stage, histology, tumor size, lymph node status, and risk score of recurrence.

▪Patients receiving total mastectomy or breast conserving surgery (BCS) plus radiation and followed the NCCN recommended systemic therapy were categorized as guideline concordant.

NCCN Guidelines for Adjuvant Systemic Therapy (AST) by Subtype and Stage

Subtype Lymph node Tumor size Hormone Chemotherapy Herceptin

Stage I, IIA, IIB, IIIA with N1; Histology not tubular and colloid 

HR+/HER2+

pN0; pN1mi (≤2mm)

≤0.5 cm or MI

pN0: Yes-c; pN1mi: Yes Yes-c

pN0: Yes-c; pN1mi:

Yes0.6-1.0 cm Yes Yes-c Yes>1.0 cm Yes Yes Yes

Node +   Yes Yes Yes

HR+/HER2-

pN0 ≤0.5 cm or MI Yes-c    

pN1mi (≤2mm) ≤0.5 cm or MI Yes    

pN0; pN1mi (≤2mm) >0.5 cm Yes Yes*  Node +   Yes Yes  

HR-/HER2+

pN0 ≤0.5 cm or MI      

pN1mi (≤2mm) ≤0.5 cm or MI   Yes-c Yes-c

pN0; pN1mi (≤2mm)

0.6-1.0 cm   Yes-c Yes-c> 1.0 cm   Yes Yes

Node +     Yes Yes

HR-/HER2-

pN0 ≤0.5 cm or MI      

pN1mi (≤2mm) ≤0.5 cm or MI   Yes-c  

pN0; pN1mi (≤2mm)

0.6-1.0 cm   Yes-c  > 1.0 cm   Yes  

Subtype Lymph node Tumor size Hormone Chemotherap

yHercepti

n Stage I, IIA, IIB, IIIA with N1; Histology tubular or colloid 

HR+pN0; pN1mi (≤2mm)

< 1.0 cm      1-2.9 cm Yes-c    ≥3.0 cm Yes    

Node +   Yes Yes-c  

HR- Treat as HR- for histology not tubular and colloid Stage IIIA with N2+, IIIB, IIIC 

HR+/HER2+ NA NA Yes Yes YesHR+/HER2- NA NA Yes Yes  HR-/HER2+ NA NA   Yes YesHR-/HER2- NA NA   Yes  

MI, Microinvasive; Yes-c, Consider adjuvant; NA, Not ApplicableHR, Homone receptor; HER2, human epidermal growth factor receptor 2 *Chemotherapy is considered if 21-gene recurrence score is 18-30. Chemotherapy is required if recurrence score ≥ 31. Note: Linked LTR with OncoType Dx DB to enhance the completeness of risk of recurrence status

Survival▪Assessed overall and cause-specific survival ▪ Patients were followed up to December 31, 2016 if alive ▪Underlying cause of death for deceased patients was obtained

from the state or the national death file. ▪Overall survival: the event was death from any cause ▪Cause-specific survival: ▪ The event was defined based on the ICD-10 code of causes of death listed in the

SEER cause-specific death classification for sequence number 00/01 ▪ For sequence number 02, the event was when cause of death coded to breast

cancer ▪ Patients who died of other causes were censored.

Description of Variables▪ Patient demographic variables: ▪ Race (white and black), ▪ Age at diagnosis (<50, 50-59, 60-69, 70-79, and ≥80 years), ▪ Insurance status at diagnosed ▪Marital status

▪ Neighborhood poverty level (< 10%, 10%-19.9%, ≥20%) at the census tract of diagnosis address.

▪ Tumor characteristics variables: ▪AJCC stage (Stages I, II, III) using 7th edition,

▪Tumor sequence (00 and 01/02), ▪Bloom-Richardson (BR) grade (low, intermediate, high, and unknown grade), ▪Deyo’s enhanced Charlson comorbidity score (no comorbidity documented, no

Charlson comorbidity, CC score = 1, and CC score ≥2)

Statistical Analysis▪ Logistic regression to examine the association between cancer subtype

and receipt of guideline-concordant AST for both unadjusted and adjusted models

▪ Kaplan-Meier method was used to estimate survival time by breast cancer subtype and statistical significant difference was based on the log-rank test.

▪ Semiparametric additive hazard regression model to estimate regression parameter which can estimate the absolute change in risk rather than the relative change. ▪The Cox-Snell residuals were used to assess the overall fit of the

semiparametric additive hazard regression model

Results▪2,214 eligible female breast cancer patients were included ▪71.5% were whites and 28.5% blacks

▪70.8% HR+/HER2-, 14.4% HR-/HER2-, 10.0% HR+/HER2+ and 4.8% HR-/HER2+ ▪Of 1,568 patients with HR+/HER2-, 35.6% (558) of them had multigene

signature results or 21-gene recurrence score and 3.4 % (54) are in high risk recurrence.

▪Mean age: HR+/HER2+ is 60.0 years old, HR+/HER2- 61.9, HR-/HER2+ 56.6, and HR-/HER2- 57.1. ▪About 78.6% (1,740) of study cohort received guideline-

concordant AST

Percentage of receiving systemic adjuvant therapy by treatment type and cancer subtype

0

23

45

68

90

Chemotherapy Hormone Herceptin

HR+/HER2+ HR+/HER2- HR-/HER2+ HR-/HER2-

NR indicates treatment is not required or considered but not received

Variables significantly associated with receipt of guideline-concordant AST

Variables

Case Count

(N=2,214)

% Received Treatmen

t

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

Subtype p < 0.0001    HR+/HER2+ 221 56.11 ref ref

HR+/HER2- 1568 81.70 3.49 (2.60, 4.69)

4.08 (2.94, 5.67)

HR-/HER2+ 107 80.37 3.20 (1.86, 5.53)

3.68 (2.06, 6.57)

HR-/HER2- 318 78.30 2.82 (1.94, 4.11)

3.46 (2.29, 5.23)

Age p < 0.0001    <50 457 79.43 ref ref

50-59 567 81.31 1.13 (0.83, 1.54)

1.00 (0.72, 1.40)

60-69 601 83.53 1.31 (0.96, 1.80)

0.96 (0.68, 1.36)

70-79 398 76.38 0.84 (0.61, 1.16)

0.51 (0.34, 0.75)

≥80 191 57.59 0.35 (0.24, 0.51)

0.22 (0.14, 0.35)

% Poverty -census p = 0.3643    

Variables

Case Count

(N=2,214)

% Received Treatment

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

AJCC stage p < 0.0001    Stage IA 1062 86.06 ref ref

Stage IB 85 84.71 0.90(0.49, 1.66) 0.94 (0.49, 1.83)

Stage IIA 527 76.66 0.53 (0.41, 0.69 0.51 (0.38, 0.67)

Stage IIB 259 68.34 0.35 (0.26, 0.48) 0.31 (0.22, 0.44)

Stage IIIA 158 64.56 0.30 (0.20, 0.43) 0.25 (0.17, 0.37)

Stage IIIB 40 45.00 0.13 (0.07, 0.25) 0.11 (0.05, 0.22)

Stage IIIC 83 63.86 0.29 (0.19, 0.46) 0.23 (0.14, 0.39)

Comorbidity p = 0.0151    

Not Doc 862 77.38 0.99 (0.79, 1.24) 0.93 (0.73, 1.19)

Non-CC 889 77.50 ref refCC score = 368 84.24 1.55 (1.13, 1.82 (1.28, 2.58)

Effect estimate from semiparametric additive hazard model fitting for overall and cause-specific survival: subtype & guideline-concordant AST status

Variables

Overall Survival Cause-Specific SurvivalUnadjusted Model Estimate (SE), p-

value

Adjusted Model Estimate (SE), p-

value

Unadjusted Model Estimate (SE), p-value

Adjusted Model Estimate (SE), p-

valuesubtype        HR+/HER2+ ref ref ref ref

HR+/HER2- 0.0025 (0.0053), 0.6394

0.0101 (0.0056), 0.0724

-0.0003 (0.0036), 0.9279

0.0070 (0.0039), 0.0757

HR-/HER2+ 0.0182 (0.0106), 0.0849

0.0225 (0.0107), 0.0362

0.0226 (0.0089), 0.0114

0.0221 (0.0091), 0.0153

HR-/HER2- 0.0274 (0.0077), 0.0004

0.0275 (0.0079), 0.0005

0.0299 (0.0063), <0.0001

0.0276 (0.0064), <0.0001

Guideline concordant        

No 0.0370 (0.0056), <0.0001

0.0221 (0.0056), 0.0001

0.0205 (0.0041), <0.0001

0.0143 (0.0043), 0.0010

Yes ref ref ref ref

Hazard of 0.0275 in adjusted overall survival model implies that on average there were 28 additional women died in any cause of death per 1,000 women with stage I-III breast cancer per year with HR-/HER2- subtype compared to HR+/HER2+ women after adjusting for covariates.

Variables with significant effect for both overall and cause-specific survival

Variables

Overall Survival Cause-Specific SurvivalUnadjusted Model Estimate (SE), p-

value

Adjusted Model Estimate (SE), p-

value

Unadjusted Model Estimate (SE), p-

value

Adjusted Model Estimate (SE), p-

valueInsurance        Private ref ref ref ref

Medicare/other public 0.0235 (0.0043), <0.0001

-0.0004 (0.0051), 0.9344

0.0053 (0.0029), 0.0635

0.0025 (0.0034), 0.4597

Medicaid 0.0297 (0.0058), <0.0001

0.0174 (0.0060), 0.0041

0.0179 (0.0045), 0.0001

0.0091 (0.0046), 0.0491

None/Unknown 0.0013 (0.0080), 0.8680

-0.002 (0.0082), 0.8028

-0.0002 (0.0060), 0.9787

-0.0049 (0.0062), 0.4326

Tumor sequence        00 ref ref ref ref

01 or 02 0.0272 (0.0051), <0.0001

0.0245 (0.0051), <0.0001

0.0059 (0.0033), 0.0752

0.0082 (0.0034), 0.0175

AJCC stage        Stage I ref ref ref ref

Stage II 0.0174 (0.0035), <0.0001

0.0146 (0.0036), 0.0001

0.0129 (0.0024), <0.0001

0.0082 (0.0024), 0.0008

Stage III 0.0696 (0.0087), <0.0001

0.0632 (0.0088), <0.0001

0.0589 (0.0074), <0.0001

0.0517 (0.0074), <0.0001

BR Grade        

Kaplan-Meier overall survival curves by cancer subtype stratified by guideline-concordant adjuvant systemic therapy status

Not received adjuvant systemic therapy Received adjuvant systemic therapy

Kaplan-Meier cause-specific survival curves by cancer subtype stratified by guideline-concordant adjuvant systemic therapy status

Not received adjuvant systemic therapy Received adjuvant systemic therapy

Summary: Guideline-Concordant AST▪ Except HR+/HER2+, all other subtype had similar percentage of

receiving guideline-concordant AST (around 80%). ▪HR+/HER2+ subtype are recommended to have all three systemic therapies,

hormone, chemotherapy, and trastuzumab, except for stage I-II with size ≤ 1.0 cm or with favorable histology type.

▪ The percentage of receiving AST decreased in older age group or in more advanced stage. ▪ Patients residing in census tract with 20% poverty or with

Charlson comorbidity score = 1 had higher likelihood of receiving AST than their counterparts.

Summary: Survival▪ Patients receiving AST had much better survival than those who didn’t

receive it in both overall and cause-specific survival. ▪ Among patients not receiving AST, those with HR-/HER2+ subtype had worse survival

than those with HR-/HER2- after 4 years. ▪ In contrast, HR-/HER2+ subtype had better survival than HR-/HER2- subtype when

observed for a longer follow-up period if AST was received. ▪ Patients with HR+/HER2+ or HR+/HER2- had the same cause-specific survival if received

AST.

▪ Age at diagnosis and Charlson comorbidity were significantly associated with overall survival, but not associated with cause-specific survival ▪ Patients aged 70 or older had increased hazard of dying in any causes than those aged

<50. ▪ Patient having Charlson comorbid condition had increased hazard of dying in any

causes than those without.

Strengths and Limitations Strengths: ▪ Collected complete treatment information for all types of systemic therapy

including National Service Center (NSC) number ▪ Able to separate Herceptin (NSC number: 688097) from chemotherapy drugs ▪ Linked with the OncoType DX® database to capture recurrence risk score to

supplement the incomplete information from SSF 23. ▪ An important indicator in determining the chemotherapy administration in the early-

stage lymph node negative HR+/HER2+ breast cancer patients Limitations: ▪ Lack of information on physician’s decision on whether to give chemotherapy

for patients age >70 : patient life-expectation, complication after surgery ▪ Completeness of comorbidity: only allowed to take the ICD-10 code that

documented on medical charts according to FORDS rules

Acknowledgments ▪CDC-NPCR in conjunction with a CDC Comparative Effectiveness Research (CER) and Patient Centered Outcomes Research (PCOR) Projects ▪National Cancer Institute’s (NCI)-SEER

Contact Information mhsieh@lsuhsc.edu