cebp.aacrjournals.org · Web viewHeaphy CM et al. 2007 23 (HEAL study) USA 530 - Age: 59 ± 13 -...

ADDITIONAL MATERIAL

Table S1: Search strategies

Table S2: Studies of telomere length measured in peripheral blood cells and survival outcomes

Table S3: Studies of telomere length measured in breast tumor tissue and survival outcomes

Table S4: Studies reporting associations of telomere length in peripheral blood with breast cancer prognostic factors

Table S5: Studies reporting associations of telomere length in breast tumor tissue with breast cancer prognostic factors

Figure S1 Risk of bias graph of studies reporting telomere length measured in peripheral blood cells and survival outcomes: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure S2: Risk of bias graph of studies reporting telomere length measured in breast tumor tissue and survival outcomes: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure S3: Risk of bias graph of studies reporting associations between telomere length measured in peripheral blood cells and prognostic factors: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure S4: Risk of bias graph of studies reporting associations between telomere length measured in breast tumor tissue and prognostic factors: review authors' judgements about each risk of bias item presented as percentages across all included studies

Table S1 - Search strategies

MEDLINE (via PubMed)

1- ((Breast [tiab] OR "mammary gland" [tiab] OR mammary [tiab]) AND (cancer [tiab] OR carcinoma [tiab] OR carcinomas [tiab] OR "malignant neoplasm" [tiab] OR "malignant neoplasms" [tiab] OR "malignant tumor" [tiab] OR "malignant tumors" [tiab] OR "malignant tumour" [tiab] OR "malignant tumours" [tiab])) OR "Breast Neoplasms" [Mesh]

2- telomere [tiab] OR telomeres [tiab] OR telomere [Mesh] OR "telomere shortening" [Mesh] OR "Telomere Homeostasis" [Mesh] OR telomerase [tiab] OR telomerase [mesh]

3- 1 AND 2

4- animals [mh] NOT humans [mh]

5- 3 NOT 4

EMBASE

1- ((Breast:ab,ti OR 'mammary gland':ab,ti OR mammary:ab,ti) AND (cancer:ab,ti OR carcinoma:ab,ti OR carcinomas:ab,ti OR 'malignant neoplasm':ab,ti OR 'malignant neoplasms':ab,ti OR 'malignant tumor':ab,ti OR 'malignant tumors':ab,ti OR 'malignant tumour':ab,ti OR 'malignant tumours':ab,ti)) OR 'breast cancer'/exp

2- telomere:ab,ti OR telomeres:ab,ti OR 'telomere'/exp OR 'telomere shortening'/exp OR 'telomere homeostasis'/exp OR telomerase:ab,ti OR 'telomerase'/exp OR 'telomerase reverse transcriptase'/exp

3- 1 AND 2

4- animals NOT humans

5- 3 NOT 4

CENTRAL (Cochrane Central Register of Controlled Trials)

1- ((Breast:ab,ti,kw OR "mammary gland":ab,ti,kw OR mammary:ab,ti,kw) AND (cancer:ab,ti,kw OR carcinoma:ab,ti,kw OR carcinomas:ab,ti OR "malignant neoplasm":ab,ti,kw OR "malignant neoplasms":ab,ti,kw OR "malignant tumor":ab,ti,kw OR "malignant tumors":ab,ti,kw OR "malignant tumour":ab,ti,kw OR "malignant tumours":ab,ti,kw)) OR MeSH descriptor: [Breast Neoplasms] explode all trees

2- telomere:ab,ti,kw OR telomeres:ab,ti,kw OR MeSH descriptor: [Telomere] explode all trees OR MeSH descriptor: [Telomere Shortening] explode all trees OR MeSH descriptor: [Telomere Homeostasis] explode all trees OR telomerase:ab,ti,kw OR MeSH descriptor: [Telomerase] explode all trees

3- 1 AND 2

4- animals NOT humans

5- 3 NOT 4

Table S2 - Studies of telomere length measured in peripheral blood cells and survival outcomes

Study

Country

Population

Telomere length (TL)

Adjustment Co-variables

Overall survival [95% CI]

Breast cancer-specific survival [95% CI]

N*

Participants

(mean ± SD)

Variables considered

(categorization)

Final adjusted model

(Variable selection method)

Duggan C et al. 201417

(HEAL study)

USA

611

- Age: 61.5% >50 years

- Stage: I to IIIA

- Blood collection:

6 months after diagnosis

- Follow-up:

median = 11.2 years

(range: NR)

- DNA extraction method: columns (Qiagen Mini-Prep)

- Measurement method: qPCR

- Measured parameter(s):

TL = rescaled T/S (telomere length minus mean) / SD

- Baseline

- 30 months

- TL change

- CV: intra-assay = 6%

inter-assay = 7%

- Statistical analysis: continuous

median split (value: 0.81 at baseline; 0.76 at 30 months)

- Age (≤50, >50)

- Ethnicity/study site (no-Hispanics white/site1, no Hispanics white/site2, Hispanics, blacks)

- Physical activity (none, <9, ≥9 Mets/hr/wk.)

- Cigarette smoking (ever, never)

- Perceived stress (low, high)

- BMI (<18.5, ≥18.5 to <25, ≥25 to <40, ≥40 kg/m2)

- Stage (local, regional)

- ER status (negative, positive)

- PR status (negative, positive)

- Micronutrient intake (NR)

- Tamoxifen treatment (yes, no, unknown)

- Age

- Ethnicity/study site

- Tumor stage

± TL at baseline

(Forward selection)

- TL at baseline:

Full follow-up:

- HR = 0.83 [0.67–1.02]

- Median split

HR† = 0.75 [0.50–1.11]

5-year censored follow-up:

- HR = 0.66 [0.45–0.96]

- Median split

HR† = 0.55 [0.28–1.06]

- TL30 months after baseline:

Full follow-up:

- HR = 0.78 [0.59–1.05]

- Median split

HR† = 0.79 [0.40–1.52]


- HR = 0.51 [0.29–0.92]

- Median split

HR† = 0.36 [0.11–1.22]

- TL change

Full follow-up:

HR = 0.42 [0.23–0.78]


HR = 0.29 [0.09–0.90]

- TL at baseline:

Full follow-up:

- HR = 0.88 [0.67–1.15]

- Median split

HR† = 0.75 [0.44–1.26]


- HR = 0.69 [0.46–1.04]

- Median split

HR† = 0.59 [0.29–1.22]

- TL 30 months after baseline:

Full follow-up:

- HR = 0.86 [0.58–1.26]

- Median split

HR† = 1.15 [0.41–3.19]


- HR = 0.57 [0.28–1.13]

- Median split

HR† = 0.54 [0.11–2.59]

- TL change:

Full follow-up:

HR = 0.33 [0.12–0.90]


HR = 0.41 [0.11–1.56]

Shen J et al. 201218

(LIBCSP study)

USA

1026

- Age: NR

- Stage: in situ or invasive

- Blood collection: few months after diagnosis

- Follow-up:

mean = 8.0 years

(range: 0.2–9.4 years)

- DNA extraction method: phenol-chloroform


- Measured parameter(s): T/S (standard curve)

- CV: range = 16-21 %

- Statistical analysis: median split (value: 0.73)

- Age (continuous)

- Race (white, other)

- Family history of breast cancer (no, yes)

- Subgroups: tumor type (invasive, in situ), ER, PR, and HER-2 status (negative, positive)

- Age

(Backward selection)

All subjects:

- HR† = 1.10 [0.83–1.46]

Subgroup analyses:

- Invasive:

HR† = 1.07 [0.80–1.44]

- HER2 negative:

HR† = 1.90 [1.12–3.22]

- Other subgroups: not statistically significant

All subjects:

HR† = 1.01 [0.69–1.47]

Subgroup analyses:

- Invasive:

HR† = 1.01 [0.69–1.50]

- HER2 negative:

HR† = 1.62 [0.77–3.39]

- Other subgroups: not statistically significant

Svenson U et al. 200819

Sweden

176

- Age: median = 57 years

(range 29-86)

- Stage: NR

(35.9% tumor size >16mm)

- Blood collection:

before chemotherapy or hormone therapy

- Follow-up:

from 2000 to 2007

- DNA extraction method: NR


- Measured parameter(s): RTL: sample’s T/S ratio on a reference cell line’s T/S ratio

- CV: inter-assay = 3.96%

- Statistical analysis: median split (value: 0.73)

- Age (<50, ≥50)

- Tumor size (median split: ≤16 mm, >16mm)

- Nodal status (negative, positive)

- Age

- Tumor size

- Nodal status

(NR)

NR

All subjects:

HR† = 2.92 [1.33–6.39]

SD: Standard deviation; TL: Telomere length; CI: Confidence interval; qPCR: quantitative polymerase chain reaction;; CV: Coefficients of variation; T/S: Telomere on single copy gene ratio; Mets/hr/wk.: Metabolic equivalent per hour per week; ER: Estrogen receptor and PR: Progesterone receptor; HER2: Human epidermal growth factor receptor 2; RTL: Relative telomere length; NR : Not reported; HR: Hazard ratio; * n; participants in analyses of survival outcomes; † long vs short telomeres (referent group: short telomeres);

Table S3 - Studies of telomere length measured in breast tumor tissue and survival outcomes

Study

Country

Population

Tissue sample


Adjustment Co-variables

Survival outcomes

[95% CI]

N*

Participants

(mean ± SD)

Variables considered (categorization)

Final model


Nagelkerke A et al. 201520

Netherlands

122

- Age: NR

- Stage: NR

- Follow-up: NR

- Frozen samples

- Tumor cells: NR



- Measured parameter(s): T/S

- CV: 0.2 to 2.2%

- Statistical analysis: median split (value: NR)

- NR

- Subgroups: hormone positive tumors (NR), triple negative tumors (NR)

NR

- Disease-free Survival: NR

- Subgroups:

- Hormone positive tumors:

HR = NR

(not statistically significant)

- Triple negative tumors:

HR = NR

(short telomeres significantly

associated with poor survival)

Simpson K et al. 201521

UK

120


(range 33-87)

- Stage: I to III

- Follow-up:

median = 4.6 years (range NR)

- Frozen samples

- Tumor cells:

20-100%

- DNA extraction method: Columns (QIAamp)

- Measurement method: STELA (XpYp telomere)

- Measured parameter(s): kb

- CV: NR

- Statistical analysis:

median split (value: 3.98 kb)

optimum fusion threshold (2.26 kb, identified in chronic lymphocytic leukaemia)

- Age (NR)

- NPI (<3.4, 3.4-5.4, >5.4)

- Tumor grade (1, 2, 3)



- HER2 status (negative, positive)

NR

(Forward selection)

- Overall survival:

- Median split:

HR† = NR

(not statistically significant)

- Fusion threshold:

HR† = 0.12 [0.08-0.19]

Lu L et al. 201122

Italy

302

- Age: mean = 57 years (range: 23-84)

- Stage: I to IV

- Follow-up:

median = 86 months

(range: 8 to 108)

- Snap-frozen fresh tumor samples

- Tumor content:

80-90%

- DNA extraction method:

Phenol-chloroform

- Measurement method:

qPCR


T/S

- CV: <15%


median split (value: NR)

- Age at surgery (NR)

- Tumor grade (1/2, 3)

- Histological type (ductal, lobular, mix, other)

- Stage (I/II, III/IV)



- Subgroups: Adjuvant treatment (chemotherapy, endocrine therapy, both)

- Age at surgery

- Stage

- Tumor grade

- Histological type

- ER and PR status

(NR)

- Overall survival:

HR† = 0.83 [0.49-1.40]

- Disease-free Survival:

HR† = 0.83 [0.53-1.31]

- Subgroups: not statistically significant

Heaphy CM et al. 200723

(HEAL study)

USA

530

- Age: 59 ± 13

- Stage: 0 to IIIA

- Follow-up:

mean = 6.7 ± 1.6 years (range: 0.45-9.16)

- FFPE tumor samples

- Tumor cells:

75%-100%


- Measurement method: slot blot

- Measured parameter(s): % of standard DNA TC

- CV: <10%


low/high (cut-off: significantly different survival intervals of the same cohort; value: 200% of standard DNA)

- Ethnicity (non-Hispanic white, Hispanic)

- Stage (0, I, IIA, IIB/IIIA)



- p53 status (none/focal/low, high)

- Chemotherapy sequence (NR)

- Adjuvant therapy (none, radiation, chemotherapy, both)

- Stage

- ER status

- p53 status

(lowest overall model

fit p-value)

- Overall survival: NR

- Breast cancer–related adverse events-

free survival‡:

HR† = 0.35 [0.14-0.86]

Fordyce CA et al. 200624

(HEAL study)

USA

77

- Age: median = 52 years (range 31–88)

- Stage: I to IV

- Follow-up:

up to 23 years

- FFPE and frozen samples

- Tumor cells:

75–100%

- DNA extraction method: Columns (Qiagen DNeasy Tissue kits)



- CV: NR


3 categories of TC (based on tertiles of the TC distribution in normal specimens; values: 36–100, 101–123, 124–247 % of standard DNA)

- NR

- Age at diagnosis

- Stage

(NR)

- Overall survival: NR

- Breast cancer-free survival:

- Tertile3 vs tertile1:

HR† = 0.23 [0.07-0.69]

SD: Standard deviation; TL: Telomere length; CI: Confidence interval; qPCR: Quantitative polymerase chain reaction; CV: Coefficients of variation; T/S: Telomere on single copy gene ratio; ER: Estrogen receptor and PR: Progesterone receptor; HER2: : Human Epidermal growth factor Receptor 2; FFPE: Formalin-fixed paraffin-embedded; TC: Telomere DNA content; NR : Not reported; HR: Hazard ratio; STELA: single telomere length analysis; TRF: terminal restriction fragments; NPI : Nottingham prognostic index;

* n: participants in analyses of survival outcomes; † long vs short telomeres (referent group: short telomeres); ‡ Breast cancer–related adverse events: death due to breast cancer, breast cancer recurrence, or development of a new primary breast tumor;

Table S4 - Studies reporting associations of telomere length in peripheral blood with breast cancer prognostic factors

Study

Country

Population


Studied factor(s)

(categorization)

Adjustment

co-variables (Variable selection method)

Associations with prognostic factors

N

Participants

(mean ± SD)

Without adjustment

With adjustment

Cross-sectional studies

Brouwers B

et al. 201525

Belgium

196

- Age: median = 64 years (range 27-90)

- Blood collection:

at diagnosis, before

any treatment

- Stage: NR


- Measurement method:

qPCR

- CV: NR



- Age (young < 60, old ≥ 70)

- Tumor size (pT)

- Nodal status (pN)

- Histologic type (ductal, lobular, ductal and lobular, ductal and other, other)

- Molecular tumor subtype (luminal A, luminal B, luminal B and - HER2, HER2, triple negative)

- Functional status (continuous)

NR

Shorter telomeres:

Age

No association:

Tumor size

Nodal status

Histologic type

Molecular tumor subtype

Functional status (frailty)

NR

Garland SN

et al. 201426

USA

392

- Age: mean = 62 years (range 33-91)

- Blood collection:

during regular follow-up

- Stage: I to III


- Measurement method: Southern blot

- CV: NR

- Measured parameter(s): TRF


- Age (<55, 55-65, >65)

- Ethnicity (white, non-white)

- Educational level (high school or less, college, graduate or higher)

- Marital status (Married/partnered, single)

- Physical activity (moderate to vigorous, none)

- Depression (normal, symptomatic)

- Anxiety (normal, symptomatic)

- BMI (<25, 25-30, >30)

- Smoking status (never, previous, current)

- Stage (0/I,II, III)

- Previous chemotherapy (none, yes)

- Current aromatase inhibitor (none, letrozole, anastrozole, exemestane)

- Comorbid conditions (none, one, two or more)

- Age

- Previous chemotherapy

(p-values <0.10 in the univariate analyses)

Shorter telomeres:

Age

Longer telomeres:

Physical activity

Previous chemotherapy

BMI

Smoking status

Ethnicity

Educational level

Marital status

Stage

Current aromatase inhibitor

Comorbid conditions

Depression

Anxiety

Shorter telomeres:

Age

Longer telomeres:

Physical activity

No association:

Previous chemotherapy

Pellatt AJ

et al. 201327

USA

NR

- Age: NR

- Blood collection: NR

- Stage: NR


- Measurement method: qPCR (multiplex)

- CV: NR


- Statistical analysis: NR

- ER and PR status (NR)

NR

No association:

ER and PR status

NR

Table S4 - Studies reporting associations of telomere length in peripheral blood with breast cancer prognostic factors (continued)

Study

Country

Population


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment

Case-control studies

Garland SN

et al. 201428

USA

140

- Age: 60 ± 10 years

- Stage: 0 to III

- Blood collection:

during regular follow-up

- Cases: moderate to severe insomnia (n = 70)

- Controls: without insomnia (n = 70)



- CV: NR

- Measured parameter(s):TRF


- Age (continuous)

- Insomnia (yes, no)

- Fatigue (continuous)

- Anxiety (continuous)

- Depression (continuous)

Matching:

Age

BMI

(NA)

Shorter telomeres:

Age

No association:

Insomnia

Insomnia severity

Fatigue

Anxiety

Depression

NA

Longitudinal cohort studies

Brouwers B

et al. 201529 *

Belgium

110

- Age: mean = 75 years

- Blood collection: before and after chemotherapy

- Stage: NR



- CV: NR



- Chemotherapy (yes, no)

NR

Not associated

NR

Benitez-Buelga C et al. 201430

Spain

379

- Age: median = 50 years (range 26-87)

- Stage: NR

- Blood collection: during and after treatment

- Follow-up:

median = 240 days

- DNA extraction method: Magnetic Glass Particles (MagNA Pure®)

- Measurement method: qPCR, Q-FISH

- CV: NR

- Measured parameter(s): T/S,

% of cells with short telomeres, telomere shortening rate


- Chemotherapy (pre-treatment, during treatment, post-treatment)

Age

(NR)

NR

Shorter telomeres:

Chemotherapy (during treatment, after 90 days)

No association:

360 days after the end of chemotherapy

Duggan C

et al. 201417

(HEAL study)

USA

611

- Age: 61.5% >50 years

- Stage: I to IIIA

- Blood collection:

6 months after diagnosis - Follow-up:

median = 11.2 years (range: NR)

- DNA extraction method: columns (Qiagen Mini-Prep)


- CV: intra-assay = 6%, inter-assay = 7%

- Measured parameter(s): LTL = rescaled T/S (telomere length minus mean) / SD

- Baseline: LTL0

- 30 months: LTL30

- LTL change


- Age (≤50, >50)

- Ethnicity/study site (no-Hispanics white/site1, no Hispanics white/site2, Hispanics, blacks)

- Menopausal status (pre, post, unknown)

- Perceived stress (low, high)

- Physical activity (none, <9, ≥9 Mets/hr/wk.)

- Cigarette smoking (ever, never) - Stage (local, regional)



- Tamoxifen use (yes, no)

- Treatment received (surgery, surgery and chemotherapy, surgery and radiation)

- Micronutrient intake (NR)

Age

(NR)

Shorter telomeres:

Age

Postmenopausal status

Higher levels of stress

Longer telomeres:

Black race/ethnicity

No association:

Physical activity

Cigarette use

Stage

ER and PR status

Tamoxifen use

Treatment received


Study

Country

Population


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment


Sanoff HK

et al. 201431

USA

33

- Age: median = 49 years (range 32–69)

- Stage: I to III


- Follow-up: 12 months



- CV: NR

- Measured parameter(s): change in LTL before and 12 months after chemotherapy


- Chemotherapy (NR)

NR

NR

No association:

Chemotherapy

Svenson U

et al. 200819

Sweden

176


(range 29-86 years)

- Stage: NR

(35.9% tumor size >16mm)

- Blood collection: before chemotherapy or hormone therapy

- Follow-up:

from 2000 to 2007




- Measured parameter(s): RTL: sample’s T/S ratio on a reference cell line’s T/S ratio



Age

(NR)

NR

No association:

ER status

Randomized controlled trials

Lengacher CA et al. 201532

USA

142

- Age: 55 ± 10

- Stage: 0 to III

- Intervention:

mindfulness-based stress reduction (n = 74) - Control: usual care

(n = 68)

- Blood collection: baseline, 6 weeks, 12 weeks

- Follow-up: 12 weeks

- DNA extraction method: salting-out



- Measured parameter(s): sample’s T/S relative to a reference DNA sample


Mindfulness-based stress reduction intervention (yes, no)

Baseline TL

(NA)

NR

No effect

Zaidi AI

et al. 201533 ¥

Pakistan

50

- Age: NR

- Stage: NR

- Intervention: mindfulness-based stress reduction (n = 25)

- Control (n = 25)

- Blood collection: NR



- Measurement method: NR

- CV: NR

- Measured parameter(s): NR


Mindfulness-based stress reduction intervention (yes, no)

Baseline TL

(NA)

NR

No effect


Study

Country

Population


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment

Carlson LE

et al. 201434

Canada

88


- Stage: 0 to III

- Intervention: mindfulness-based cancer recovery

(n = 34), supportive-expressive group therapy (n = 36)

- Control: stress management seminar

(n = 18)

- Blood collection: 3 months after treatments (except hormonal or trastuzumab therapy)


- DNA extraction method: columns (DNeasy)


- CV: NR

- Measured parameter(s): sample’s T/S normalized to the average T/S of a pooled reference standard


- Age (NR)

- Education (NR)

- Time since diagnosis (NR)

- Marital status (single, married/cohabitating, or separated/

divorced/widowed)

- Employment (full-time

work, part-time work, or retired/unemployed)

- Alcohol intake (NR)

Nicotine intake (NR)

- Daily physical activity level (NR)

- Quality of diet (NR)

- Quality of sleep (NR)

- Stage (NR)

- Treatment received (NR)

- Mood disturbances (NR)

- Subjective stress (NR)

- Psychosocial intervention (mindfulness-based cancer recovery and supportive-expressive

group therapy, stress management seminar)

None

None associated

NR

Schröder CP et al. 200135

Netherlands

33


- Stage: II and III

- Intervention: high dose chemotherapy with autologous transplantation (n= 16)

- Control: standard-dose group (n = 17)


- Follow-up:

mean = 34.5 weeks

- DNA extraction method: salting-out


- CV: intra-assay = 1.4%

- Measured parameter(s): sample’s TRF normalized to healthy donor sample TRF


- Chemotherapy (standard-dose, high-dose)

NR

No effect

No effect

SD: Standard deviation; TL: Telomere length; TRF: Terminal restriction fragments; CV: Coefficients of variation; T/S: Telomere on single copy gene ratio; ER: Estrogen receptor and PR: Progesterone receptor; pT: pathological size according to the TNM classification; pN: pathological nodal status according to the TNM classification; SNP: Single nucleotide polymorphisms; qPCR: quantitative polymerase chain reaction; Q-FISH: Quantitative fluorescence in situ hybridization; LTL: Leukocyte telomere length; NR: Not reported; NA: Not applicable; * Conference abstract;

Table S5 - Studies reporting associations of telomere length in breast tumor tissue with breast cancer prognostic factors

Study

Country

Population

Tissue sample


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment


Kammori M et al. 201536

Japan

44

- Age: 54 ±14 years

- Stage: 0 to III

FFPE tumor samples

- DNA extraction method: NA

- Measurement method: Q-FISH

- CV: NR

- Measured parameter(s): TCR


- Stage (TNM)

- Tumor size (≤20, 20-50, >50 mm)

- Nodal status (pN)

- Vascular invasion



- HER2 status (0-1, 2, 3)

- Ki-67 (<20, ≥20%)

NR

Shorter telomeres:

Stage III

Large tumor size Vascular invasion

Node positive

ER positivity

PR positivity

Ki67 ≥20%

No association:

HER2 status


USA

48


- Stage: I to III

FFPE tumor samples†


- Measurement method: FISH

- CV: NR

- Measured parameter(s): qualitative : tumor cells vs benign cells

- Statistical analysis: short, normal, long

- Age (continuous)

- Ethnicity (white, African - American, other)

- Tumor size (continuous)

- Stage (I, II, III)


- Molecular subtype (luminal/Her2−, luminal/Her2+, Her2+, triple negative)

- Ki-67 (continuous)

NR

Shorter telomeres:

Age

Longer telomeres:

Ki67

No association:

Molecular subtype

Martinez-Delgado B et al. 201338

Spain

104


- Stage: NR

FFPE tumor samples



- CV: NR


Mean TL

% cells with short TL

% short TL

- Statistical analysis: continuous, median split (short, long)

- Age (continuous)

- Hereditary origin (hereditary, sporadic)





- Caspase3 (<10, 10–25, >25 %)

- Ki-67 (<10, 10–25, >25 %)

- Age

- Tumor grade (significant variables in univariate analyses)

Shorter telomeres:

Age

Hereditary origin

Higher tumor grade

Caspase3

ER negative

No association:

PR status

HER2 status

Ki67

Shorter telomeres:

Higher tumor grade

No association:

Age

Caspase3

Hereditary origin


USA

103


- Stage: I to IV

FFPE tumor samples



- CV: NR

- Measured parameter(s): qualitative : tumor cells vs benign cells

- Statistical analysis: normal and long, short

- Age (continuous)

- Weight (continuous)

- Ethnicity (Caucasian, African American, other)

- Parity status (yes, no, missing)

- Menopausal status (pre, post, missing)


- Stage (I, II, III, IV)




- P53 (negative, positive)

- Ki-67 (<20, ≥20%)

Molecular subtype (luminal A, luminal B, HER, triple negative)

NR

Shorter telomeres:

ER-negative

PR negative

HER2 positive

p53 positive

Aggressive subtypes

NR

Table S5 - Studies reporting associations of telomere length in breast tumor tissue with breast cancer prognostic factors (continued)

Study

Country

Population

Tissue sample


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment



USA

657


- Stage: 0 to IIIA

Frozen and FFPE tumor samples

- DNA extraction method: columns (DNeasy®)


- CV: ≤10%



- Ethnicity (non-Hispanic White, hispanic, unknown)

- Nodal status (negative positive, unknown)

- ER status (negative positive, unknown)

- PR status (negative positive, unknown)

- Stage (0, I, IIA, IIB, IIIA)

NR

Shorter telomeres:

Stage

NR

Kurabayashi R et al. 200841

Japan

30

- Age: mean = 58 years (range 34- 91)

- Stage: NR

FFPE tumor samples



- CV: NR

- Measured parameter(s): TCR


- Age (continuous)



- Nodal status (negative, 1-3, ≥4)

- ER/PR status (negative/positive, both negative, both positive, positive/negative)

- HER2 status (0, 1+, 2+, 3+)

- Ki-67 (continuous)

NR

None associated

NR

Poonepalli A et al. 200842

Singapore

38

- NR


- DNA extraction method: columns (QIAamp)

- Measurement method: Southern blot, Q-FISH

- CV: NR


- Statistical analysis: % telomere shortening (continuous)




- Node status (absent, present)

- Tumour size (<2, ≥2 cm)

NR

Shorter telomeres:

Tumor grade

No association:

ER status

PR status

Node status

Tumour size

NR

Meeker AK et al. 200443

USA

143

- Age: NR

- Stage: NR

(in situ and invasive)

FFPE tumor samples



- CV: NR

- Measured parameter(s): qualitative (tumor cells vs benign cells)

- Statistical analysis: very short, short, normal, long, heterogeneous


NR

Not associated

NR

Griffith JK et al. 199944

USA

41


- Stage: NR (69% metastatic)




- CV: NR


- Statistical analysis: 53–90, 91-150, 151-370%

- Age (continuous)

- Metastatic disease (yes, no)



NR

Shorter telomeres:

Metastatic disease

No association:

Age

Tumor size

Tumor grade

NR


Study

Country

Population

Tissue sample


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment


Rha SY

et al. 199945

South Korea

71

- Age: median = 49 (range: 36-66) years

- Stage: 0 to III

Frozen tumor samples



- CV: NR

- Measured parameter(s): cancer cells/normal cells TRF difference

- Statistical analysis: same, different TRF

- Tumor size (T0-2, T3-4)


- Stage (0-II, III)

NR

None associated

NR

Takubo K et al. 199846

Japan

64

- Age: range 20 to 89 years

- Stage: NR*

NR*

- DNA extraction method: NR*


- CV: NR*


- Statistical analysis: NR*

- Age (NR*)

- Histological type (NR*)

NR*

None associated

NR*

Rogalla P

et al. 199647

Germany

83

- Age: NR

- Stage: NR

Frozen tumor samples



- CV: NR



- Age (NR)

- Nodal status (NR)

- Steroid receptor status (NR)

- Histological type (ductal, lobular)

- Tumor grade (NR)

- Tumor volume (NR)

NR

None associated

NR

Hiyama E

et al. 199648

USA-Japan

60

- Age: NR

- Stage: NR

NR



- CV: NR


- Statistical analysis: shortened (<8 kb), elongated (>15 kb)

- Tumor size (<2, ≥2 cm)



NR

None associated

NR

Case-control studies

Zhou X et al. 201249

USA

152


- Stage: 0 to IV

- Cases: local recurrence (n=74)

- Controls: no local recurrence (n=106)

- Follow-up:

82.6 ± 60.2 months

FFPE tumor samples





RLT ( cell type telomere FIU/lymphocytes telomere FIU), TLV (CV of telomere length among 30 cells)

- Statistical analysis: small/large (median value in control patients)

Local recurrence (yes, no)

Matching:

Age at diagnosis

Year of surgery

Type of surgery

Adjustment:

Stage

ER status

(variable selection: NR)

NR

Low vs high TLV:

OR = 5.1 [1.2 to 22.2]


Study

Country

Population

Tissue sample


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment


Simpson K et al. 201521

UK

120

- Age: median = 61 (range 33-87) years

- Stage: I to III

- Follow-up:

median = 4.6 years (range NR)

Frozen samples

Tumor content:

20-100%


- Measurement method: STELA (XpYp telomere)

- CV: NR

- Measured parameter(s): kb TL

- Age (continuous)

- NPI (<3.4, 3.4-5.4, >5.4 )





-Molecular subtype (luminal A, luminal B, HER2+/ER-, triple negative)

NR

None associated

NR

Lu L

et al. 201122

Italy

336


(range: 23-84)

- Stage: I to IV

- Follow-up:

median = 86 months

(range: 8 to 108)

Snap-frozen fresh tumor samples

Tumor content:

80-90%



- CV: <15%


- Statistical analysis: median split (value: NR)

- Tumor grade (1/2, 3)

- Histological type (ductal, lobular, mix, other)

- Stage (I/II, III/IV)




NR

None associated

NR

Subhawong AP et al. 200950

USA

71


- Stage: NR

- Follow-up: NR

FFPE tumor samples



- CV: NR

- Measured parameter(s): ALT

- Statistical analysis: negative, positive

Molecular subtype (luminal A, luminal B, HER2, basal-like, unclassifiable triple negative)

NR

ALT phenotype associated with HER2 positive tumors

NR

Heaphy CM

et al. 200723

(HEAL study)

USA

530


- Stage: 0 to IIIA

- Follow-up:

mean = 6.7 ± 1.6 years (range: 0.45-9.16)

FFPE tumor samples

Tumor cells:

75% to 100%



- CV: <10%


- Statistical analysis: low/high (cut-off: significantly different survival intervals of the same cohort; value: 200% of standard DNA)

- Age (<55, >55)

- Ethnicity (non-Hispanic white, Hispanic)

- Family history (none, 1° relative, 2° relative)

- Post-menopausal (yes, no)

- Tumor grade

- Stage (0, I, IIA, IIB/IIIA)



- p53 status (negative, focal, low, high)

- HER2 status (negative, focal, low, high)

- Chemotherapy (none, after surgery)

- Adjuvant therapy (none, radiation, chemotherapy, both)

- Tamoxifen (yes, no)

NR

None associated

NR


Study

Country

Population

Tissue sample


Studied factor(s)

Adjustment

co-variables



N

Participants

(mean ± SD)

Without adjustment

With adjustment


Fordyce CA

et al. 200624

(HEAL study)

USA

77

- Age: median = 52 (range 31–88) years

- Stage: I to IV

- Follow-up: up to 23 years

FFPE and frozen samples

Tumor cells:

75–100%

- DNA extraction method: columns (Qiagen DNeasy Tissue kits)


- CV: NR



- Age

- Tumor size (≤2, >2)


- Stage (0, I, IIA, IIB, IIIA, IIIB, IV)

- Histological type (ductal, lobular)

NR

Shorter telomeres:

Tumor >2cm

Nodal involvement

Higher stages

No association:

Age

Histological type

NR

Odagiri E

et al. 199451

Japan

41

- Age: range 24-73 years

- Stage: I to IV

- Follow-up : NR

FFPE tumor samples



- CV: NR


Statistical analysis: continuous

- Age (continuous)

- Histological type (papillo-tubular, solid-tubular, scirrhous, other)


- Tumor size (1, 2, 3, 4, 5 cm)




NR

Longer telomeres:

Nodal involvement

No association:

Age

Histological type

Tumor size

Stage

ER status

PR status

NR

SD: Standard deviation; TL: Telomere length; FFPE: Formalin-fixed paraffin-embedded; kb: kilo base; pN: pathological nodal status according to the TNM classification; NPI : Nottingham pronostic index; HER2: Human Epidermal growth factor Receptor 2; FISH: Fluorescence in situ hybridization; Q-FISH: Quantitative FISH; TCR: Telomere-to-centromere ratio; TRF: Terminal restriction fragments; TC: Telomere DNA content; ALT: Alternative lengthening of telomeres; NR: Not reported; NA: Not applicable;

* Full text not accessed; † Lobular carcinomas;

Figure S1: Risk of bias graph of studies reporting telomere length measured in peripheral blood cells and survival outcomes: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure S2: Risk of bias graph of studies reporting telomere length measured in breast tumor tissue and survival outcomes: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure S3: Risk of bias graph of studies reporting associations between telomere length measured in peripheral blood cells and prognostic factors: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure S4: Risk of bias graph of studies reporting associations between telomere length measured in breast tumor tissue and prognostic factors: review authors' judgements about each risk of bias item presented as percentages across all included studies

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Biasinselec5onofpar5cipantsintothestudy

Biasduetoconfounding

Biasinmeasurementoftelomerelength

Biasinmeasurementofoutcomes

Biasduetomissingdata(selec5on)

Biasinselec5onofthereportedresult

Lowrisk Moderaterisk Noinforma5on Seriousrisk Cri5calrisk

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%








0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%








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