CBCTR Prognostic TMA (Generation III)

Design Considerations

July 29, 2008

The purpose of these TMAs is to allow investigators to examine potential
prognostic markers in non-metastatic breast cancer. Separate TMAs will
be constructed for each of the three non-metastatic TNM stages, I-III
(as defined by AJCC Manual for Staging of Cancer, 5^th^ edition). Only
the Stage I TMA is constructed at this time. The Stage II and II TMAs
are expected to be available in 2009.

# Eligibility criteria

1.  No prior contralateral or ipsilateral primary breast cancer.

2.  No synchronous bilateral invasive breast cancers (These are cases in
    which a new primary *invasive* cancer occurs in the opposite breast
    within two months of the original invasive breast cancer.)

3.  Female.

4.  Patient age at diagnosis known.

5.  Diagnosed prior to 1998 but no earlier than 1985.

6.  Invasive cancer present.

7.  Most prominent histologic type is Ductal or Lobular. If most
    prominent histologic type is Mixed ductal/lobular, the case will not
    be used for the prognostic TMA. Any secondary histologic type is
    allowed, including ductal secondary type accompanying a
    predominately lobular histology or lobular secondary type
    accompanying a predominately ductal histology. For cases with
    secondary histologic types present, the tissue represented on the
    TMA will be the most prominent histologic type.

8.  T-stage known and not inflammatory.

9.  N-stage known.

10. If N-stage = N0, then number of nodes examined must be at least 5.

11. M-stage = M0.

12. Size of invasive cancer (tumor size) ≥ 0.5 cm.

13. Not multifocal.

14. Radiation therapy known (yes or no).

15. Chemotherapy known (yes or no).

16. Hormone therapy known (yes or no).

17. Not never disease-free if stage I or II. *(Not required for stage
    III cases.)*

18. Not eligible if the patient had another (non-breast) cancer first
    diagnosed 5 years or less prior to the breast cancer unless that
    cancer was non-melanomatous skin cancer or a non-invasive cancer of
    the cervix which are considered to be essentially 100% curable with
    surgery or other local measures. If the prior cancer occurred and
    was successfully treated (no evidence of recurrence or persistent
    disease) with only local/regional therapy (e.g. surgery and/or
    radiation) [more than 5 years previously]{.underline}, the case is
    eligible. Any recurrence or metastasis of the other cancer before
    the breast cancer diagnosis will make the case ineligible unless the
    recurrence is local and successfully treated without systemic
    therapy more than 5 years prior to the breast cancer diagnosis. If
    the patient underwent chemotherapy for the other cancer within the
    10 years prior to diagnosis of the breast cancer, the case is not
    eligible.

19. The case must have a tissue block available for which estimated
    tissue depth is at least 1.5mm and from which at least four 0.6mm
    tissue cores can be obtained.

# Data to be supplied to TMA users

-   Age at diagnosis

-   Year of diagnosis

-   Most prominant histologic type

-   Secondary histologic type (if any)

-   Laterality of primary breast cancer

-   T-stage

-   N-stage

-   M-stage (always M0)

-   Tumor size (in cm)

-   Number of nodes positive

-   Number of nodes examined

-   Tumor grade (each of T, N, and M subscores in addition to overall
    Nottingham grade)

-   Chemotherapy (Y/N)

-   Radiation therapy (Y/N)

-   Hormone therapy (Y/N)

-   Immunotherapy (Y/N, unknown)

-   Other therapy (Y/N, unknown; if yes, specify type)

-   Vital status (dead, alive)

-   Length of follow-up for overall survival (OS\*)

-   Cancer status at death (if deceased)

-   Type/site of first recurrence (if any) outside of ipsilateral breast
    *(applicable only if patient was disease free after initial
    surgery)*

-   Site of distant recurrence *(if any, and applicable only if patient
    was disease free after initial surgery)*

-   Length of follow-up for first recurrence outside of ipsilateral
    breast

-   Indicator of ipsilateral breast recurrence *(applicable only if
    surgery was breast-conserving and patient was disease free following
    initial surgery)*

-   Length of follow-up for ipsilateral breast recurrence

-   Type of first RFS\* event observed (ipsilateral invasive breast
    tumor recurrence, local/regional recurrence, distant recurrence,
    death due to any cause, or none) *(applicable only if patient was
    disease free after initial surgery.)*

-   Length of follow-up for RFS

-   Comments -- includes any information known about prior or subsequent
    primary cancers (breast or non-breast) and their recurrences (if
    any)

[]{.mark}

[]{.mark}

# \*Clinical endpoints 

-   Overall survival (OS) -- Time from date of diagnosis to date of
    death due to any cause.

-   Recurrence-free survival (RFS) -- Time from date of diagnosis to the
    date of first occurrence of ipsilateral invasive breast tumor
    recurrence, local/regional recurrence (chest wall, ipsilateral
    axillary and internal mammary nodes), distant recurrence, or death
    due to any cause. If patient was never disease free, this endpoint
    cannot be computed.

Note: The definitions of OS and RFS used here are the same as those
proposed in Hudis et al. (Journal of Clinical Oncology, v. 25, no. 15,
May 20, 2007).

# Statistical design 

-   Simple random sample, from within each of stage groups I-III, of
    cases meeting eligibility criteria above.

-   Sample sizes for each stage group (approximately 600 for stage I,
    400 for stage II, and 200 for stage III) were determined so that
    there would be about 80% or greater power in the subgroup of ductal
    cancers within each stage group to detect a hazard ratio of 2.0 for
    OS associated with a binary marker that has prevalence between 20%
    and 80%. For marker prevalence between 30% and 70%, the power is
    greater than 90%. If 25% of cores are missing/unusable, the power
    typically drops 5-10%. See Tables 1-3 for further details.

-   RFS is considered only in the Stage I and II groups. The power for
    RFS comparisons within each stage subgroup of ductal cancers to
    detect a hazard ratio of 2.0 for RFS associated with a binary marker
    that has prevalence between 20% and 80% is usually greater than
    approximately 80%. For marker prevalence between 30% and 70%, the
    power is usually greater than about 90%. If 25% of cores are
    missing/unusable, the power typically drops 5-10%. See Tables 4 and
    5 for further details.

-   Power calculations were performed using an iterative search method
    based on the standard error formula for the hazard ratio as
    presented in Rubinstein, Gail, and Santner (J. Chron. Dis., v. 34,
    pp. 469-479, 1981). The search fixed the ratio of the hazard rates
    at the targeted value of 2.0 and found hazard rates and follow-up
    times that were consistent with the observed total number of events
    and the overall Kaplan-Meier estimate of 5-year survival.

Table 1. Power estimates for OS endpoint examining Stage I ductal subset
only. 533 (90%) of the 590 Stage I cases have predominant ductal
histology. The number of OS events among those 533 cases is 196 (37%).
Example power calculations for comparison of OS between marker positive
(M+) and negative (M−) groups within the ductal Stage I subset are
presented in the following table.

+-----------+----------+----------+----------+----------+----------+
| Marker    | Hazard   | 5-yr OS  | 10-yr OS | Power    | Power    |
| p         | rate     | rate (%) | rate (%) | (%) if   | (%) if   |
| revalence | ratio    |          |          | all      | only 75% |
|           | (M+/M−)  | (M+, M−) | (M+, M−) | cores    | of cores |
|           |          |          |          | usable   | usable   |
+-----------+----------+----------+----------+----------+----------+
| 0.1       | 2.0      | 82.4,    | 68.0,    | 94       | 85       |
|           |          | 90.8     | 82.4     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.2       | 2.0      | 83.6,    | 69.9,    | 99       | 97       |
|           |          | 91.5     | 83.6     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.3       | 2.0      | 84.7,    | 71.8,    | \> 99    | 99       |
|           |          | 92.0     | 84.7     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.4       | 2.0      | 85.7,    | 73.5,    | \> 99    | 99       |
|           |          | 92.6     | 85.7     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.5       | 2.0      | 86.6,    | 75.0,    | \> 99    | 98       |
|           |          | 93.1     | 86.6     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.6       | 2.0      | 87.5,    | 76.6,    | 99       | 96       |
|           |          | 93.5     | 87.5     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.7       | 2.0      | 88.3,    | 77.9,    | 97       | 92       |
|           |          | 93.9     | 88.3     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.8       | 2.0      | 88.9,    | 79.1,    | 89       | 79       |
|           |          | 94.3     | 88.9     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.9       | 2.0      | 89.6,    | 80.2,    | 63       | 51       |
|           |          | 94.6     | 89.6     |          |          |
+-----------+----------+----------+----------+----------+----------+

(Overall Kaplan-Meier estimate of 5-year OS is approximately 91%.)

Table 2. Power estimates for OS endpoint examining Stage II ductal
subset only. 362 (90%) of the 400 Stage II cases have predominant ductal
histology. The number of OS events among those 362 cases is 163 (45%).
Example power calculations for comparison of OS between marker positive
(M+) and negative (M−) groups within the ductal Stage II subset are
presented in the following table.

+-----------+----------+----------+----------+----------+----------+
| Marker    | Hazard   | 5-yr OS  | 10-yr OS | Power    | Power    |
| p         | rate     | rate (%) | rate (%) | (%) if   | (%) if   |
| revalence | ratio    |          |          | all      | only 75% |
|           | (M+/M−)  | (M+, M−) | (M+, M−) | cores    | of cores |
|           |          |          |          | usable   | usable   |
+-----------+----------+----------+----------+----------+----------+
| 0.1       | 2.0      | 63.0,    | 39.7,    | 88       | 77       |
|           |          | 79.4     | 63.0     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.2       | 2.0      | 65.2,    | 42.4,    | 98       | 93       |
|           |          | 80.7     | 65.2     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.3       | 2.0      | 67.2,    | 45.1,    | 99       | 96       |
|           |          | 82.0     | 67.2     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.4       | 2.0      | 69.1,    | 47.7,    | 99       | 97       |
|           |          | 83.1     | 69.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.5       | 2.0      | 70.9,    | 50.2,    | 99       | 96       |
|           |          | 84.2     | 70.9     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.6       | 2.0      | 72.5,    | 52.6,    | 98       | 93       |
|           |          | 85.2     | 72.5     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.7       | 2.0      | 74.1,    | 54.9,    | 95       | 87       |
|           |          | 86.1     | 74.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.8       | 2.0      | 75.5,    | 57.0,    | 84       | 73       |
|           |          | 86.9     | 75.5     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.9       | 2.0      | 76.8,    | 59.0,    | 56       | 45       |
|           |          | 87.6     | 76.8     |          |          |
+-----------+----------+----------+----------+----------+----------+

(Overall Kaplan-Meier estimate of 5-year OS is approximately 76%.)

Table 3. Power estimates for OS endpoint examining Stage III ductal
subset only. 181 (85%) of the 212 Stage III cases have predominant
ductal histology. The number of OS events among those 181 cases is 131
(72%). Example power calculations for comparison of OS between marker
positive (M+) and negative (M−) groups within the ductal Stage III
subset are presented in the following table.

+-----------+----------+----------+----------+----------+----------+
| Marker    | Hazard   | 5-yr OS  | 10-yr OS | Power    | Power    |
| p         | rate     | rate (%) | rate (%) | (%) if   | (%) if   |
| revalence | ratio    |          |          | all      | only 75% |
|           | (M+/M−)  | (M+, M−) | (M+, M−) | cores    | of cores |
|           |          |          |          | usable   | usable   |
+-----------+----------+----------+----------+----------+----------+
| 0.1       | 2.0      | 26.1,    | 6.8,     | 75       | 62       |
|           |          | 51.0     | 26.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.2       | 2.0      | 28.3,    | 8.0,     | 93       | 84       |
|           |          | 53.1     | 28.3     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.3       | 2.0      | 30.6,    | 9.4,     | 97       | 91       |
|           |          | 55.3     | 30.6     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.4       | 2.0      | 33.1,    | 11.0,    | 98       | 93       |
|           |          | 57.5     | 33.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.5       | 2.0      | 35.7,    | 12.8,    | 97       | 92       |
|           |          | 59.8     | 35.7     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.6       | 2.0      | 38.4,    | 14.8,    | 96       | 92       |
|           |          | 62.0     | 38.4     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.7       | 2.0      | 41.1,    | 16.9,    | 92       | 83       |
|           |          | 64.1     | 41.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.8       | 2.0      | 43.8,    | 19.2,    | 80       | 68       |
|           |          | 66.2     | 43.8     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.9       | 2.0      | 46.5,    | 21.6,    | 53       | 42       |
|           |          | 68.2     | 46.5     |          |          |
+-----------+----------+----------+----------+----------+----------+

(Overall Kaplan-Meier estimate of 5-year OS is approximately 48%.)

Table 4. Power estimates for RFS endpoint examining Stage I ductal
subset only. 531 (90%) of 587 Stage I cases had predominant ductal
histology and had follow-up for recurrence and survival. The number of
RFS events among those 531 cases is 147 (28%). Example power
calculations for comparison of RFS between marker positive (M+) and
negative (M−) groups within the ductal Stage I subset are presented in
the following table.

+-----------+----------+----------+----------+----------+----------+
| Marker    | Hazard   | 5-yr RFS | 10-yr    | Power    | Power    |
| p         | rate     | rate (%) | RFS rate | (%) if   | (%) if   |
| revalence | ratio    |          | (%)      | all      | only 75% |
|           | (M+/M−)  | (M+, M−) |          | cores    | of cores |
|           |          |          | (M+, M−) | usable   | usable   |
+-----------+----------+----------+----------+----------+----------+
| 0.1       | 2.0      | 78,4,    | 61.4,    | 87       | 76       |
|           |          | 88.5     | 78.4     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.2       | 2.0      | 79.9,    | 63.8,    | 97       | 92       |
|           |          | 89.4     | 79.9     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.3       | 2.0      | 81.2,    | 66.0,    | 99       | 95       |
|           |          | 90.1     | 81.2     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.4       | 2.0      | 82.4,    | 67.9,    | 99       | 95       |
|           |          | 90.8     | 82.4     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.5       | 2.0      | 83.5,    | 69.8,    | 98       | 94       |
|           |          | 91.4     | 83.5     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.6       | 2.0      | 84.5,    | 71.4,    | 96       | 90       |
|           |          | 91.9     | 84.5     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.7       | 2.0      | 85.4,    | 72.9,    | 91       | 82       |
|           |          | 92.4     | 85.4     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.8       | 2.0      | 86.2,    | 74.3,    | 78       | 66       |
|           |          | 92.8     | 86.2     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.9       | 2.0      | 86.9,    | 75.6,    | 50       | 39       |
|           |          | 93.2     | 86.9     |          |          |
+-----------+----------+----------+----------+----------+----------+

(Overall Kaplan-Meier estimate of 5-year RFS is approximately 87%.)

Table 5. Power estimates for RFS endpoint examining Stage II ductal
subset only. 362 (90%) of 400 Stage II cases have predominant ductal
histology and had follow-up for recurrence and survival. The number of
RFS events among those 362 cases is 130 (36%). Example power
calculations for comparison of RFS between marker positive (M+) and
negative (M−) groups within the ductal Stage II subset are presented in
the following table.

+-----------+----------+----------+----------+----------+----------+
| Marker    | Hazard   | 5-yr RFS | 10-yr    | Power    | Power    |
| p         | rate     | rate (%) | RFS rate | (%) if   | (%) if   |
| revalence | ratio    |          | (%)      | all      | only 75% |
|           | (M+/M−)  | (M+, M−) |          | cores    | of cores |
|           |          |          | (M+, M−) | usable   | usable   |
+-----------+----------+----------+----------+----------+----------+
| 0.1       | 2.0      | 52.8,    | 27.8,    | 82       | 70       |
|           |          | 72.6     | 52.8     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.2       | 2.0      | 55.4,    | 30.6,    | 95       | 88       |
|           |          | 74.4     | 55.4     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.3       | 2.0      | 57.8,    | 33.5,    | 97       | 92       |
|           |          | 76.1     | 57.8     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.4       | 2.0      | 60.1,    | 36.2,    | 98       | 93       |
|           |          | 77.5     | 60.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.5       | 2.0      | 62.3,    | 38.8,    | 97       | 91       |
|           |          | 78.9     | 62.3     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.6       | 2.0      | 64.2,    | 41.3,    | 94       | 86       |
|           |          | 80.1     | 64.2     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.7       | 2.0      | 66.1,    | 43.6,    | 88       | 78       |
|           |          | 81.3     | 66.1     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.8       | 2.0      | 67.8,    | 45.9,    | 74       | 62       |
|           |          | 82.3     | 67.8     |          |          |
+-----------+----------+----------+----------+----------+----------+
| 0.9       | 2.0      | 69.3,    | 48.0,    | 46       | 36       |
|           |          | 83.3     | 69.3     |          |          |
+-----------+----------+----------+----------+----------+----------+

(Overall Kaplan-Meier estimate of 5-year RFS is approximately 70%.)

# Appendix A. Percentage of Events for Stage I Cases

Percentage of cases with Ipsilateral Recurrence = 7/590 (1.2%)

Percentage of cases with Recurrence Outside of Ipsilateral Breast =
69/587 (11.8%)

Percentage of deceased cases = 219/590 (37.12%)

Percentage of cases with Any Recurrence = 75/587 (12.78%)