Castle

Question 1

What was the objective of Gastman et al 2019 JAAD?

Answer 1

To assess risk prediction by the 31-GEP test within 3 low risk populations of patients with cutaneous melanoma

Question 2

In Gastman et al 2019 JAAD what were the 3 low risk populations (per AJCC)?

Answer 2

1. Those with less than or equal to 1mm tumors [T1a&b]
2. Those with Stage I and IIA tumors (Up to 2mm with ulceration and up to 4mm w/o ulceration)
3. Those with SLN neg tumors

Question 3

What are the characteristics of a path stage IA tumor?

Answer 3

A stage IA tumor is T1 and can be:
T1a (<8mm w/o ulceration)
T1b (<8mm w/ ulceration or 0.9 or 1.0 without ulceration)

Question 4

What are the characteristics of a path stage IB tumor?

Answer 4

A stage IB tumor is T2a

(1.1-2 w/o ulceration)

Question 5

What are the characteristics of a path stage IIA tumor?

Answer 5

A stage IIA tumor is T2b or a T3a
T2b (1.1-2 w/ ulceration)
T3a (2.1-4.0 w/o ulceration)

Question 6

Where did the 690 Gastman 2019 JAAD patients come from?

Answer 6

All from previous studies:
Gerami et al. CCR 2015
Gerami et al. JAAD 2015
Zager et al. BMC Cancer 2018

Question 7

What was the median Breslow Thickness in Gastman JAAD 2019

Answer 7

1.3mm

Question 8

How many of the 690 patients in Gastman JAAD 2019 were tested for SLN and how many were positive and negative.

Answer 8

Of 690, 459 were tested and 200 were positive (259 were negative)

Question 9

How do we know that the 690 patients in Gastman 2019 JAAD were not Cherry-Picked?

Answer 9

Supplemental Table 1 shows that these 690 patients show the same melanoma-specific survival for stages I, II and III as the AJCC 8th edition International Melanoma database shows.

Question 10

What is the definition of recurrence-free survival?

Answer 10

Disease Free Survival (a special case of Progression Free Survival) after surgery to completely remove all visible cancer. In this case “progression” means the patient has had a recurrence.

• key is specifics regarding what was included and excluded as recurrence events
• even more importantly how an event was ascertained
• NEVER used in metastatic patients (even complete responders)

Question 11

What is the definition of distant metastasis-free survival?

Answer 11

Time from a defined start point (diagnosis, or beginning of treatment) to appearance of a distant metastasis. A distant metastasis refers to cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Also known as distant cancer.

Question 12

What is the definition of melanoma-specific survival?

Answer 12

The length of time from either the date of diagnosis or the start of treatment for melanoma to the date of death from the melanoma. Patients who die from causes unrelated to the melanoma are not counted in this measurement.

Question 13

In Gastman 2019 JAAD what key conclusion was reached on the full 690 patients before the 3 subgroups were analyzed?

Answer 13

1. For the 690 patients, Castle 1A and 2B survival curves show a significant split (RFS, DMFS, MSS).

Question 14

In the 259/690 Gastman 2019 JAAD SLN negative patients what were the two key conclusions?

Answer 14

1. SLN-neg/Castle 2B had a worse KM survival curve than did SLN-neg/Castle 1A.
2. Castle 2 identified about 3/4 of all node negative patients with events

Question 15

In the 393/690 Gastman2019 JAAD “low risk” defined as no mets, non-ulcerated to 4mm and ulcerated to 2mm (Stage I to IIA) what were the two key conclusions?

Answer 15

1. Stage I-II/Castle 2B had a worse KM survival curve than did Stage I-II/Castle 1A (and behaved more like T3b tumors compared to Castle 1A like T1a tumors)
2. Castle 2B results were better predictors of survival than thickness, ulceration, or mites.

Question 16

in the 281/690 Gastman 2019 JAAD “thin tumors” (1mm or less) how many were Castle 1, how many were Castle 2b?

Answer 16

251/281 were Castle 1

15/281 (5.3%) were Castle 2B

Question 17

Of the 15/281 Gastman 2019 JAAD “thin tumors” (1mm or less) that were Castle 2b, what percentage of T1a and what percentage of T1b tumors were Castle 2b?

Answer 17

T1a - 2.0%

T1b - 13.9%

Question 18

In the 281/690 Gastman 2019 JAAD “thin tumors” (1mm or less) what were the two key conclusions?

Answer 18

1. Castle 2B results had worse KM curves
2. The Castle 2B was the only predictor of recurrence in thin tumors (not thickness, mites, ulceration or EVEN a positive node)

Question 19

What percentage of all MM deaths come from “thin melanomas”

Answer 19

24-30% of all deaths.

Question 20

What was the goal of the Marks 2019 Skin paper

Answer 20

To help define an appropriate population for the Castle test.

Question 21

What was the conclusion of the Marks 2019 Skin paper

Answer 21

Appropriate use of the Castle test for management decisions is in melanoma greater than or equal to 0.3mm thick.

Question 22

In the Marks 2019 paper, where did the first 1497 cases come from?

Answer 22

gastman JAAD 2019
Greenhaw Derm Surg 2018
Hsueh J Hemtol Oncol 2017
Greenhaw AAD Wash DC 2019

Question 23

In Marks 2019 what data points were used from the first 1497 cases and what was the conclusion? (Figure 1)

Answer 23

1. Breslow, Castle, Clinical recurrence out to 3.3 years median
2. Between 0.2 and 0.3 mm the Castle 1A cases and the Castle 2B cases show different likelihood of recurrence.

Question 24

In Marks 2019 (Figure 2) Cockerell’s 437MM and Castle’s 8944MM up to 1mm were examined and what was the conclusion?

Answer 24

No clinical outcomes but the vast majority (all of cockerell’s and most of castle’s) of MM less than 0.3mm were Castle 1A. From 0.3-1mm 16% of CJC and 11% of castle were not Castle 1A.

Question 25

In Marks 2019 (Figure 3) looked at clinical outcome from a subset of 403 patients.

1. What was the subset?
2. What was concluded?

Answer 25

1. 160 patients with tumors less than 1.1mm
2. a. 25% of patients with tumors 0.3-1.0mm had a management change - and 11% of patients less than 0.3 had a management change.

Question 26

What are the two areas where the Castle test informs management decisions?

Answer 26

1. Guides SLNB decision on any tumor with adverse features and/or greater than breslow 0.7
2. Guides prognostication regarding recurrence on any tumor 0.3mm or thicker

Question 27

according to the cleveland clinic website, in their study of 896 patients who had a SLNB, what percent of all deaths occured in their node negative patients?

Answer 27

70%

Question 28

According to Conic 2017, when does a delay in treatment after biopsy start to increase mortality in Stage I MM? How about stages II and III?

Answer 28

Stage 1 - 43-46 days (6-9 weeks)

Stage II - surgical timing doesn’t’ significantly affect survival

Question 29

What is the AIM of the Vetto 2019 Future onc paper?

Answer 29

To examine whether gene expression profiling be used to ID patients with T1-T2 MM at low risk for SLN positivity.

Question 30

Methods for the Vetto 2019 onc paper?

Answer 30

1. bioinformatics established a population where Castle predicted <5% SLN positivity.
2. Validation was done on n=1421 prospective and n=690 restropective cohorts.

Question 31

Key result of Vetto 2019 onc paper wrt SLN positivity rates.

Answer 31

1. Patients with MM up to 2mm (T1 and T2) with a Castle 1A have 4.9% (55-64y) and a 1.6% (65+y) SLN positivity rates. Castle 2B is 30.8% and 11.9%.

Question 32

Key result of Vetto 2019 onc paper wrt MSS.

Answer 32

MSS is 99.3% for patients 55+ with castle 1A, MM up to 2mm and 55% for Castle 2B, SLN+ tumors up to 2mm.