Malignant Melanoma: Prognostic Factors and Approach … F012 - Mi… · Malignant Melanoma:...

Malignant Melanoma: Prognostic Factors and Approach to Therapy

Martin C. Mihm M.D. Director Mihm Cutaneous Pathology Consultative Service (MCPCS) Brigham and Womens Hospital

Director Melanoma Program Brigham and Womens Hospital and Harvard Medical School

Co-Director Melanoma Program Dana-Farber Cancer Institute and Harvard Medical School European Organization for the Research and Treatment of Cancer (EORTC)

Chairman Scientific Advisory Board Caliber I.D. Inc.

Member Scientific Advisory Board MELA Sciences Inc.

Consultant Novartis Consultant Alnylam

Conflicts of Interest

Staging Melanoma 1. Characterize tumor status. 2. Stratify the risk of recurrence and metastasis. 3. Prognostication. 4. Guide clinical and surgical management/decision making. Melanoma staging, as defined by the current 7th edition AJCC staging system, reflects tumor biology and survival outcomes.

AJCC has released the 8th edition of its cancer staging manual

To be implemented in January 2018, to allow time for clinical practices to adapt

Introduces few major and some minor changes to the staging of melanoma compared to the 7th edition

Survival data are not yet published, but may be released as part of an online tool that uses complicated algorithms to calculate patient survival

Staging Melanoma

Gershenwald J et al. Melanoma of the Skin. Chapter in AJCC Cancer Staging Manual. 8th Ed. 2017.

Some changes include: T0: used if there is no evidence of primary tumor Tis: used for in-situ melanoma Mitoses are no longer part of the T category. Ulceration remains. T1 category uses 0.8 mm as threshold with the introduction of a second

T1b category defined as 0.8 1 mm with or without ulceration Microscopic and macroscopic detection of tumor in lymph nodes is

now referred to as clinically occult and clinically detected respectively

New N1c, N2c, and N3c categories that take into consideration the presence of microsatellites, satellite metastases, and in-transit metastases

New M1d for distant metastasis to CNS

Staging Melanoma


Malignant Melanoma Prognosis For the following cases, we will be using

the 7th edition of the AJCC staging manual I will then elaborate on the answers and go

through both the 7th and the 8th edition staging criteria

Case 1: Prepare to vote 56 yo lady whose mother had melanoma,

presented with a complaint of changing lesion on her left lower extremity. Physical exam reveals multiple other dysplastic nevi, but none worrisome for melanoma.

The lesion on the left lower extremity was biopsied and was read as: Malignant melanoma, superficial spreading

type, with a measured thickness of 0.9 mm. No ulceration, no mitoses.

Subsequent sentinel lymph node biopsy was negative for melanoma.

Case 1: Prepare to vote

Case 1: VOTE A. Patient is Stage IIC B. Patient has an estimated 5 year survival of

95% C. Patient had no risk factors for developing

melanoma D. Mitoses are not important

Case 1: Answer A. Patient is Stage IIC

Stage IIC requires a Breslow thickness of > 4 mm. with ulceration

B. Patient has an estimated 5 year survival of 95% C. Patient had no risk factors for developing melanoma

Patient had dysplastic nevi and a family history of melanoma D. Mitoses are not important

Mitoses are important for T1 staging according to the AJCC 7 In the AJCC 8, mitoses are not used for staging purposes, but

must nevertheless be reported because of their significance

Case 1: Answer According to the 7th edition of the AJCC, the patient is T1a,

N0, M0 and is therefore Stage IA with an estimated 5 year survival of 95%. Calculation of T stage is based on Breslow thickness < 1 mm. and

considering that the patient had neither ulceration nor mitoses

However, the 8th edition of the AJCC uses Breslow cutoff of 0.8 mm. and only considers ulceration for T staging. Therefore according to the new system, the patient will be T1b, N0,

M0 falling into Stage IA.


0.9 mm

Edge SB et al. AJCC Staging Manual. 7th edition. 2009

T Category Thickness Ulceration status Tis (melanoma in situ) Not applicable T1 1.0 mm Unknown or unspecified T1a 1.02.0 mm Without ulceration T2b >1.02.0 mm With ulceration T3 >2.0-4.0 mm Unknown or unspecified T3a >2.04.0 mm Without ulceration T3b >2.04.0 With ulceration T4 >4.0 mm Unknown or unspecified T4a >4.0 mm Without ulceration T4b >4.0 mm With ulceration

AJCC 8th Edition Proposed T Categories


0.9 mm

N Category

Number of tumor-involved regional lymph node(s)

Presence of in-transit, satellite and/or microsatellite metastases

N0 No regional metastases detected None N1

N1a 1 clinically occult (i.e., detected by SLN biopsy) None

N1b 1 clinically detected None

N1c No regional lymph node disease Yes

N2 N2a 2-3 clinically occult (i.e., detected by SLN biopsy) None

N2b 2-3, at least 1 of which clinically detected None

N2c 1 clinically occult or clinically detected Yes

N3 N3a 4 or more clinically occult (i.e., detected by SLN biopsy) None

N3b 4 or more, at least 1 of which clinically detected, or presence of any number of matted nodes

None

N3c 2 or more clinically occult or clinically detected Yes

AJCC 8th Edition Proposed N Categories


AJCC 8th Edition Proposed M Categories


AJCC 8th Edition Proposed Pathological Stage Groups


Tumor Thickness (Breslow thickness)

Primary determinant of T staging As there is no hematogenous marker as of yet

to predict high risk melanomas associated with positive nodes and no evidence of metastasis (Stage III), the Breslow thickness is used as a surrogate marker.

Measuring Breslow Thickness

Using a calibrated ocular micrometer at a right angle to the adjacent normal skin: The upper point of reference is: The granular layer of the epidermis of the overlying skin. In an ulcerated lesion use the base of the ulcer. The lower reference point is the deepest point of tumor invasion.

Ulceration Also factors into the T classification and staging system. Historically, ulceration was defined as microscopic

interruption of the surface epithelium by tumor. Currently defined as the combination of: full-thickness epidermal defect evidence of reactive changes thinning, effacement, or reactive hyperplasia of the surrounding epidermis without trauma or evidence of a recent surgical procedure

Balch CM et al. Annals of Surgery. 1978

True Ulceration

No Ulceration

Stratum corneum maintained No Ulceration

No Ulceration

CHARACTERISTICS OF ULCERATED MELANOMA

5 year survival decreased from 80% to 55% in Stage I/II; 53% to 12% in Stage III Majority of melanomas > 4.0 mm are ulcerated Width of ulcer > 6 mm. associated with even worse prognosis

Balch CM et al. J Surg Oncol. 2011

Primary Tumor Ulceration

Independently correlates with adverse prognosis.

In the same T category, patients with ulcerated tumors have a worse survival than non-ulcerated tumors.

In fact, ulcerated tumors behave like non-ulcerated tumors of the next higher T category.

Dermal Mitoses

One of the most significant prognostic factors in the 7th AJCC staging system.

Count dermal mitoses only. Number of mitoses per mm2. 1mm2= approx. 4 to 5 HPFs (40X).

Gimotty PA et al. J Clin Oncol 2007 Gimotty PA et al. J Clin Oncol 2004 Karakousis GC et al. Ann Surg Oncol 2007 Kesmodel SB et al. Ann Surg Oncol 2005

Prognostic Factors: Dermal Mitoses (Hot Spot)

Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, Flaherty KT, Gimotty PA, Johnson T, Johnson MM, Leong SP, Ross MI, Byrd DR, Cascinelli N, Cochran AJ, Eggermont AM, McMasters KM, Mihm MC Jr, Morton DL, Sondak VK. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011 Jun 1;29(16):2199-2205.

Slide_45: Survival Curve By Mit_int_6g: number of Mitoses/mm2

group 0 1 2 3 4 5

Survi

val F

uncti

on

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival Time in Years

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

0 1

2-4 5-10

11-19

20

AJCC Collaborative Melanoma Database Stage I/II: Mitotic Rate

Case 2: Prepare to vote 60 yo woman with a history of subungal

melanoma of the left great toe (1.9 mm. Breslow thickness, no ulceration) S/p partial amputation and negative sentinel lymph node biopsy.

Presents one year later with a rapidly growing dermal nodule on the amputation stump.

Photo Courtesy of Dr. Jeffrey Gershenwald

Case 2: VOTE A. 5 year survival depends solely on Breslow

thickness B. Clinical stage is the same as if the patient

had a metastasis to the arm C. Patient is not eligible for adjuvant therapy D. Stump lesion is a satellite metastasis"

Case 2: Answer A. 5 year survival depends solely on Breslow thickness

N and M staging affect prognosis B. Clinical stage is the same as if the patient had a

metastasis to the arm Distant cutaneous metastasis is considered M1

C. Patient is not eligible for adjuvant therapy Stage III patients are eligible for FDA approved adjuvant

therapy D. Stump lesion is a satellite metastasis"

Satellite and Metastasis Microsatellite: foci of metastatic tumor cells in the skin or

subcutis adjacent or deep to but discontinuous from the primary tumor detected by microscopic examination of tissue

Satellite Metastasis: Foci of clinically evident cutaneous and/or subcutaneous metastases occurring within 2 cm of but discontinuous from the primary melanoma

In-Transit Metastasis: Clinically evident cutaneous and/or subcutaneous metastases occurring > 2 cm from the primary melanoma in the region between the primary and the regional lymph node basin

Any cutaneous metastasis that does not fall into the above categories is considered Distant metastasis and is staged under the M category

Microsatellite

Satellite/In-transit Metastases

Photo Courtesy of Dr. Jeffrey Gershenwald

Develop in 6%-12% of pts with primary melanoma High risk groups: thick, ulcerated, positive SLN, lower extremity

Potential source of significant morbidity

50% risk for distant metastasis Photo Courtesy of Dr. Jeffrey Gershenwald

Satellite/In-transit Metastases

Edge SB et al. AJCC Staging Manual. 7th edition. 2009

T Category Thickness Ulceration status Tis (melanoma in situ) Not applicable T1 1.0 mm Unknown or unspecified T1a 1.02.0 mm Without ulceration T2b >1.02.0 mm With ulceration T3 >2.0-4.0 mm Unknown or unspecified T3a >2.04.0 mm Without ulceration T3b >2.04.0 With ulceration T4 >4.0 mm Unknown or unspecified T4a >4.0 mm Without ulceration T4b >4.0 mm With ulceration

AJCC 8th Edition Proposed T Categories


N Category

Number of tumor-involved regional lymph node(s)

Presence of in-transit, satellite and/or microsatellite metastases

N0 No regional metastases detected None N1

N1a 1 clinically occult (i.e., detected by SLN biopsy) None

N1b 1 clinically detected None

N1c No regional lymph node disease Yes

N2 N2a 2-3 clinically occult (i.e., detected by SLN biopsy) None

N2b 2-3, at least 1 of which clinically detected None

N2c 1 clinically occult or clinically detected Yes

N3 N3a 4 or more clinically occult (i.e., detected by SLN biopsy) None

N3b 4 or more, at least 1 of which clinically detected, or presence of any number of matted nodes

None

N3c 2 or more clinically occult or clinically detected Yes

AJCC 8th Edition (2017) Proposed N Categories


AJCC 8th Edition Proposed M Categories


AJCC 8th Edition Proposed Pathological Stage Groups

T2a N1c M0


Malignant Melanoma Target and Immune Checkpoint Blockade

Therapy

Molecular Targeted and Immune Checkpoint Therapy in Malignant

Melanoma Recent understanding of the molecular

pathways of melanoma, as well as elucidation of molecular aspects of the immune response to malignancy have opened new horizons in the treatment of metastatic melanoma.

MAPK pathway in melanoma

BRAF

MEK

ERK

Gene expression

RAS

Proliferation Adapted from Vultur et al. Clin Cancer Res 2011.

BRAF V600E

Proliferation, survival, invasion, and angiogenesis.

Growth receptor

BRAF inhibitors

MEK inhibitors

Molecular Targeted Therapy in Malignant Melanoma

Some therapeutic agents under investigation: BRAF: Vemurafenib, Dabrafenib, XL281,

RAF265 MEK: Trametinib, Selumetinib, Cobimetinib, TAK-733, PD0325901, AZD8330.

Target Therapy Medians Vemurafenib Dacarbazine Overall Response Rate (ORR)

48% 5%

Progression Free Survival (PFS)

5.3 months 1.6 months

Overall Survival (OS) 13.2 months 9.6 months

Medians Dabrafenib + Trametinib

Vemurafinib

Overall Response Rate (ORR)

64% 51%

Progression Free Survival (PFS)

11.4 months 7.3 months

Overall Survival 18.3 months 17.2 months

Niezgoda A et al. Biomed Res Int. 2015

Immune Checkpoint Blockade in Melanoma Immunotherapy

Two examples are CTLA4 antigen and Programmed Death Ligand Receptor (PDL)

CTLA4 is a global immune checkpoint that affects all antigen priming activity in the central lymphoid tissue. Hence, there are many side effects, for example, colitis, lupus like

changes, arthritis, etc.

Anti-CTLA4 is associated with ~24% response rate

Topalian et al, NatureRevMed. 2016 Hodi et al. NEJM. 2010

Immune Checkpoints in Melanoma Immunotherapy

PD-1 is present on activated T cells PDL-1 and PDL-2 are found on tumor cells PD1-PDL-1 interaction results in cytotoxic T cell inhibition. Therefore, T

cells become ineffective against melanoma cells The role of anti-PD-1 therapy is to prevent PD-1 and PDL-1 interaction Antibodies against PD-1 result in tumor destruction with a response rate

up to 40% Because anti-PD-1 functions at the site of the tumor, there are minimal

AEs when compared to anti-CTLA4 Topalian et al, NEJM 366; 2012 Moreno et al. Seminars in Onco, 42; 2015 Tumeh et al. Nature Letter 515; 2014 Robert C et al. NEJM. 2014

Case 3: Prepare to vote

51 year old man presents with malignant melanoma that is metastatic to the lung and colon. BRAF testing revealed the presence of the BRAF V600E mutation.

Case 3: VOTE A. Patient is not eligible for mutated BRAF target

therapy B. Patient should receive only immune checkpoint

blockade therapy C. Start patient on Anti-CTLA4 therapy until complete

remission is achieved D. Patient should receive anti-PD-1 therapy first

followed by target therapy upon failure of anti-PD1 therapy

Case 3: Answer A. Patient is not eligible for mutated BRAF target therapy

Patients melanoma expressed BRAF mutation and is eligible for target therapy

B. Patient should receive only immune checkpoint blockade therapy

If immune checkpoint blockade therapy fails, patient is still eligible to receive target therapy

C. Start patient on Anti-CTLA4 therapy until complete remission is achieved

Anti-CTLA4 is associated with ~24% response rate with worse AEs than anti-PD-1

D. Patient should receive anti-PD-1 therapy first followed by target therapy upon failure of anti-PD1 therapy

Current Approach at DFCI Retrospective trial showed worse prognosis in patients who

started Target therapy first then switched to Immune checkpoint blockade therapy1 Possibly because immune system changes after target therapy2 New prospective study underway

Anti-PD-1 is associated with ~40% response rate3 Anti-CTLA4 is associated with ~24% response rate with worse

AEs than anti-PD-14 Combination therapy of anti-PD-1 and anti-CTLA4 is associated

with ~60% response rate but severe AEs 1. Ackerman A et al. Cancer. 2014 2. Cooper ZA et al. Oncoimmunology. 2016 3. Hamid O. et al., NEJM 2013 4. Moreno et al. Seminars in Onco 42; 2015 5. Hodi et al. NEJM. 2010

Current Approach at DFCI If patient has the BRAF V600E mutation: We start with anti-PD1 therapy until

complete remission (CR) or failure. If CR achieved, then we continue therapy for 6 months and stop.

New study1 showed that 3/29 melanoma patients receiving PD-1 blockade for a median 7-9 months and stopping (after CR achieved) had a relapse 8 months after stopping therapy.

Optimal duration of therapy with PD-1 blockers still unknown

If failure, we begin target therapy

If patient has the BRAF wildtype: We start anti-PD1 therapy until CR or failure. If failure, we switch to Anti-CTLA4 therapy or combination therapy

Follow-up while on therapy: Clinical visits: Q3 months for 2 years, then Q6 months for 5 years, then annually CT scans: Q3 months while on therapy. PET scans not done because may exhibit

avidity in inflammation due to therapy (false positive) MRI Brain yearly

1. Ladwa R and Atkinson V. Mel Res. 2017

Acknowledgments Brigham and Womens Hospital Department of Dermatology Jennifer Lin, MD Adriano Piris, MD Labib Zakka, MD, MA

Mihm Cutaneous Pathology Consultative Service: Adriano Piris, MD Labib Zakka, MD, MA

Dana-Farber Cancer Institute: Stephen F. Hodi, MD Elizabeth Buchbinder, MD

Melanoma Institute Australia: Richard Scolyer, MD

THANK YOU FOR YOUR KIND ATTENTION!

Malignant Melanoma: Prognostic Factors and Approach to TherapyConflicts of InterestStaging MelanomaStaging MelanomaStaging MelanomaMalignant Melanoma PrognosisCase 1: Prepare to voteSlide Number 8Slide Number 9Slide Number 10Case 1: VOTECase 1: AnswerCase 1: AnswerSlide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Tumor Thickness (Breslow thickness)Measuring Breslow ThicknessSlide Number 22UlcerationSlide Number 24True UlcerationSlide Number 27Slide Number 28Slide Number 29Slide Number 30Primary Tumor UlcerationDermal MitosesPrognostic Factors: Dermal Mitoses (Hot Spot)Slide Number 35Slide Number 36Case 2: Prepare to voteSlide Number 38Case 2: VOTECase 2: AnswerSatellite and MetastasisMicrosatelliteSlide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47Slide Number 48Slide Number 49Slide Number 50Malignant Melanoma Target and Immune Checkpoint Blockade TherapyMolecular Targeted and Immune Checkpoint Therapy in Malignant MelanomaMAPK pathway in melanomaMolecular Targeted Therapy in Malignant MelanomaTarget TherapyImmune Checkpoint Blockade in Melanoma ImmunotherapyImmune Checkpoints in Melanoma ImmunotherapyCase 3: Prepare to voteCase 3: VOTECase 3: AnswerCurrent Approach at DFCICurrent Approach at DFCIAcknowledgmentsTHANK YOU FOR YOUR KIND ATTENTION!

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