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Medical oncology > Early Breast Cancer > Flashcards

Early Breast Cancer Flashcards

1
Q

When is an MRI of the breast considered?

A

Familial breast cancer a/w BRCA mutations
Breast implants
Lobular Cancer
Multifocality/multicentricity (ESP in lobular cancers)
Large discrepancies between conventional imaging and clinical examination

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2
Q

What defines HER2 positivity?

A

By IHC:
3+ when >10% of the cells harbour a complete membrane staining
(Previously, this value was 30%)

By In-situ Hybridisation:
Positive if the number of HER2 gene copies is 6 or more; OR
HER2/Chromosome 17 is 2 or more, instead of 2.2

*** If a case is defined as equivocal after 2 tests, it is eligible for Trastuzumab, and should be discussed in MTB

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3
Q

Tell me the T staging for breast cancer

A

T1 2cm or less
T1mi = Tumor 1mm or less

T1a Tumor >1mm but 5mm or less
T1b Tumor >5mm but 10mm or less
T1c Tumor >10mm but 20mm or less

T2 Tumor >20mm but 50mm or less

T3 Tumor >5cm

T4 Tumor of any size, with direct extension to the chest wall +/- skin (ulceration or skin nodules)

  • Chest wall includes Ribs, intercostal muscles, serratus anterior muscle. NOT pectoral is muscle.
  • Dimpling, nipple retraction/skin changes does not count unless T4b and T4d.
T4a = Extension to chest wall
T4b = ulceration and/or ipsilateral satellite nodules +/- oedema (incl peau d' orange) of the skin, which do not meet criteria for inflammatory carcinoma
T4c = T4a+T4b
T4d = Inflammatory carcinoma
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4
Q

What is inflammatory carcinoma

A

A clinical-pathological entity

Characterized by diffuse erythema and oedema (peau d’orange) involving a third or more of the skin of the breast.
Skin changes are due to lymphoedema caused by tumor emboli within dermal lymphatic system.

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5
Q

What is the pathological N staging for breast cancer?

A

pN1 = Micromets; or mets in 1-3 Axillary LN; +/- internal mammary LN with mets detected by SLNB

pN1mi = Micromets >0.2mm +/- >200 cells but none >2mm 
PN1a = mets in 1-3 Axillary LN, at least one >2mm 
PN1b = internal mammary LN with Micromets or Macromets detected by SLNB
pN1c = 1-3Axillary LN + internal mammary LN with Micromets/Macromets detected by SLNB
pN2 = mets in 4-9 Axillary LN; or in clinically detected internal mammary LN in the absence of Axillary LN
pN2a = 4-9 Axillary LN, at least one >2mm 
pN2b = mets in clinically detected internal mammary LN in the absence of Axillary LN
pN3 = 10 or more Axillary LN; OR
Infra clavicle (level 3); OR
Clinically detected ipsilateral Int mammary LN in the presence of one or more positive level I, II Axillary LN; OR in >3 Axillary LN + internal mammary LN with Micromets or Macromets detected by SLNB; OR ipsilateral supraclav LN

pN3a = 10 or more Axillary LN, at least one >2mm; OR infraclavicular LN
pN3b = ipsilateral internal mammary LN + 1 or more Axillary LN; OR
- >3 Axillary LN and in INT mammary LN with micromet o Macromets
pN3c = ipsilateral supracalvicular LN

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6
Q

Some conclusions from staging of breast cancer?

A 
T1N0M0 = Stage IA 
T2N0M0 = Stage IIA
T3N0M0 = Stage IIB
T4N0M0 = Stage IIIB 
N2 = At least Stage IIIA
N3 = At least Stage IIIC
T4 = At least Stage IIIB
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7
Q

In DCIS, does Tamoxifen work?

A

Yes, in ER+DCIS.
Tamoxifen:
- decreases the risk of invasive & non-invasive recurrences.
- reducEs the incidence of a 2nd contralateral primary breast cancer

*But no effect on OS

After mastectomy, Tamoxifen might be considered to decrease the risk of Contralateral breast cancer in those at high risk of new breast tumors.

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8
Q

How is HER2 status assessed?

A

By measuring the number of HER2 Gene copies using in-situ Hybridisation (ISH) techniques;
OR
By a complementary method in which the quantity of HER2 cell surface receptors by IHC

  • Assigment of HER2 status based on mRNA assays or Multigene arrays is NOT recommended
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9
Q

What is classified as HER2+ ?

A

3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells

OR

Demonstrate HER2 Gene amplification by ISH method

  • Single probe, average HER2 copy number is 6 or more signals/cell
  • Dual probe HER2/CEP17 ratio = 2 or more with an average of HER2 copy number as 4 or more signals/cell
  • Dual probe HER2/chromosome enumeration probe (CEP)17 ratio = 2 or more wth an average HER2 copy number
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10
Q

How often will there be invasive cancer found when only pure DCIS was detected on core needle biopsy?

A

25%

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11
Q

What is considered widespread disease in DCIS?

How is the management different?

A

Disease in 2 or more quadrants
- Patients will then require a total mastectomy WITHOUT LN dissection

As opposed to just lumpectomy with negative margins, followed by +/- whole breast radiation

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12
Q

What is the recurrence rate in excised DCIS?

A 
1) Retrospective study of 220 patients:
DCIS + RT:
- 4 y Recurrence rate 0
DCIS - RT:
- 4y Recurrence rate 5.5%

2) Prospective phase II study on women with low-risk DCIS s/p WE alone. (No adjuvant RT, no adjuvant Tamoxifen)
- 10y local recurrence rate 1.5%
- Low risk: mammographically detected DCIS, 2.5cm or less, G1/2, margin 1cm or more or a negative re-excision

3) Retrospective series:
- margin width 10mm, RT had no additional benefit. 8y local recurrence rate 4%
- margin with 1mm to

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13
Q

What does NCCN recommend in the management of DCIS?

A

1) Lumpectomy + Whole breast R
2) Total mastectomy +/- SLNB +/- Reconstruction
3) lumpectomy –> Observation

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14
Q

What are the side-effects of GnRH agonists?

A

Vast motor symptoms

Loss of bone density

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15
Q

Tell me about the POEMS study

A

The Prevention Of Early Menopause Study
Moore et al NEJM 2015

Aim: to evaluate GnRH agonists efficacy in protecting ovarian function

N=200
Premenopausal, hormone receptor negative
2 arms:
1) Standard chemo with Goserelin
2) Standard chemo without Goserelin

Goserelin was given SC 3.6mg Q4weeks
- beginnings 1week before chemo and continued to within 2weeks before or after final chemo

RESULTS:

  • Ovarian failure rate was 8% in Goserelin group and 22% in chemo-alone group
  • Pregnancy occurred more in Goserelin group. 20% vs 10%
  • Goserelin group had improved OS 80% in chemo-alone group and 90% in Goserelin group.
  • Improved 4y DFS in Goserelin group at 90% and 80%
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16
Q

When is lumpectomy contraindicated?

A

Pregnant women. (And who would require RT during pregnancy)
Diffuse suspicious or malignant-appearing microcalcifications
Widespread disease that cannot be incorporated by local excision through a single excision with satisfactory cosmetic result
Diffuse lay positive pathologic margins

Relative contraindications:
- previous RT to breast/chest wall
Active connective tissue disease involving the skin (ESP scleroderma/lupus)
Tumors >5cm
Positive pathologic margins
17
Q

Tell me about the SOFT and TEXT trials conclusions.

A

Premenopausal women with Hormone receptor+ early stage breast cancer were assigned to:
1) Exemestane + ovarian suppression
2) Tamoxifen + ovarian suppression
Both for 5 years each.

Ovarian suppression methods:

  • GnRH agonist Triptorelin
  • Oophrectomy
  • Ovarian irradiation

RESULTS:
DFS 93% (EO) vs 89% (TO)
OS~

============

18
Q

Tell me about the SOFT trial

A 
Premenopausal women with HR+ breast cancer were randomized to:
1) Tamoxifen
2) Tamoxifen+Ovarian suppression
3) Exemestane+Ovarian suppression
Each for 5 years

RESULTS:

(1) Primary analysis: Tam+Ovarian suppression was NOT superior to Tam alone for DFS.
- AFter 5.5 years, DFS rate 86.5% (TO) vs 84.7% (Tam) [trend]
(2) Subgroup analysis: women at high risk of recurrence s/p prior chemo, had improved outcomes with Ovarian suppression
- 5y DFS: 78% (Tam); 82.5%(TO); 86%(EO)

19
Q

Tell me about the ARNO95 Study

A

Kaufmann JCO 2007

Aim: To evaluate the benefits of switching to Anastrozole after 2y of Tam treatment VS continuing on Tam for total 5y

N=1000
S/p Tam for 2 years
2 arms:
1) Tamoxifen for 3 more years
2) Anastrozole 1mg/day for 3 years

RESULTS

1) Reduction in risk of disease recurrence HR 0.66 (=34% reduction in the RR of disease recurrence/death)
- 5y DFS 93.5% for Anastrozole and 89.5% for Tam
2) Improved OS HR 0.53 (= 47% improvement in OS)

20
Q

Tell me about the IES study

A

Coombes Lancet 2007

n=4700
Post-menopausal
Unilateral, invasive, ER+ or ER Unknown breast cancer who were Disease-free on 2-3 y of Tamoxifen randomized to:
1) Exemestane 
2) Continue Tamoxifen

RESULTS:
F/u 4.5 years
DFS better with Exemestane HR 0.76
Adjusted HR for death 0.83, in favor of Exemestane

21
Q

Any benefit beyond 5 years of hormonal treatment?

A

Yes

MA.17 Peter Goss, JNCI 2005

Aim: Determine if extended adjuvant therapy with Letrozole reduces the risk of late recurrences

N=5000
Post-menopausal
S/p 5 years of Tamoxifen, randomized to:
1) Letrozole
2) Placebo

F/u 2.5 years:
RESULTS:
1) Improved DFS and distant DFS HR 0.6
2) In main group, OS similar, except in LN+, OS improved with HR 0.6
3) more hormonally related s/e with Letrozole, but incidences of bone fractures and CVS events similar.

22
Q

Tell me about the BIG 1-98 study

A

Thurlimann NEJM 2005

Aim:
Letrozole shown to be more effective in MBC and in neoadjuvant setting as cf to Tamoxifen. hence, trial done to compare Letrozole and Tamoxifen.

N=8000
HR+ post-menopausal women

4 arms:

1) Letrozole
2) Letrozole –> Tamoxifen
3) Tamoxifen
4) Tamoxifen –> Letrozole

F/u 2years
RESULTS:
5y DFS 84% (Letrozole) vs 81.4% (Tamoxifen)
ESP risk of distant met HR 0.73

After a longer f/u of 6years,
No significant improvement in DFS noted with Tam–> Let OR Let–>Tam a cf to Letrozole alone.

23
Q

What are the 5 trials that studied the use of Tamoxifen–>AI vs continued Tamoxifen ?

A

1) Italian Tamoxifen Anastrozole trial
2) IES trial
3) ABGSG8 trial
4) ARNO 95
5) TEAM trial

24
Q

Tell me about the Italian Tamoxifen Anastrozole trial (ITA)

A

N=400 post menopausal women
S/p 2-3 years of Tamoxifen, randomized to:
1) Continued Tamoxifen
2) Anastrozole

HR for relapse strongly favored sequential treatment with Anastrozole HR 0.35

25
Q

What did the combined analysis of ARNO-95 and ABCSG 8 trial show?

A

Randomized following 2 years of Tamoxifen to complete:

1) total 5 years of Tamoxifen
2) Anastrozole X 3 years

2y f/u :
EFS superior with crossover to Anastrozole
No difference in survival

26
Q

Tell me about the TEAM trial

A

Cornelis et al Lancet 2011

Compared Exemtestane vs Tamoxifen –> Exemestane
N=10 000
Post-menopausal women, HR+

RESULTS:
5y DFS 85% (Sequential) vs 86%
Sequential tx a/w more Gynaecoloical symptoms, venous thrombosis and endometrial abnormalities

27
Q

Wha is the NCCN recommendations for Adjuvant endocrine therapy for POST menopausal women?

A

1) AI for 5 years
2) Tamoxifen for 2-3 years followed by:
- AI (total 5 years endocrine therapy)
- AI 5 years
3) Tamoxifen for 4.5-6 years –> 5 years of AI
4) Tamoxifen for 10 years

** Use of Tam in post-menopausal for 5 years or up to 10 years is limited to those who decline or have a contra-indication to AI

28
Q

What is the NCCN recommendations for Adjuvant endocrine therapy for PRE-menopausal women?

A

1) 5 years of Tamoxifen + Ovarian suppression
2) 5 years of Tamoxifen - Ovarian suppression
3) Ovarian suppression + AI for 5 years

After 5y of initial endocrine therapy, for women who are post menopausal then, Consider:

  • EXTENDED Therapy with AI for p to 5 years; OR
  • Tamoxifen for another 5 years (as per ATLAS trial)

Those who remain premenopausal,
Continue Tam up to 10 years

29
Q

Which cytochrome enzyme is involved in the conversion of Tamoxifen to endoxifen?

A

CYP450 enzyme, CYP2D6

30
Q

Tell me more about CYP2D6 in relation to Tamoxifen metabolization

A

CYP2D6 is responsible for converting Tamoxifen to Endoxifen.

1) wtCYP2D6 = extensive metabolizes of Tamoxifen
2) If one or two variant alleles with either reduced/no activity = Intermediate metabolizes/ poor metabolizes respectively

31
Q

Give examples of CYP2D6 inhibitors:

A 
Fluoxetine
Paroxetine
Methadone
Quinidine
Vinblastine
Amino drone
Chlorpromazine 
COdeine
Doxorubicin
Haloperidol 
Lomustine 
Ranitidine 
Venlafaxine (weak) 
Vincristine
Vinorelbine 
Celecoxib
32
Q

Tell me about the ECOG E1199 study

A 
4-arm trial n=5000
N+ or high-risk N- 
1) AC --> weekly Pac
2) AC --> 3-weekly Pac
3) AC --> weekly Doc
4) AC --> 3-weekly Doc

F/u 5 years
DFS and OS ~ when comparing Pac to Doc, and when comparing 3-weekly to weekly.

    • Secondary series of comparisons:
  • Weekly Pac > 3-weekly Pac for DFS (HR 1.27) and OS (HR 1.32)
  • 3-weekly Docetaxel > 3-weekly Pac in DFS, but OS ~

Therefore, we do not use 3-weekly Docetaxel anymore.
In addition, this is added on by CALGB 9741: ddAC–>Pac Q2w has survival benefit when compared to AC–>Q3w Pac.

33
Q

What did NSABP B-36 showed?

A

4# AC is preferable over 6#FEC

8yDFS ~for both
But toxicities with FEC were higher including:
- fatigue
- FN
- Thrombocytopenia 
- death rate
- QoL
34
Q

What do you know about Medullary Carcinoma of the breast?

A

Uncommon variant of infiltrating duct all carcinoma

Characterized by:

  • High nuclear grade
  • Lymphocytic infiltration
  • A pushing tumor border
  • presence of a syncytial growth pattern
35
Q

Any value in the addition of Zoledronic acid to adjuvant hormonal therapy?

A

Yes in terms of DFS.

ABCSG-12 study by Michael Gnant et al. 
N=1800 
Premenopausal, HR+ early breast cancer
Randomized to:
1) Goserelin + Tamoxifen + Zoledronic acid 
2) Goserelin + Tamoxifen
3) Goserelin + Anastrozole + Zoledronic acid
4) Goserelin + Anastrozole

RESULTS:
4y DFS: No difference btwn Anastrozole and Tamoxifen group
4y DFS when comparing Zoledronic acid and without, addition of Zoledronic resulted in absoulte reduction of 3.2% and a RR of 36% in disease progression. HR 0.64
Addition of Zoledronic acid did not significantly reduce risk of death

36
Q

How much calcium and Vitamin D should be given while on treatment?

A

Calcium 1200 to 1500 mg OD

Vitamin D3 400 to 800IU OD

37
Q

Can we give chemo and adjuvant Tamoxifen together? Why?

A

No. It is better to give this sequentially as evidenced by the study done by Kathy Albain published in Lancet 2009.
(SWOG 8814 study/INT-0100)

Phase 3. 
N=1500
Post-menopausal, HR+, N+ to test:
1) whether DFS is longer with Cyclo/Doxo/Fluorouracil given Q4w x6 + 5y of Tamoxifen as opposed to Tamoxifen alone. 
2) DFS is longer if CAF-->T or CAFT

RESULTS after 13y f/u:

1) CAFT or CAF–>T was better than T alone
- DFS HR 0.76
- OS marginally better HR 0.8 p 0.06
2) CAF–>T better than CAFT
- did not reach stat sig for DFS nor OS
3) S/e of neutropenia/stomatitis/thromboembolism/CCF/leukemia more common in combination group

38
Q

Between Letrozole and Anastrozole, which is preferred?

A

Equivalent

FACE trial
(Femara vs Anastrozole Clinical Evaluation) study

N=4000 post-menopausal HR+ and LN+ breast cancer 
2 arms:
1) Letrozole 2.5mg OM
2) Anastrozole 1 mg OM 
Each for 5 years

RESULTS:

  • 5y DFS 85% (Letrozole) vs 83% (Anastrozole) (not sig)
  • OS ~
  • safety profiles ~
39
Q

Between Exemestane and Anastrozole, which is preferred and why

A

Equivalent

MA.27 by Goss et al JCO 2013

N=7500 post menopausal, HR+
2 arms:
1) Exemestane
2) Anastrozole

RESULTS:
- 4y EFS/OS/DFS/Disease-specific survival all similar

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