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Flashcards in Early Breast Cancer Deck (39)

When is an MRI of the breast considered?

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


What defines HER2 positivity?

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


Tell me the T staging for breast cancer

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


What is inflammatory carcinoma

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.


What is the pathological N staging for breast cancer?

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


Some conclusions from staging of breast cancer?

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


In DCIS, does Tamoxifen work?

Yes, in ER+DCIS.
- 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.


How is HER2 status assessed?

By measuring the number of HER2 Gene copies using in-situ Hybridisation (ISH) techniques;
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


What is classified as HER2+ ?

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


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


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



What is considered widespread disease in DCIS?
How is the management different?

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


What is the recurrence rate in excised DCIS?

1) Retrospective study of 220 patients:
- 4 y Recurrence rate 0
- 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


What does NCCN recommend in the management of DCIS?

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


What are the side-effects of GnRH agonists?

Vast motor symptoms
Loss of bone density


Tell me about the POEMS study

The Prevention Of Early Menopause Study
Moore et al NEJM 2015

Aim: to evaluate GnRH agonists efficacy in protecting ovarian function

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

- 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%


When is lumpectomy contraindicated?

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


Tell me about the SOFT and TEXT trials conclusions.

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

DFS 93% (EO) vs 89% (TO)



Tell me about the SOFT trial

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

(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)


Tell me about the ARNO95 Study

Kaufmann JCO 2007

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

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

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)


Tell me about the IES study

Coombes Lancet 2007

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

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


Any benefit beyond 5 years of hormonal treatment?


MA.17 Peter Goss, JNCI 2005

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

S/p 5 years of Tamoxifen, randomized to:
1) Letrozole
2) Placebo

F/u 2.5 years:
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.


Tell me about the BIG 1-98 study

Thurlimann NEJM 2005

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

HR+ post-menopausal women

4 arms:
1) Letrozole
2) Letrozole --> Tamoxifen
3) Tamoxifen
4) Tamoxifen --> Letrozole

F/u 2years
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.


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

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


Tell me about the Italian Tamoxifen Anastrozole trial (ITA)

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


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

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


Tell me about the TEAM trial

Cornelis et al Lancet 2011

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

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


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

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


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

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


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

CYP450 enzyme, CYP2D6


Tell me more about CYP2D6 in relation to Tamoxifen metabolization

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


Give examples of CYP2D6 inhibitors:

Amino drone
Venlafaxine (weak)


Tell me about the ECOG E1199 study

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.


What did NSABP B-36 showed?

4# AC is preferable over 6#FEC

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


What do you know about Medullary Carcinoma of the breast?

Uncommon variant of infiltrating duct all carcinoma

Characterized by:
- High nuclear grade
- Lymphocytic infiltration
- A pushing tumor border
- presence of a syncytial growth pattern


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

Yes in terms of DFS.

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

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


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

Calcium 1200 to 1500 mg OD
Vitamin D3 400 to 800IU OD


Can we give chemo and adjuvant Tamoxifen together? Why?

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.
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


Between Letrozole and Anastrozole, which is preferred?


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

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


Between Exemestane and Anastrozole, which is preferred and why


MA.27 by Goss et al JCO 2013

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

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