Green Book

Question 1

What is locally advanced breast cancer (LABC)?

Answer 1

Typically, the term refers to stage III Dz (T3N1, N2-3, or T4). However, stage IIB pts with T3N0 Dz may be included. IBC is included, but metastatic Dz is not.

LABC can be separated into those cancers that are operable and those that are not.

Question 2

What are the epidemiologic trends and incidence of LABC?

Answer 2

The incidence of T3-4 Dz decreased by 27% from 1980 to 1987 (coincident with the institution of mammography).

Analysis of the SEER database from 1992 to 1999 indicated that LABC (stage III other than IBC) and IBC made up 4.6% and 1.3% of all female breast carcinomas, respectively.

Question 3

What are the diagnostic criterial for inflammatory breast cancer (IBC)?

Answer 3

The consensus min diagnostic criteria for a Dx of IBC are (Dawood et al.,
Ann Oncol 2011):
1. Rapid onset of breast erythema, edema, and/or peau d’orange, and/or warm
breast, with or without an underlying palpable mass
2. Duration of Hx of no more than 6 mos
3. Erythema occupying at least one-third of the breast
4. Pathologic confirmation of invasive carcinoma

Question 4

What is the pathognomonic feature that is more characteristic of IBC than other forms of LABC?

Answer 4

Presence of tumor emboli (aka dermal lymphatic invasion [DLI]) in the dermis of the skin overlying the breast; however, DLI is not necessary for the Dx of IBC

Question 5

What is the prevalence of IBC?

Answer 5

1-4% of breast cancer cases are IBC.

70% present with regional Dz and 30% with distant Dz.

Question 6

What are the histologic subtype of LABC?

Answer 6

The histologic subtypes are the same for LABC as for earlier-stage Dz.

Invasive ductal carcinoma is still most common, but FHs, such as tubular, medullary, and mucinous, are less frequently represented.

Question 7

Are there genetic/molecular factors associated with LABC?

Answer 7

No. There are no molecular markers that define LABC. However, tumors with avian erythroblastic leukemia viral oncogene homolog 2/human epidermal growth factor receptor 2 (HER2) positivity, BRCA1 mutation, and triple-negative status (ER-, PR-, Her2-) are associated with aggressive phenotypes.

The basal-like (triple negative) and HER2 molecular subtypes are associated with a poor prognosis as well, though outcomes for pts with HER2+ Dz have been dramatically improved with trastuzumab.

Question 8

what is the work-up for locally advanced invasive BC?

Answer 8

H&P, CBC, liver profile, ER/PR/Her2 status, bilateral diagnostic mammogram; imaging with US, CT, PET, bone scan, MRI optional per NCCN 2018

Question 9

What are the 5 regional LN stations in BC?

Answer 9

Regional LN stations in BC:
- Infraclavicular (ICV) nodes typically refer to the level III axillary nodes in RT oncology

Station I: nodes inf/lat to pectoralis minor muscle
Station II: nodes deep to pectoralis minor and the interpectoral Rotter nodes
Station III: nodes sup/med to pectoralis minor
Station IV: SCV nodes
Station V: IM nodes

Question 10

What are the most important factors that predict for LRR in LABC?

Answer 10

Increasing number of LNs with Dz and breast tumor size are the most important factors that predict for LRR.

Question 11

What are the basic principles of treating LABC?

Answer 11

Inoperable LABC: neoadj chemo is used to shrink the tumor and potentially convert it to be operable.

Operable LABC: Neoadj or adj chemo are used.

Modified radical mastectomy (MRM) (including levels I-II axillary LNs) is the definitive locoregional Tx.

PMRT is indicated in all initial stage III Dz.

Hormonal therapy and trastuzumab are incorporated as appropriate per receptor status of Dz

Question 12

What is Halsted radical mastectomy?

Answer 12

Halsted radical mastectomy includes resection of all breast parenchyma with overlying skin and major and minor pectoral muscles en bloc with axillary LNs

Question 13

What is spared with a modified radical mastectomy vs. radical mastectomy?

Answer 13

MRM spares the pectoralis muscles

Question 14

What is spared with a total or simple mastectomy?

Answer 14

In a total or simple mastectomy, only the breast tissue is removed with overlying skin.

Axillary LNs are not dissected.

Question 15

What is considered an “adequate” axillary LND for purpose of staging and clearance?

Answer 15

Oncologic resection of levels I-II is considered standard and adequate.

The LNs and axillary fat pad need to be removed en bloc.

An axillary LND is considered full if >= 10 LNs are removed without neoadj chemo; often after neoadj chemo the LN yield is reduced.

If suspicious nodes are palpable on intraop evaluation of level III, then level III dissection should be performed.

Question 16

Which major trial demonstrated that not all pts with sentinel lymph nodes (SLN) Bx+ Dz need completion of axillary LND?

Answer 16

The American College of Surgeons Oncology Group (ACOSOG) Z11 enrolled 856 pts with cN0 T1-2 who underwent upfront breast-conserving surgery and SLN Bx.

Pts with 1-2+ SLN were randomized to axillary lymph node dissection (ALND) + tangent RT vs. RT alone.

There was no difference in breast/axillary recurrence.

Question 17

Do clinically node+ pts always need axillary LND?

Answer 17

Yes - always!

Whether the pt receive upfront surgery or neoadj chemo, a fully axillary LND is always needed for clinically node positive (cN+) Dz.

Omission of ALND should only be considered on protocol.

Question 18

What is the standard systemic chemo for LABC?

Answer 18

Standard chemo at present includes an anthracycline and taxane-based regimen (eg - doxorubicin (adriamycin)/cyclophosphamide[AC] and paclitaxel).

Question 19

Does adding paclitaxel to standard AC chemo improve the outcomes of pts with BC?

What were the trials that showed that?

Answer 19

Yes. Adding paclitaxel improves response rates, DFS, and Os

NSABP 27 randomized operable pts to preop AC, preop AC + taxol, the addition of taxol did not improve survival outcomes but did improve pCR in the preop group (26% vs 13%)

The CALGB 9344 study randomized 3,121 operable pts with LN+ Dz and found that adding taxol q3wks x 4 to AC x 4 improved DFS and OS.

ECOG E1199 randomized 4,950 stage II-IIIA BC pts to AC q3wks x 4 –> taxol q3wks x 4, AC q3wks x 4 –> taxol x 12 weekly, AC q3wks x 4 –> Taxotere q3wks x 4, and AC q3wks x 4 –> Taxotere x 12 weekly.

The weekly taxol arm had improved DFS (HR 1.27) and OS (HR 1.32).

The effect was significant in all pts, including those with ER+/Her2- tumors.

Question 20

Which meta-analysis showed the benefit of anthracyclines?

Answer 20

The EBCTG/Oxford Overview meta-analysis of 18,000 women showed a benefit of anthracyclines over cyclophosphamide/methotrexate/5-fluorouracil (CMF) improved DFS and OS, although CMF > no chemo.

Question 21

What is meant by “dose-dense” chemo ?

Answer 21

Dose-dense chemo is administered q2wks as opposed to q3wks.

Question 22

Has dose-dense chemo been demonstrated to be superior in a prospective randomized trial?

Answer 22

Yes, intergroup trial C9741 randomized 2,005 node+ pts to AC x 4 –> taxol x 4 given q3wks vs. q2wks.

Filgrastim was given for BM support in the q2wks arm.

4 yr DFS improved from 75% to 82% with the q2wk schedule.

The risk ratio for OS was 0.69 in favor of the q2wk schedule.

Median f/u was 36 months.

Severe neutropenia was also less frequent with the dose-dense schedule.

Question 23

What is the rational for the use of neoadj chemo for LABC?

Answer 23

Neoadj chemo may convert pts with unresectable LABC to resectability.

It may also be used to shrink large breast tumors requiring mastectomy in resectable pts to be managed with breast conserving surgery.

Neoadj trials have the advantage of providing pathologic assessment of chemo response at the time of surgery.

If the tumor is not responsive to 1 chemo regimen and progresses clinically, a different chemo regimen can be used.

Question 24

Which pts have inoperable Dz and definitely need neoadj chemo?

Answer 24

Women with fixed axillary LN (stage N2a), major skin involvement (stage T4b-4d), +/- CW involvement