Locally Advanced Breast Cancer

Owen C. Thomas and Tse-Kuan Yu

Background

What is locally advanced breast cancer (LABC)?

Typically, the term refers to stage III Dz (T3N1, N2-N3, or T4). However, stage IIB pts with T3N0 Dz may be included. Inflammatory breast cancers (IBCs) are included, but metastatic Dz is not. LABC can be separated into those cancers that are operable and those that are not.

What is the meaning of LABC historically?

LABC refers to those breast cancers that demonstrate poor outcomes when managed surgically. Haagensen & Stout (Ann Surg 1943) published an analysis of 1,135 pts treated with radical mastectomy alone. This analysis revealed 5 “grave signs” of LABC and an understanding of the limited efficacy of mastectomy alone in managing locally advanced pts.

What are the 5 grave signs of LABC as defined by Haagensen & Stout?

Grave signs of LABC (per Haagensen & Stout):

Limited edema of skin or “peau d–orange” appearance
Ulceration of skin
Fixation of tumor to chest wall (CW)
Axillary LNs ≥2.5 cm
Fixation of axillary LN

What are the epidemiologic trends and incidence of LABC?

The incidence of T3-T4 Dz decreased by 27% from 1980–1987 (coincident with the institution of mammography.) Analysis of the SEER database from 1992–1999 indicated that LABC (stage III other than IBC) and IBC made up 4.6% and 1.3% of all female breast carcinomas.

What is the distinct prognosis of IBC compared to other pts with LABC?

Pts with IBC have twice the risk of death compared to other pts with LABC.

What is the prevalence of IBC?

1%–4% of breast cancer cases are IBC.

Is LABC more common among certain ethnic groups?

Yes. A higher proportion of black women have LABC.

What are the histologic subtypes of LABC?

The histologic subtypes are the same for LABC as for earlier-stage Dz. Infiltrating ductal carcinoma is still the most common, but favorable histologies, such as tubular, medullary, and mucinous, are less frequently represented.

Are there genetic/molecular factors associated with LABC?

No. There are no molecular markers that define LABC. However, tumors with HER2/Neu positivity, BRCA1 mutation, and triple-negative (estrogen receptor [ER]–, progesterone receptor [PR]–, HER2–) are associated with aggressive phenotypes. A genomic profile of basal and HER2 subtypes is associated with a poor prognosis as well. The use of Herceptin in HER2+ positive tumors has improved their outcome, though.

Workup/Staging

What is the workup for locally advanced invasive breast cancer?

Invasive breast cancer workup: H&P, CBC, liver profile, ER/PR/HER2 status; diagnostic mammogram and US as necessary; bone scan, CXR (CT chest optional), and CT abdomen; US or MRI abdomen as needed

In a pt with T1-T2 breast cancer and a clinically– axilla, what is the rate of pathologic axillary involvement?

In T2-T3 pts with a clinically– axilla, there is pathologic axillary involvement in ~30%.

In a breast cancer pt with a clinically+ axilla, what is the chance that the axilla is negative upon resection?

In pts with a clinically+ axilla, there is a ~25% chance for a negative axilla upon resection.

What are the 5 regional LN stations in breast cancer?

Regional LN stations in breast cancer:

Station I: nodes inf/lat to pectoralis minor
Station II: nodes deep to pectoralis minor
Station III: nodes sup/medial to pectoralis minor
Station IV: supraclavicular nodes
Station V: internal mammary (IM) nodes

“Infraclavicular” nodes typically refers to the level III axillary nodes by radiation oncology.

How is IBC diagnosed?

IBC is a clinical Dx, with characteristics of rapid onset (<3 mos), generalized induration, often without an associated mass (classic type), peau d–orange appearance, and a diffuse skin erythema affecting more than two thirds of the breast. Enlargement, flattening and retraction of the nipple with warmth, and tenderness are common. IBC is characterized pathologically by cancer cells in dermal lymphatics (not necessary for Dx). Random Bx of breast parenchyma may yield cancer cells.

Treatment/Prognosis

What are the most important factors that predict for LRR?

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

What are the basic principles of treating LABC?

Inoperable LABC: neoadj chemo is used to shrink the tumor and potentially convert it to be operable. Neoadj or adj chemo should be included.
Operable LABC: Neoadj or adj chemo are used. Modified radical mastectomy (including level I–II axillary LNs) is the definitive locoregional Tx. PMRT is indicated in most circumstances. Hormonal therapy and Herceptin are incorporated as appropriate per receptor status of Dz.

What is a Halsted radical mastectomy?

Halsted radical mastectomy includes resection of all breast parenchyma, a large portion of breast skin, and major and minor pectoral muscles en bloc with axillary LNs.

What is spared with a modified radical mastectomy?

Modified radical mastectomy spares the pectoralis muscle.

What is spared with a total or simple mastectomy?

In a total or simple mastectomy, only the breast tissue is removed with overlying skin. Axillary LNs are not dissected.

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

Oncologic resection of levels I–II is considered standard and adequate. The LNs and axillary fat pad need to be removed en bloc. If suspicious nodes are present in level III, then level III dissection should be performed.

What is standard systemic chemo?

Standard chemo at present includes an anthracycline- and taxane-based regimen (e.g., Adriamycin/cyclophosphamide [AC] and Taxol).

What is meant by “dose-dense” chemo?

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

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

Yes. Intergroup trial C9741 randomized 2,005 node+ pts to AC × 4 > Taxol × 4 given q3wks vs. q2wks. 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 follow-up was 36 mos. Severe neutropenia was also less frequent with the dose-dense schedule.

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

Neoadj chemo may convert pts with unresectable LABC to resectability. It may also be used to shrink large breast tumor requiring mastectomy in resectable pts to be managed with breast conservation surgery (BCS). 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.

What major study determined whether neoadj chemo improves survival compared to adj chemo in LABC?

NSABP B18 was designed to assess whether preop AC resulted in improved DFS and OS compared to postop AC. Secondary aims were to assess response to preop AC and correlate with survival and LR outcomes. Rates of BCS were also assessed. All women were deemed operable at enrollment, and the majority had T2 or smaller primary and clinically node– Dz. At the most recent follow-up (16 yrs) (Rastogi et al., JCO 2008), there has been no significant difference in OS or DFS between the women treated with neoadj vs. adj chemo. There is a trend, however, for women <50 yo for improved DFS and OS when treated preoperatively (p = 0.09 and 0.06). There was a 27% conversion rate from mastectomy to BCS.

What procedures should be done prior to starting neoadj chemo for LABC?

Core Bx and wire localization for the Bx bed (in case the pt has a CR to chemo). Perform sentinal lymph node (SLN) Bx if cN0; if cN+, consider FNA Bx.

Does adding Taxol to standard AC chemo improve the outcomes of pts with breast cancer?

Yes. Adding Taxol improves response rates, DFS, and OS.

NSABP 27 randomized operable pts to preop AC, preop AC + Taxol, or preop AC + postop Taxol. Here, the addition of Taxol did not improve survival outcomes but did improve pCR in the preop group (26% vs. 13%). (Rastogi et al., JCO 2008)

The CALGB 9344

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