Ca Breast

Question 1

Genetic Risk factors

Answer 1

Genetics (5%–10% hereditary):

1. BRCA1—AD (17q21)
   -60% to 80% lifetime risk of breast cancer,
   -30% to 50% lifetime risk of ovarian cancer,
   - higher risk of triple negative
2. BRCA2—AD (13q12)
   -50% to 60% lifetime risk of breast cancer,
   -10% to 20% lifetime risk of ovarian cancer,
   -male breast cancer,
   -prostate, bladder, endometrial, and
   -pancreatic cancers
3. Li–Fraumeni—AD (17p), p53,
   a/w sarcoma, leukemia, brain, adrenocortical carcinoma
4. Cowden syndrome—AD (10q23), PTEN, a/w hamartomas of skin and oral cavity;
5. Ataxia–telangiectasia—AR (11q22), ATM
6. Peutz–Jeghers

Question 2

Major Invasive Carcinoma Types:

Answer 2

1. Invasive Ductal Carcinoma (IDC): (80% of cases)
2. Invasive Lobular Carcinoma (ILC): (5-10% of cases) (“Indian filing” pattern of cells)
3. Mixed Invasive Ductal and Lobular Carcinoma:

Less Common Invasive Subtypes:
1 Tubular: A small, well differentiated variant of IDC; usually ER+/PR+.
2 Medullary: Often linked to BRCA1; presents younger (<50); associated lymph nodes can be large; most are triple negative.
3 Mucinous/Colloid: Tends to occur in older patients; generally favorable prognosis.
4 Papillary: Tends to occur in older patients; often in multiple spots; can involve lymph nodes even when small.
5 Cribriform: Usually ER+/PR+.
6 Other Uncommon Variants: Include types like Metaplastic (often poor prognosis), Squamous cell, Micropapillary, Adenoid cystic, etc.

Specific Presentations and Related Lesions:
1 Extensive Intraductal Carcinoma (EIC): Non-invasive carcinoma (DCIS) making up ≥25% of the specimen and extending beyond the invasive tumor edges.
2 Paget’s Disease of the Nipple: Presents as chronic skin changes on the nipple; indicates underlying non-invasive (DCIS) or invasive cancer in the nipple.
3 Cystosarcoma Phyllodes: Fibroepithelial tumor (“leaf-like”), usually benign and encapsulated, though can grow rapidly. Malignant forms and nodal spread are rare.

Question 3

Molecular Classification

Answer 3

1 Luminal A: (best prognosis)
ER+/HER2- with low Ki-67 (<14%), OR intermediate Ki-67 (14-19%) and PR+ (≤20%).

2 Luminal B:
ER+/HER2- with high Ki-67 (≤20%), OR intermediate Ki-67 (14-19%) and PR- or low (<20%), OR ER+/PR+ with HER2+.

3 HER2 Enriched:
ER-/PR-, HER2+, high Ki-67.

4Basal-like: (worst prognosis) Triple Negative (ER-/PR-/HER2-), high prevalence in young Black women and BRCA mutation carriers.

Question 4

BIRADS

Answer 4

• BI-RADS 0 (Incomplete): 1% Malignancy; Requires completion of imaging or review of previous imaging.
• BI-RADS 1 (Negative): <1% Malignancy; Routine annual screening recommended.
• BI-RADS 2 (Benign lesion): <1% Malignancy; Routine annual screening recommended.
• BI-RADS 3 (Probably benign): <2% Malignancy; Short interval follow-up (6 months) recommended.
• BI-RADS 4a (Low suspicion for malignancy): 2%–10% Malignancy; Biopsy recommended.
• BI-RADS 4b (Moderate suspicion for malignancy): 10%–50% Malignancy; Biopsy recommended.
• BI-RADS 4c (High suspicion for malignancy): 50%–95% Malignancy; Biopsy recommended.
• BI-RADS 5 (Highly suggestive of malignancy): >95% Malignancy; Biopsy recommended.
• BI-RADS 6 (Biopsy-proven malignancy): 100% Malignancy; Appropriate treatment per stage.

Question 5

Surgery

Answer 5

• Simple or total mastectomy: Removal of breast tissue, nipple-areola complex, and skin.
• Extended simple mastectomy: Removal of breast tissue, nipple-areola complex, skin, and Level I axillary nodes.
• Modified radical mastectomy: Removal of breast tissue, nipple-areola complex, skin, and Level I and II axillary lymph nodes (LNs).
• Halstead’s radical mastectomy: Removal of breast tissue, nipple-areola complex, skin, pectoralis major and minor muscles, and Level I, II, and III axillary LNs.
• Extended radical mastectomy: Radical mastectomy plus removal of internal mammary LNs.
• Super radical mastectomy: Radical mastectomy plus removal of internal mammary LNs, mediastinal, and supraclavicular LNs.

Question 6

Is there a role for radical mastectomy in the modern era?

Answer 6

• Key Study: NSABP B-04 trial (n = 1079 LN- and n = 586 LN+ operable breast cancer patients).
• Comparison: Compared Radical Mastectomy (RM) to less extensive surgeries:
  
  • cN0 patients: RM vs. Total Mastectomy (TM) + RT vs. TM alone.
  • cN+ patients: RM vs. TM + RT.
• Main Finding: No statistically significant differences in 25-year outcomes (DFS, RFS, OS, Distant DFS, Local Recurrence) between the compared arms in either LN- or LN+ patients.
  
  • Illustrative OS (25-year): LN-: RM 25%, TM+RT 19%, TM 26%; LN+: RM 14%, TM+RT 14%.
  • Illustrative LR (25-year): LN-: RM 5%, TM+RT 1%, TM 7%; LN+: RM 8%, TM+RT 3%.
• Occult Nodes: 40% of cN0 patients undergoing RM had hidden pathologically positive lymph nodes found, but removing these did not provide a survival advantage.
• Delayed Surgery: Only 17.8% of TM alone patients required delayed axillary lymph node dissection for axillary failure.
• Conclusion: Based on these results, Radical Mastectomy is not necessary for operable breast cancer.

Question 7

How does mastectomy compare with breast conservation?

Answer 7

• At least six randomized trials have demonstrated no significant differences in Overall Survival (OS) between Breast Conservation Therapy (BCT) and mastectomy.
• Trial Results (from Table 23.5):
  
  • Milan (1973–1980; N=701; Stage I): Q (BCT) vs. RM. 20 yrs F/U. OS: 58%/59% (NS). DFS: 9%/2% (<.001). LR: (Not in table, see below from text).
  • Gustave-Roussy (1972–1980; N=179; Stage I): WE (BCT) vs. MRM. 15 yrs F/U. OS: 73%/65% (p=.19). DFS: 9%/14% (NS). LR: (Not in table).
  • NSABP B-06 (1976–1984; N=1,851; Stage I–II): WE (BCT) vs. MRM. 20 yrs F/U. OS: 46%/47% (p=.74). DFS: 35%/36% (p=.95). LR: 2.7%/10.2%.
  • NCI (1979–1987; N=237; Stage I–II): WE (BCT) vs. MRM. 25 yrs F/U. OS: 38%/44% (p=.38). DFS: 56%/29% (p=.0017). LR: 22%/1.0% (<.001).
  • EORTC 10801 (1980–1986; N=868; Stage I–II): LE (BCT) vs. MRM. 22 yrs F/U. OS: 39%/45% (NS). DFS: 20%/12% (p=.01). LR: (Not in table).
  • Danish (1983–1989; N=904; Stage I–III): Q, WE (BCT) vs. MRM. 6 yrs F/U. OS: 79%/82% (NS). DFS: 70%/66% (NS). LR: 3%/4% (NS).
• Two trials that did not require negative margins found higher LR rates with BCT (text mentions likely due to inadequate surgery).
  
  • The EORTC trial mentioned had 48% positive margins in the BCT arm.
• At 20-year follow-up in the Milan trial, there were higher LR rates in the BCT arm (8.8% after quadrantectomy) vs. RM (2.3%). However, two thirds of these recurrences were new primary tumors, and only one third occurred in the index quadrant scar.
• A 1992 NCI consensus statement declared both mastectomy and BCT to be acceptable standards of care for operable breast cancer.

Question 8

What is the role of adjuvant WBI after breast-conserving surgery?

Answer 8

Rationale: Up to 40% of women after surgical resection have residual microscopic disease. The Holland study showed 43% of unifocal cancers in mastectomy specimens had tumor foci >2 cm from the index lesion.
* Local Recurrence (LR) Reduction: Adjuvant Whole Breast Irradiation (WBI) significantly reduces local recurrence.
* NSABP B-06 trial (1,851 patients, Stage I-II, up to 20 yrs F/U) showed 20-year In-Breast Tumor Recurrence (IBTR) reduced from 39% (lumpectomy alone) to 14% (lumpectomy + RT).
* Survival Benefit: Large meta-analyses demonstrated that preventing local recurrence with RT improves survival.
* EBCTCG 2005 Meta-Analysis (N=7,311 patients in 10 trials of BCS + RT vs. BCS alone):
* RT reduced the Relative Risk (RR) of 5-year LR by 70%.
* Absolute 5-year LR was 7% (BCS + RT) vs 26% (BCS alone) for all patients.
* This 19% absolute reduction in 5-year LR translated to a 5% absolute reduction in 15-year Breast Cancer Mortality (BCM) (31% with RT vs 36% without RT for all patients).
* Supported a “4:1 ratio”: one breast cancer death avoided by year 15 for every four local recurrences prevented by year 5.
* 15-year BCM: LN- (N=6,097): 26% (BCS + RT) vs 31% (BCS alone) (p=.006); LN+ (N=1,214): 48% (BCS + RT) vs 55% (BCS alone) (p=.01).
* 15-year OS: All patients: 65% (BCS + RT) vs 60% (BCS alone) (p=.005).
* EBCTCG 2011 Meta-analysis (N=10,801 early-stage patients from 17 PRTs, 77% pN0):
* RT reduced the 10-year risk of any recurrence by approximately half.
* 10-year Recurrence (Any): All: 19% (BCS + RT) vs 35% (BCS alone); pN0: 16% vs 31%; pN+: 43% vs 64%.
* Reiterated a ~4:1 ratio: one breast cancer death avoided by year 15 for every four overall recurrences avoided at 10 years.
* 15-year BCM: All: 21% (BCS + RT) vs 25% (BCS alone); pN0: 17% vs 21%; pN+: 43% vs 51%.
* Subgroup Benefit: There has been no subgroup (age, grade, size, hormone status) shown not to benefit from RT.

Question 9

Does completion ALND after a positive SLNB benefit cN0 patients? Can RT replace ALND in select cN0 patients?

Answer 9

Early Insight: NSABP B-04 demonstrated that not all undissected nodal disease results in clinical recurrence.
* Several randomized trials show similar rates of axillary recurrence and DFS between Sentinel Lymph Node Biopsy (SLNB) and ALND among clinically node-negative patients, most receiving adjuvant RT.
* Evidence from Key Trials:
* ACOSOG Z0011 (891 patients, cT1-T2 N0, 1-2 SLN+) comparing completion ALND vs. SLNB alone (with lumpectomy + WBI):
* Median 17 ALNs removed in ALND arm vs 2 in SLNB arm (p < .001).
* 27% had additional mets in ALND arm; 14% had ≤4 LN+.
* Similar 10-year OS (84% ALND vs 86% SLNB).
* Similar 10-year DFS (78% ALND vs 80% SLNB).
* Similar 10-year IBTR (6.2% ALND vs 5.3% SLNB, p = NS).
* Nodal recurrence: 0.5% (ALND) vs 1.5% (SLNB) at 10 years.
* Significantly higher subjective lymphedema with ALND: 13% vs 2% at 1 year (p < .0001).
* Conclusion: Completion ALND is not necessary for patients with 1 to 2 SLN metastases receiving WBI and systemic therapy (patients undergoing mastectomy were excluded).
* IBCSG 23-01 (931 patients, cT1-2N0, ≤1 micrometastatic (≤2 mm) SLN):
* Compared completion ALND vs. SLNB alone.
* 91% underwent BCT, 9% mastectomy.
* Median 21 LNs removed at ALND; 13% had additional nodal metastases.
* Similar 10-year DFS (76.8% SLNB vs 74.9% ALND, p = .24).
* Similar 10-year OS (90.8% SLNB vs 88.2% ALND).
* Conclusion: Supports omitting completion ALND for low-volume SLN micrometastases.
* AMAROS (1,425 SLN+ patients randomized from 4,806 registered):
* Compared axillary RT (50Gy/25 fx) vs. completion ALND.
* 82% underwent BCT and 18% mastectomy.
* 33% of ALND patients had additional LN+.
* Similar 5-year axillary recurrence: 0.43% (ALND) vs 1.19% (axillary RT) (NS).
* Similar 10-year DFS (82% ALND vs 78% RT, p = .18) and OS (85% ALND vs 81% RT, p = .34).
* Significantly less lymphedema with axillary RT: 14% vs 28% (p < .001).
* Conclusion: For SLN+ patients, axillary RT provides similar control with less lymphedema than ALND (mastectomy patients not well represented).
* Role After Mastectomy: Completion ALND remains appropriate for SLN+ patients after mastectomy as they were not well represented in trials like AMAROS.
* Omitting All Axillary Surgery: Select patients receiving PMRT may potentially be spared ALND if no grossly enlarged nodes exist. The Wong, Harvard single-arm trial (74 patients >55 y/o stage I/II cN0 ER+, median age 74.5, median tumor size 1.2 cm) treated with lumpectomy, WBI (high tangents), and hormonal therapy without ALND or SLNB showed no local or axillary recurrence at median 52 months F/U, suggesting this may be an option in very select older patients.