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• Among breast cancer patients:
  • It is estimated that 2% to 6%:
    • Carry a BRCA1 / BRCA 2 mutation
• Among epithelial ovarian cancer patients:
  • It is estimated that 10% to 15%:
    • Carry a BRCA1 / BRCA 2 mutation
• The lifetime risk of breast cancer for BRCA1 / BRCA2 mutation carriers:
  • Is approximately 45% to 80%
• The lifetime ovarian cancer risk is:
  • 45% to 60% for BRCA1 mutation carriers
  • 11% to 35% for BRCA2 mutation carriers
• BRCA1 mutation carriers:
  • Tend to be diagnosed with ovarian cancer at a younger age:
    • Than BRCA2 mutation carriers or sporadic cases
• BRCA-linked ovarian cancers:
  • Are associated with improved survival and longer disease-free interval:
    • Compared to patients with sporadic ovarian cancer
• To date, there is no reliable screening method to detect early ovarian cancer:
  • The prognosis of advanced ovarian cancer:
    • Is poor
• Risk-reducing bilateral salpingo-oophorectomy (RRSO):
  • Is associated with an 80% relative risk reduction:
    • For the development of ovarian and fallopian tube cancers
  • BSO causes a decrease in estrogen production:
    • Which is thought to lead to a 50% risk reduction in the development of future breast cancer:
      • Particularly among BRCA2 mutation carriers
• National Comprehensive Cancer Network (NCCN) guidelines recommend:
  • That BRCA1 mutation carriers be offered RRSO between the ages of 35 and 40
  • BRCA2 mutation carriers are recommended to undergo RRSO between the ages of 40 and 45
• A recent meta-analysis, which included three prospective studies of BRCA patients undergoing RRSO:
  • Found that this procedure salpingo-oophorectomy was associated with a decreased ovarian cancer risk, and decreased all-cause mortality:
    • With the largest risk reduction seen among BRCA1 mutation carriers
  • RRSO is associated with premature menopause, osteoporosis, cardiovascular disease, in addition to other medical issues which can impact quality of life:
    • Patients wishing to undergo RRSO should be counseled regarding these risks
• References:
  • Bougie O, Weberpals JI. Clinical Considerations of BRCA1- and BRCA2-mutation carriers: a review. Int J Surg Oncol. 2011;2011:374012.
  • National Comprehensive Cancer Network. Genetic/familial high risk assessment: breast and ovarian, Version 1.2020 https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf Accessed February 23, 2023.
  • Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967-975.
  • Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331-1337.
  • Finch AP, Lubinski J, Moller P, Singer CF, Karlan B, Senter L, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547-1553.
  • Marchetti C, De Felice F, Palaia I, Perniola G, Musella A, Musio D, et al. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health. 2014;14:150.

• Neoadjuvant chemotherapy (NAC) and the axilla:
  • Biopsy-proven cN1 starting NAC – what to do before therapy?
    • Clip / mark the positive node to enable targeted axillary dissection (TAD) after NAC
  • After NAC, exam / US cN0 – can SLNB be used? Main concern?
    • Yes:
      • But false-negative rate (FNR) is the issue
    • Use techniques to reduce FNR:
      • Dual tracers
      • ≥ 2 to 3 SLNs
      • Retrieval of the clipped node
  • Z1071 FNR headline and mitigation strategies:
    • Overall FNR about:
      • 12% to 13%
    • ≥ 3 SLNs, dual tracers, and removal of the clipped node lower FNR
  • SENTINA insights:
    • Identification and FNR vary by timing:
      • SLNB after NAC in initially node-positive patients has higher FNR unless optimized
    • SN-FNAC findings:
      • With rigorous pathology (IHC) and adequate technique, FNR can be ≈ 8% to 13%:
        • Still requires careful selection
  • What is TAD and why use it post-NAC?
    • TAD = SLNB + removal of the clipped metastatic node:
      • Improves accuracy and lowers FNR versus SLNB alone
  • If post-NAC axilla remains cN+ clinically or by imaging / biopsy – management?
    • ALND (and consideration of RNI) remains standard
  • Subtype and nodal pCR expectations after NAC:
    • HER2+ and TNBC have higher nodal pCR, supporting de-escalation strategies when cN1→cN0 with optimized technique
  • Do you routinely perform SLNB before NAC in cN0 to “bank” nodes?
    • Not routinely; most proceed with SLNB after NAC in cN0, reserving pre-NAC SLNB for select scenarios
  • If the clipped node is not retrieved at surgery post-NAC but SLNs are negative – what now?
    • Higher FNR concern; many advocate completion ALND or targeted re-localization to ensure the clipped node is removed
• Radiation interfaces (ASTRO-ASCO-SSO; PMRT/RNI):
  • How do PMRT / RNI guidelines intersect with axillary surgery choices?
    • Updated ASTRO-ASCO-SSO PMRT guidance:
      • Chest wall / breast plus regional nodes (including axilla) are addressed based on pathologic and clinical risk
      • In some SLN+ cases axillary RT may substitute for ALND
      • Z0011 vs regional nodal irradiation (RNI) big picture:
        • Z0011 patients had excellent outcomes with tangents; comprehensive nodal RT can also control axilla but with different toxicity trade-offs
  • After mastectomy with 1 to 3 positive nodes – axillary management?
    • Often PMRT with RNI is recommended
    • ALND may be performed depending on surgical/RT plan and extent of disease
  • Can axillary RT replace ALND for SLN+ in BCS patients (AMAROS principle)?
    • Yes – axillary RT offers comparable control with less lymphedema vs ALND
  • Does omission of SLNB (SOUND / INSEMA) change systemic therapy decisions?
    • In properly selected low-risk cohorts, nodal information rarely changes systemic therapy, enabling safe omission
• Practical technique and pathology:
  • Minimum SLN count to reduce FNR post-NAC?
    • Try to retrieve ≥ 2 to 3 SLNs:
      • More is better for accuracy
  • Mapping agents: single vs dual tracer?
    • Dual tracer (radioisotope + blue dye / ICG) reduces FNR:
      • Especially post-NAC
  • What to do with ITCs (pN0[i+]) post-NAC?
    • Treat as node-negative for surgical decision-making
    • Escalate RT / systemic therapy only if other factors indicate
  • How do micrometastases (pN1mi) affect ALND decisions in upfront BCS
    • Per IBCSG 23-01:
      • ALND can be omitted with micrometastases
  • Grossly matted / fixed nodes at presentation (cN2 to N3) – initial surgical plan?
    • These patients generally need systemic therapy and ALND (with RNI), not SLNB
• Special scenarios:
  • Pregnancy and SLNB – allowed?
    • Yes, with Tc-99m only (avoid blue dye anaphylaxis risk; methylene blue contraindicated in 1st trimester):
      • Institutional policies vary. (ASBrS technique guidance)
  • Prior breast / axillary surgery – impact on SLN mapping?
    • Prior surgery / radiation can alter drainage:
      • SLNB still feasible but may have lower identification rates:
        • Consider imaging aid
  • Local recurrence after previous SLNB – repeat SLNB?
    • Possible in selected cases; mapping may identify alternate basins; MDT discussion is key
  • Male breast cancer – apply same axillary algorithms?
    • Generally yes:
      • SLNB for cN0 invasive disease, with similar de-escalation logic when applicable
  • Medullary-like or tubular carcinoma – special SLNB rules?
    • No unique rules:
      • Follow general cN0 invasive management:
        • SLNB unless low-risk omission criteria met
• Gray zones and decision-making:
  • If genomic assay selection might hinge on nodal status, should you still omit SLNB?
    • If nodal status would alter systemic therapy decisions (e.g., chemotherapy indication):
      • Perform SLNB
    • Omission is for cases where nodal information won’t change therapy
  • How do you counsel about lymphedema risk when comparing SLNB vs ALND vs axillary RT:
    • Lymphedema risk:
      • ALND > axillary RT > SLNB > omission
    • AMAROS shows less lymphedema with RT vs ALND
  • If SLN is positive and patient is not a candidate for whole-breast RT (e.g., declines RT) after BCS – omit ALND
    • Z0011 required WBRT; without RT coverage, many favor ALND
  • Clinically negative axilla but suspicious single node on imaging with benign core biopsy – proceed with SLNB or omit?
    • Proceed with SLNB (or omission only if fully meeting SOUND / ASCO criteria and MDT agrees imaging is truly negative / safe)
• Bottom line:
• When is ALND still clearly indicated today?
  • Inflammatory breast cancer
  • Persistent cN+ after NAC
  • >2 SLNs positive in upfront BCS /mastectomy
  • Gross ENE
  • When RT plans won’t cover low axilla
  • Nodal information is needed

• Diffusely invasive carcinoma:
  • Has a mammographic appearance of:
    • Diffuse architectural distortion:
      • Usually involving a large area, often larger than a lobe:
        • With no central tumor mass and no calcifications
  • It sometimes has the appearance of a “spider’s web” as shown in Image

• The diffusely infiltrating cancer:
  • Forms concave contours with the surrounding fat in a manner similar to normal fibroglandular tissue (Images Above)
• The imaging findings of diffusely infiltrating breast cancer:
  • Are strikingly different from the imaging findings of breast cancers originating either from the terminal ductal lobular units (TDLUs) or the lactiferous ducts:
    • Suggesting that it may have a different site of origin
• It has been recently proposed that diffusely infiltrating breast cancers:
  • May originate from mesenchymal stem cells (progenitors):
    • Through a complex process of both:
      • Epithelial-mesenchymal transformation and more frequently, mesenchymal-epithelial transformation
  • The clinical presentation is typically a:
    • Recently detected, extensive, firm lesion:
      • Often appearing as an interval cancer following a previous mammogram which was interpreted as normal
    • On clinical breast examination:
      • The cancer does not have a distinct tumor mass or focal skin retraction seen in other cancers:
        • But rather an indistinct “thickening” and eventually a shrinkage of the breast
      • In order to make the diagnosis before the development of a palpable mass and a decrease in size of the breast:
        • The radiologist and breast surgeon must have a high level of suspicion and a thorough knowledge of the underlying pathophysiology
• The subgross (3D) histopathology images:
  • Show how growth of the mesenchymal tissue distorts the normal, harmonious connective tissue framework:
    • By causing nonuniform thickening of the fine sheets of connective tissue
• The predominance of mesenchyme in the diffusely infiltrating breast malignancy:
  • Allows it to be imaged with greater sensitivity by ultrasound than by mammography
• The thin sheets or veils of tissue reflect the ultrasound waves:
  • But are relatively easily penetrated by x-rays
• The structural / architectural distortion, while difficult to detect mammographically:
  • Is readily detectable on 2-mm thick coronal sections of automated breast ultrasound
• The hypoechoic changes:
  • Can also usually be seen on hand-held ultrasound
• The growth pattern and cell type of diffusely invasive breast cancer is very similar to that of diffuse gastric carcinoma (linitis plastica):
  • Both of these diseases can be associated with a deleterious mutation in the CDH1 gene:
    • Which is located on chromosome 16q22 and codes for e-cadherin protein
• References:
  • Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1(1):23-32.
  • Tot T. The diffuse type of invasive lobular carcinoma of the breast: morphology and prognosis. Virchows Arch. 2003;443(6):718-724.
  • Tot T. Diffuse invasive breast carcinoma of no special type. Virchows Arch. 2016;468(2):199-206.

• Phases and Timelines:
  • Hemostasis (minutes – hours):
    • Platelets → fibrin clot:
      • Releases PDGF, TGF-β, vWF, fibrinogen, Factor V, thrombospondin
  • Inflammatory phase:
    • Last roughly from day 0 to day 3/4:
      • Can last up to ~7 days in larger / contaminated wounds
    • PMNs dominate first 48 hours:
      • Macrophages peak ~ 48 hours to 72 hours
    • Key signals:
      • TNF-α, IL-1, IL-6, TGF-β, PDGF
  • Proliferative / Regenerative Phase:
    • From rougly day 3 to day 21
    • Fibroblasts:
      • Lay down type III collagen
    • Endothelial cells:
      • Neovascularization
    • Keratinocytes:
      • Re-epithelialization:
        • Approximalty 1 mm / day, (range 0.5 mm to 1.5 mm)
    • Growth factors:
      • PDGF, FGF (including KGF / FGF-7), EGF, VEGF, TGF-β
  • Remodeling / Maturation phase:
    • From 3 weeks to 12 to 18 months
    • Collagen Type III → type I collagen:
      • Collagen fibers re-align, cross-link; decreased cellularity and vascularity
• Who Arrives When?
  • Immediate: 
    • Platelets
  • Hours to Day 2: 
    • PMNs
  • Day 2 to 4: 
    • Macrophages:
      • Switch from M1 → M2 phenotype to drive repair
  • Day 3+:
    • Peak ~ 1 to 2 weeks): 
      • Fibroblasts and endothelial cells
  • ~ Day 5+: 
    • Lymphocytes:
      • Modulate later phases
• Matrix and Collagen:
  • Provisional matrix: 
    • Fibrin + fibronectin + hyaluronic acid:
      • Scaffold for cells
  • Fibronectin (from fibroblasts, platelets):
    • Chemotactic for macrophages
    • Anchors fibroblasts
  • Collagen synthesis requires: 
    • α-ketoglutarate, O₂, Fe²⁺, vitamin C for prolyl/lysyl hydroxylases:
      • Hydroxylation → triple-helix stability
    • Cross-linking: 
      • Lysyl oxidase (Cu²⁺-dependent) forms intermolecular cross-links:
        • Equals tensile strength
    • Triple helix motif: 
      • Glycine is every 3rd amino acid (Gly-X-Y; X/Y often Pro/Hyp).
  • Collagen types (surgical high-yield):
    • Type I: 
      • Skin, tendon, bone:
        • Predominant in healed wounds
    • Type II: 
      • Cartilage
    • Type III: 
      • Granulation tissue, vessels, early wound
    • Type IV: 
      • Basement membranes
    • Type V: 
      • Widespread
      • Enriched in cornea / placenta
  • Drugs: 
    • d-Penicillamine (and β-aminopropionitrile:
      • Impair cross-linking
  • Tensile Strength (what really matters for primary closure):
    • ~ 10% by end of week 1
    • ~ 20%to 30% by 3 weeks:
      • Collagen content near max by ~ 3 to 4 weeks
    • ~ 50% to 60% by 6 to 8 weeks
    • 80% by ~ 3 months:
      • Plateau (never returns to 100%) through 6 to 12 months
• Epithelialization and Contraction:
  • Epithelialization sources: 
    • Hair follicles (#1), wound edges, sweat glands
  • Rate ≈ 1 mm / day
  • Requires healthy granulation bed
  • Myofibroblasts (α-SMA+, gap junctions):
    • Drive wound contraction:
      • Greatest where skin is lax:
        • Perineum, scrotum
      • Least on scalp / tight skin
• Open wounds (secondary intention): 
  • Epithelial integrity is key; until closed
  • Leak protein-rich exudate and are prone to colonization
• Practical Timelines:
  • Suture removal (general guide; adjust for tension / vascularity):
    • Face: 5 to 7 days
    • Scalp: 7 to 10 days
    • Trunk / Upper limb: 10 to 14 days
    • Lower limb / Joints/Back: 12 to 14 days
  • Bowel strength:
    • Submucosa is the strength layer:
      • Anastomosis weakest at day 3 to 5:
        • Collagenolysis > synthesis
  • Peripheral nerve regeneration: ~ 1 mm/day (range: 0.5 mm to 3 mm/day)
• Essentials to Optimize Healing:
  • Moist wound environment:
    • Avoid desiccation
  • Oxygen delivery: 
    • Correct anemia, optimize perfusion, pain control, stop nicotine (vasoconstriction), consider revascularization if PAD
  • Transcutaneous oxygen measurement (TCOM) targets:
    • Greater than 40 mm Hg predicts healing
    • 25 to 40 mm Hg borderline
    • < 25 mm Hg poor
  • Edema control: 
    • Elevation, compression (if ABI adequate)
  • Debridement: 
    • Remove necrotic tissue / biofilm:
      • Consider enzymatic or surgical debridement
  • Infection control: 
    • ≥ 10⁵ CFU/g tissue (not per cm²) impairs healing:
      • Debride +/- topical / systemic therapy as indicated
  • Nutrition: 
    • 1.2 to 1.5 g/kg/day protein
    • Adequate calories, vitamin C, zinc (short-term if deficient), copper, arginine / glutamine if malnourished
• Impediments and Meds (nuance):
  • Diabetes:
    • Impaired neutrophil chemotaxis / killing
    • Microvascular disease and neuropathy → pressure injury
  • Tight peri-op glycemic control helps.
    Steroids: 
    • Blunt inflammation and collagen synthesis → ↓ tensile strengt
    • Vitamin A 25,000 IU/day for 1 to 2 weeks can reverse steroid effects (avoid in pregnancy / liver disease)
  • Cytotoxics / antimetabolites (5-FU, MTX) and calcineurin inhibitors (cyclosporine, tacrolimus):
    • Impair early proliferative phase
    • Biggest impact within ~2 weeks of injury
  • Radiation: 
    • Endarteritis obliterans, fibroatrophy
    • Consider HBOT for selected compromised grafts / flaps
  • Smoking / nicotine: 
    • Vasoconstriction, ↑ COHb, ↓ oxygen delivery – cessation is critical
• Specific Clinical Entities:
  • Keloids: 
    • Extend beyond original borders
    • Familial predisposition (higher in patients of African / Asian ancestry)
    • Treatment:
      • Intralesional triamcinolone ± 5-FU, silicone, pressure therapy
      • Consider post-excision RT in select cases
  • Hypertrophic scars: 
    • Confined within original wound
    • Common in high-tension areas (shoulders, presternal, joints)
    • Treatment as above:
      • Often regress with time
  • Pyoderma gangrenosum: 
    • Neutrophilic dermatosis
    • Avoid aggressive debridement (pathergy)
    • Treatment: steroids / immunosuppressants
  • Epidermolysis bullosa: 
    • Structural protein defects:
      • Examples – keratin, laminin, collagen VII
    • Supportive care; wound-care expertise
  • Diabetic foot ulcers: 
    • Most commonly plantar metatarsal heads and heel
  • Charcot midfoot deformity shifts pressure to plantar midfoot:
    • Treatment: 
      • Off-loading (total contact cast), debridement, infection control, revascularization if needed
  • Leg ulcers: 
    • ~ 70% to 80% venous, 10% to 15% arterial, rest mixed
    • Use ABI before compression:
      • Unna boot or multilayer compression for venous disease
  • Scar revision: 
    • Delay roughly 12 to 18 months for maturation
  • Infants vs fetal healing: 
    • Fetal wounds (early gestation) may heal scar-lessly
    • Infants still scar (often less conspicuously)
• Primary vs Secondary Intention:
  • Primary intention: 
    • Tensile strength hinges on collagen deposition and cross-linking
  • Secondary intention: 
    • Epithelial integrity over a healthy granulation bed is paramount
  • Delayed primary (tertiary) closure: 
    • Leave open initially for contaminated wounds:
      • Close once clean – reduces infection risk:
        • Ensure no residual infection to avoid abscess
• Platelet Granules and Aggregation:
  • Alpha granules: 
    • PDGF, TGF-β, vWF, fibrinogen, Factor V, thrombospondin, P-selectin, β-thromboglobulin
  • Dense granules: 
    • ADP / ATP, serotonin, Ca²⁺, (± epinephrine)
  • Key aggregation / activation mediators: 
  • It’s β-thromboglobulin in platelets:
    • Binds thrombin
  • PF4 (CXCL4):
    • Is a chemokine that neutralizes heparin and modulates coagulation

• In assessing a family history, consider how likely it is that there is a deleterious mutation, and how likely it is that your patient could carry that mutation
• Factors to consider include:
  • Age at diagnosis
  • What degree relative is affected
  • If a cancer type is associated with a hereditary syndrome
• Cancers suggestive of a hereditary mutation include:
  • Those occurring in young patients:
    • For example premenopausal cancers
  • Those occurring in 1^st or 2^nd degree relatives
  • Multiple generations with cancer
  • Multiple cancers in a single person
  • The presence of cancers associated with certain syndromes
• References
  • Daly MB, Axilbund JE, Buys S, Crawford B, Farrell CD, Friedman S, et al. Genetic/familial high-risk assessment: breast and ovarian. J Natl Compr Canc Netw. 2010;8(5):562-594.
  • Domchek SM, Gaudet MM, Stopfer JE, Fleischaut MH, Powers J, Kauff N, et al. Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat. 2010;119(2):409-414.
  • Streff H, Profato J, Ye Y, Nebgen D4, Peterson SK5, Singletary C, et al. Cancer Incidence in first- and second-degree relatives of BRCA1 and BRCA2 mutation carriers. Oncologist. 2016;21(7):869-874.

• Positive deep margin + ENE(+):
  • Best adjuvant plan: 
    • Cisplatin–Post-op RT (CRT):
      • Why: 
        • These are the classic high-risk pathologic features that derived clear benefit from adding concurrent high-dose cisplatin to adjuvant RT in the two landmark randomized trial:
          • EORTC 22931 and RTOG 9501, and in their comparative analyses
• What the trials showed:
  • EORTC 22931 (Bernier et al., NEJM 2004):
    • Population: 
      • Resected stage III to IV HNSCC with high-risk features:
        • Definition broader than RTOG 9501
    • Arms: 
      • RT alone (66 Gy) vs RT + cisplatin 100 mg / m² q3wk ×3
    • 5-yr outcomes (Kaplan–Meier):
      • Overall survival: 
        • 53% (CRT) vs 40% (RT) (significant)
      • Progression-free survival:
        • 47% (CRT) vs 36% (RT) (significant)
      • Locoregional control: 
        • Improved with CRT
    • Interpretation: 
      • Clear KM curve separation favoring CRT for DFS / OS in the high-risk post-op setting New England Journal of Medicine+2PubMed+
  • RTOG 9501 (Cooper et al., NEJM 2004; 10-yr update 2012):
    • Population: 
      • Resected HNSCC with prespecified high-risk factors
    • Arms: 
      • RT 60 Gy/6 wk vs RT + cisplatin 100 mg / m² on days 1, 22, 43
    • Entire cohort (10-yr KM): 
      • OS and DFS not significantly different overall
      • LRF numerically lower with CRT but not significant
    • Crucial prespecified subset:
      • Positive margins and / or ENE(+):
        • Locoregional failure: 
          • 33.1% (RT) vs 21.0% (CRT), p = 0.02
        • Disease-free survival: 
          • 12.3% (RT) vs 18.4% (CRT), p = 0.05
        • Overall survival: 
          • 19.6% (RT) vs 27.1% (CRT), trend in favor of CRT
    • Interpretation: 
      • KM curves diverge in R+ / ENE(+):
        • Establishing concurrent cisplatin as the adjuvant standard exactly for these features New England Journal of Medicine+2PMC+2
  • Combined / Comparative analyses (what ties it together):
    • Bernier et al., Head & Neck 2005 (comparative look at EORTC 22931 and RTOG 9501):
      • Concluded that the greatest and most consistent benefit from adjuvant CRT accrues to patients with:
        • Extranodal extension and / or positive margins: PubMed+1
    • Updated combined analysis (Zumsteg et al., 2025, Annals of Oncology—abstract): 
      • Pooling EORTC 22931 + RTOG 9501:
        • Shows OS improvement with postoperative CRT overall:
          • ENE and margin status were prognostic but not strictly predictive:
            • Patients without these features may still benefit
        • While cancer-specific mortality fell with CRT:
          • But some benefit was offset by other-cause mortalit:
            • Underscoring need for careful patient selection Annals of Oncology+1
• Practical plan for positive deep margin + ENE(+):
  • Adjuvant CRT:
    • RT with cisplatin 100 mg / m² q3wk ×2 to 3:
      • Goal cumulative ≥ 200 mg / m²:
        • Is guideline-concordant and evidence-based to improve LRC / DFS and likely OS vs RT alone in this risk profile New England Journal of Medicine+1
    • If cisplatin-ineligible: 
      • Acknowledge that randomized survival benefit in this setting is with cisplatin:
        • Alternatives (e.g., RT alone or RT+cetuximab) are considered when cisplatin cannot be given:
          • But are not proven equivalent post-op (See NCCN.) NCCN
• Bottom line: 
  • For positive deep margin plus ENE(+):
    • The weight of EORTC 22931, RTOG 9501 (10-yr), and subsequent comparative work:
      • Supports adjuvant cisplatin-RT as the best plan to maximize locoregional control and survival

•  BRCA 1 and BRCA 2 are genes:
  • That produce tumor suppressor proteins:
    • Which help repair damaged DNA
  • They are the most common gene alterations:
    • Seen in the hereditary breast cancer population
  • They are associated with an increased risk of breast cancer estimated to be:
    • 55% to 70% for BRCA 1 carriers by age 70
    • 45% to 70% in BRCA 2 carriers by age 70
  • While both BRCA 1 and BRCA 2 mutations are associated with an increased risk of breast cancer:
    • BRCA 1 breast cancers more commonly occur in:
      • Younger
      • Premenopausal women
      • Are more likely to be triple negative
      • High grade lesions
  • BRCA 1 is associated with a higher risk of ovarian cancer compared to BRCA 2:
    • With a lifetime risk of 40% to 45% in BRCA 1 carriers compared to 15% to 20% in BRCA 2 carriers
  • BRCA 2 breast cancers more closely resemble the sporadic breast cancer pattern:
    • With a predominance of hormone receptor positive cancers in women greater than 50 years
• CHEK 2 and PALB 2 are moderate penetrance genes:
  • That are less common than BRCA mutations
  • Similar to BRCA 2 deleterious mutations:
    • CHEK 2 and PALB 2 mutations are associated with:
      • Hormone receptor positive postmenopausal breast cancer
• References:
  • Loi M, Desideri I, Olmetto E, Francolini G, Greto D, Bonomo P, et al. BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management. Breast J. 2018;24(6):1019-1023.
  • Peshkin BN, Isaacs, C et al. Overview of hereditary breast and ovarian cancer syndromes. UpToDate website. Updated February 10, 2020. https://www.uptodate.com/contents/genetic-testing-and-management-of-individuals-at-risk-of-hereditary-breast-and-ovarian-cancer-syndromes. Accessed February 15, 2020.
  • Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41(1):1-8.

• The CREATE-X trial:
  • Studied adjuvant capecitabine in patients with HER2-negative breast cancer:
    • Who had residual invasive disease after neoadjuvant chemotherapy:
      • Did not achieve a pathological complete response
  • It found that adding capecitabine:
    • Improved disease-free survival (DFS) and overall survival (OS) compared to observation in that specific patient population
  • The effect was more pronounced in certain subgroups:
    • Particularly patients with triple-negative breast cancer
  • In long-term follow-up, for example:
    • 5-year DFS was higher in capecitabine arm vs control
• So the key message of the Create -X trial:
  • In patients who have residual disease after neoadjuvant chemotherapy (i.e. higher risk of relapse):
    • Adding capecitabine may provide a survival benefit
• Is CREATE-X Still Applicable Today?
  • Yes:
    • But one must interpret in light of modern advances
  • Some important considerations:
    • Population and treatment context have changed:
      • In CREATE-X, many patients did not receive newer therapies that are more commonly used today (e.g. immunotherapy, targeted agents)
      • The neoadjuvant regimens used then may differ from current ones (some now include platinum drugs, immunotherapy, etc.)
      • Thus, whether the magnitude of benefit from capecitabine is identical in today’s more aggressive or modern regimens is uncertain
• Evolving standard of care:
  • In triple-negative breast cancer (TNBC):
    • Immunotherapy (checkpoint inhibitors) is now incorporated into neoadjuvant and adjuvant settings in many protocols:
      • Some patients receive pembrolizumab or other immune agents in the neoadjuvant plus adjuvant phase
  • In patients with germline BRCA mutations:
    • Adjuvant PARP inhibitors (e.g. olaparib) have been shown to improve outcomes in high-risk disease, including non-pCR settings
  • Newer antibody-drug conjugates (ADCs) and other novel therapies are being tested in residual disease settings:
    • Sacituzumab govitecan in SASCIA trial:
      • That could potentially surpass capecitabine in benefit
• Subgroup-specific relevance:
  • The benefit in the original CREATE-X was strongest in certain subtypes (especially TNBC)
  • For hormone receptor–positive, HER2-negative disease:
    • The benefit is less clear or more modest
  • Some meta-analyses and reviews suggest that in modern TNBC:
    • The role of capecitabine is still valid:
      • Especially for patients with residual disease after standard therapy
• Ongoing trials and unanswered questions:
  • As newer therapies emerge, trials are ongoing to compare or combine capecitabine with immunotherapy or other agents in the post-neoadjuvant (residual disease) setting:
    • One open question is whether capecitabine adds incremental benefit on top of modern therapies (immunotherapy, PARP inhibitors) or whether it’s supplanted in certain subgroups
• My Bottom Line / Practical View:
  • Yes, clinicians often still use the CREATE-X findings as a rationale for giving adjuvant capecitabine in patients with residual disease after neoadjuvant chemotherapy:
    • Particularly in HER2-negative / triple-negative cases, when no more effective alternative is clearly indicated:
      • But, the decision must be individualized:
        • Consider what neoadjuvant therapy was used (did it include immunotherapy or platinum?)
        • Consider patient risk factors, subtype (TNBC vs HR+), mutation status (BRCA), comorbidities, etc
        • Consider newer options that may be more beneficial (e.g. PARP inhibitors in BRCA carriers, or ADCs if approved in that setting)

• What was the primary research question of the INSEMA trial?
  • Answer:
    • To determine whether sentinel lymph node biopsy (SLNB) can be safely omitted in patients with clinically node-negative early-stage breast cancer undergoing breast-conserving surgery and whole breast radiation, without compromising invasive disease-free survival (iDFS)
• What type of study was this, and how was it designed?
  • Answer:
    • It was a prospective, randomized, multicenter, non-inferiority trial conducted in Germany and Austria
    • Patients were randomized in a 4:1 ratio to no SLNB vs. SLNB
• What were the eligibility criteria for patients to be included in the trial?
  • Answer:
    • Female patients
    • Clinically node-negative (cN0) invasive breast cancer
    • Tumor size T1 to T2 (≤ 5 cm)
    • Candidates for breast-conserving surgery and whole-breast irradiation
    • No prior axillary surgery, neoadjuvant therapy, or mastectomy
• What was the primary endpoint, and what was the non-inferiority margin?
  • Answer:
    • Primary endpoint:
      • 5-year invasive disease-free survival (iDFS)
    • Non-inferiority margin:
      • Hazard Ratio upper limit of 1.271 and ≥ 85% iDFS in the no-SLNB arm
• What were the main results regarding iDFS
  • Answer:
    • iDFS: 91.9% (no-SLNB) vs. 91.7% (SLNB)
    • HR: 0.91 (95% CI, 0.73–1.14) → Non-inferiority was met
• Was there a difference in overall survival (OS)
  • Answer:
    • Yes, but it favored no-SLNB slightly:
      • 5-year OS: 98.2% (no-SLNB) vs. 96.9% (SLNB):
        • Difference was not statistically significant
• What was the axillary recurrence rate in both groups?
  • Answer:
    • No-SLNB: 1.0%
    • SLNB: 0.3%
      • While slightly higher in the no-SLNB group:
        • Both rates were very low and clinically acceptable
• What secondary outcomes were assessed?
  • Answer:
    • Lymphedema incidence
    • Arm / shoulder function and pain
    • Quality of life
      • All significantly favored the no-SLNB group
• What are the main clinical implications of this study?
  • Answer:
    • In selected low-risk patients:
      • SLNB may be safely omitted:
        • Reducing surgical morbidity and improving quality of life without compromising survival
• Which subgroup of patients benefits most from SLNB omission based on this trial?
  • Answer:
    • Women ≥ 50 years old with T1, grade 1 to grade 2, hormone receptor-positive, HER2-negative tumors undergoing lumpectomy with whole breast radiation
• Can we apply the findings of this trial to patients undergoing mastectomy or partial-breast irradiation?
  • Answer:
    • No:
      • Those patients were excluded, so the results cannot be extrapolated to those scenarios
• How might omitting SLNB affect adjuvant therapy decisions?
  • Answer:
    • Without nodal staging, decisions about chemotherapy or genomic testing might become more challenging:
      • Multidisciplinary evaluation is essential
• How do these findings compare to axillary de-escalation trends seen in trials like ACOSOG Z0011 or SOUND?
  • Answer:
    • Similar direction:
      • All support less axillary surgery in low-risk, clinically node-negative patients
    • INSEMA takes it a step further by testing omission of SLNB itself
• What are some limitations of the INSEMA trial
  • Answer:
    • Limited generalizability:
      • Mostly postmenopausal, low-risk tumors
    • Exclusion of higher-risk patients:
      • HER2+, triple-negative, T2 > 3 cm
    • Lack of data in mastectomy or neoadjuvant settings
• If one of your patients meets criteria from this trial, how would you counsel them on omitting SLNB?
  • Answer:
    • Explain that in select low-risk early-stage breast cancer, omitting SLNB does not affect survival, reduces the risk of complications like lymphedema, and improves quality of life:
      • However, thorough discussion with oncology and radiation teams is important to individualize care

• The NSABP P-2, or STAR trial:
  • Enrolled 19,747 postmenopausal women with a 5-year Gail risk assessment score of ≧ 1.66% for the development of invasive breast cancer at 5 years
  • The women were randomized to receive:
    • 20 mg of tamoxifen plus placebo or 60 mg of raloxifene plus placebo
  • The updated results of the STAR trial (median follow-up 81 months):
    • Reported more cases of invasive breast cancer in the raloxifene group than the tamoxifen group (risk ratio [RR]: 1.24; 95% confidence interval [CI]: 1.05–1.47):
      • Demonstrating that raloxifene is about 76% as effective as tamoxifen in reducing breast cancer risk
    • There were significantly fewer cases of invasive uterine cancer with raloxifene compared to tamoxifen (RR: 0.55; 95% CI, 0.36–0.83)
    • Thromboembolic events occurred less often in the raloxifene group (RR: 0.75; 95% CI: 0.6–0.93)
    • There were fewer cataracts and cataract surgeries in the women taking raloxifene (RR: 0.79; 95% CI: 0.68–0.92)
    • Importantly, there was no significant difference in mortality between the two groups
• References
  • Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al; for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-2741.
  • Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther. 2009;9(1):51-60.
  • Mamounas EP, Wicherham DL, Fisher B, Geyer CE, Julian TB, Wolmark N. The NSABP experience. In: Kuerer HM, ed. Kuerer’s Breast Surgical Oncology. New York, NY: McGraw-Hill Companies; 2010:475-508.

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