Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• 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)

• 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.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #BreastCancer #NSABPP2 #Raloxifen #Tamoxifen

• Full name:
  • “Rx for Positive Node, Endocrine Responsive Breast Cancer”:
    • SWOG S1007
• Population:
  • Women with hormone receptor (HR)-positive, HER2-negative breast cancer:
    • With 1 to 3 positive axillary lymph nodes:
      • Who have had surgery
  • All had a 21-gene Recurrence Score (RS) of:
    • ≤ 25
• Key question:
  • Among patients with 1 to 3 positive nodes and RS ≤ 25:
    • Which patients benefit from adding adjuvant chemotherapy to endocrine therapy vs endocrine therapy alone? 
• Trial Design:
  • Multi-center trial:
    • 632 sites across 9 countries (USA, Canada, Mexico, Colombia, Ireland, France, Spain, South Korea, Saudi Arabia):
      • Enrolled over 5,000 women
  • Enrollment:
    • ~ 5,083 women assigned
    • ~ 5,015 analyzed
    • Approximately two-thirds were postmenopausal
    • One-third premenopausal
  • Treatment arms:
    • Randomized to endocrine therapy alone vs chemotherapy + endocrine therapy
  • Chemotherapy regimens included:
    • Taxane and / or anthracycline
  • Recurrence Score stratifications within ≤ 25:
    • RS categories 0 to 13 vs 14 to 25 used for some analyses
  • Also stratified by menopausal status, number of nodes (1 vs 2 to 3), tumor size / grade
  • Follow-up:
    • Median ≈ 5.1 years for primary results

• Other data:
  • Overall survival at 5 years among premenopausal women:
    • 98.6% with chemotherapy + endocrine therapy vs 97.3% endocrine therapy only (absolute ~ 1.3%) – HR ~ 0.47; P ≈ 0.032
  • Among postmenopausal women, OS was virtually identical:
    • 96.2% vs 96.1% (chemo vs no chemo) – HR ~ 0.96; not statistically significant
  • Also:
    • The benefit in premenopausal women:
      • Was consistent across RS levels (0 to 13 and 14 to 25):
        • Though absolute benefit tended to be larger in those with RS 14 to 25
    • The benefit was also seen irrespective of number of positive nodes (1 vs 2 to 3):
      • But, again, the magnitude of benefit varied
• Secondary / Extended Analyses and Modeling:
  • A modeling study (Wojcik et al., 2024) simulated 10-year distant recurrence-free survival, life-years, and quality-adjusted life-years (QALYs) for women like those in RxPONDER:
    • In premenopausal women:
      • 10-year distant RFS ~ 85.3% with chemo-endocrine therapy vs 80.1% endocrine therapy alone (absolute benefit ~ 5.6%) in the simulation
    • In postmenopausal women:
      • No meaningful benefit; distant RFS practically the same between arms
    • Modeled life-years gained:
      • ~ 2.1 years for premenopausal women; no gain or even small losses for postmenopausal receiving chemotherapy (due to toxicity and side effects) when weighed
  • Another RxPONDER analysis looked at racial / ethnic outcomes:
    • Non-Hispanic Black women had worse 5-year IDFS and DRFS compared to non-Hispanic White women despite similar RS, node numbers, and treatment:
      • Asian women had somewhat better outcomes
    • But chemotherapy efficacy didn’t differ significantly by race
• Implications / Guidelines Impact:
  • For postmenopausal women with HR+ / HER2- disease, 1 to 3 positive nodes, and RS ≤ 25:
    • Chemotherapy can generally be omitted without compromising IDFS:
      • Endocrine therapy alone is acceptable in most
  • For premenopausal women in the same category:
    • Chemotherapy + endocrine therapy provides meaningful benefit:
      • Omission risks worse IDFS
  • The decision should consider absolute benefit, potential side effects, and patient preferences
  • Also – it is not completely certain how much of the
  • Recurrence Score:
    • Remains a useful tool in node-positive disease (for nodes 1 to 3) to stratify risk and guide therapy
  • Previously, Oncotype DX was used more in node-negative disease (TAILORx):
    • But RxPONDER expands its utility
  • The data supports more personalized treatment – sparing many postmenopausal women unnecessary chemotherapy, reducing overtreatment and its toxicities
• Things to Remember / Caveats:
  • Follow-up duration:
    • Median ~ 5 years:
      • Longer-term data (10+ years) may reveal differential distant recurrence or survival effects:
        • Especially in HR+ disease which often has late recurrences
  • Chemotherapy regimens, adherence, patient comorbidities:
    • The trial setting may not fully reflect “real world” in all respects – e.g. older women with comorbidity may suffer more chemotherapy toxicity
  • Menopausal status matters:
    • Distinct differences in benefit. Also, in premenopausal women, part of chemotherapy’s benefit may be mediated via ovarian suppression (or ablation), which was not fully controlled for
  • Patient preferences are key:
    • Absolute benefit for many is modest; potential chemotherapy toxicities (short-term and long-term) need weighing
  • RS >25 were excluded – standard indications for chemotherapy remain for high RS or more nodes, etc
• Key Points:
  • No significant chemotherapy benefit in postmenopausal women:
    • Absolute IDFS gain only ~ 0.6 % at 5 years, hazard ratio ~1.0
  • Clear benefit in premenopausal women:
    • Absolute IDFS gain ~ 4% to 5 %, distant recurrence reduction ~ 3 %, and a small OS improvement (~ 1 %)
    • Benefit was consistent across Recurrence Score 0 to 13 vs 14 to 25 and for 1 vs 2 to 3 positive nodes
• Clinical implication:
  • Postmenopausal patients with RS ≤ 25 and 1 to 3 positive nodes:
    • Can usually omit adjuvant chemotherapy
  • Premenopausal patients in the same setting should be offered chemotherapy:
    • As the IDFS and DRFS advantages are clinically meaningful
• Primary source:
  • Kalinsky K et al. N Engl J Med 2021;385:2336-2347 【NEJM doi:10.1056/NEJMoa2108873】

• The CREATE-X study:
  • Randomly assigned 910 patients with HER2 negative breast cancer and residual disease after undergoing neoadjuvant chemotherapy:
    • To standard postsurgical treatment and capecitabine or placebo
  • The primary end point:
    • Was disease-free survival (DFS)
  • Secondary end points included:
    • Overall survival (OS)
• DFS was longer in the capecitabine group than in the control group:
  • 74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years
• Among patients with triple-negative disease:
  • DFS was 69.8% in the capecitabine group versus 56.1% in the control group
  • The OS rate was 78.8% versus 70.3%
• Residual disease after completion of neoadjuvant chemotherapy:
  • Is associated with worse outcomes
• References
  • Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Eng J Med. 2017;376(22):2147-2159.
  • Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.

• Design:
  • Multicenter, open-label, phase II / III noninferiority RCT:
    • In resected, high-risk LA-SCCHN:
      • Features such as positive / close margin and / or ENE
  • Randomized to:
    • q3-weekly cisplatin 100 mg m² × 2 to 3 with RT vs
      weekly cisplatin 40 mg / m² with the same RT
  • Primary (phase III): 
    • Overall survival (OS); NI margin HR 1.32 PubMed
• Patients and follow-up:
  • 261 enrolled:
    • 132 q3-weekly
    • 129 weekly
  • Planned third interim analysis
  • Median follow-up 2.2 years at the time of the report;:
    • Updated curves included in the article figures PubMed
  • Efficacy:
    • Noninferiority met
  • OS: 
    • Weekly noninferior to q3-weekly:
      • HR 0.69, 99.1% CI 0.374–1.273; one-sided P for NI 0.0027 < 0.0043
    • Kaplan–Meier curves:
      • Show overlapping survival with no detriment for weekly dosing PubMed
  • Relapse-free survival (RFS): 
    • KM curves presented:
      • No signal of inferiority for weekly dosing in subgroup displays PubMed
  • Safety (clinically meaningful reductions with weekly dosing):
    • Grade ≥ 3 neutropenia: 
      • 35% weekly vs 49% q3-weekly
    • Infections (grade ≥ 3): 
      • 7% weekly vs 12% q3-weekly
    • Renal impairment and hearing impairment: 
      • Less frequent with weekly cisplatin:
        • Favors organ preservation of kidney / ear
    • Treatment-related deaths: 
      • 0 in q3-weekly
      • 2 (1.6%) in weekly arm (rare) PubMed
• Interpreting the curves and endpoint strategy:
  • The trial was powered for OS noninferiority, not superiority:
    • The KM OS plots (and RFS plots) are consistent with therapeutic equivalence on survival while achieving lower nephro / ototoxicit:
      • A clinically relevant trade-off in the post-op population where competing risks (nutrition, wound healing, dysphagia) matter PubMed
• External context and follow-ups:
  • Editorial perspective:
    • JCOG1008 provides some of the strongest evidence supporting weekly cisplatin as a standard alternative in the adjuvant setting: PMC
      • Subsequent / supplementary analyses continue to explore renal events and adherence:
        • Without overturning the primary conclusion of noninferior OS with improved tolerability PMC+1
• Practical takeaways for tumor board:
  • Either schedule is acceptable:
    • For post-op high-risk patients (positive / close margin and / or ENE):
      • Weekly 40 mg / m² is a guideline-consistent alternative to 100 mg / m² q3-weekly:
        • With less nephrotoxicity and ototoxicity PubMed
  • Maintain attention to cumulative dose (aim ≥ 200 mg /m² overall when feasible) and supportive care:
    • Weekly scheduling can improve deliverability in frailer patients.:
      • General principle supported across cisplatin CRT literature MDPI
• Key citation: 
  • Kiyota N, et al. JCOG1008—J Clin Oncol. 2022;40:1980–1990. 

• Contemporary breast cancer care:
  • Increasingly relies on a personalized multidisciplinary approach to treatment
• In order to provide individual counseling of risk:
  • Several risk assessment models are available
• The most important risk factor for the development of breast cancer is:
  • Gender:
    • The female-to-male ratio for breast cancer is:
      • 100:1
• Multiple additional factors are associated with an increased risk of developing breast cancer, including:
  • Age, genetic predisposition, a history of proliferative breast disease, prior radiation exposure, a personal or family history of breast cancer, obesity, and hormone exposure
• Age:
  • According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program:
    • The incidence of breast cancer increases rapidly:
      • During the fourth decade of life
      • After menopause:
        • The incidence continues to increase but at a much slower rate – peaking in the fifth and sixth decades of life and slowly leveling off during the sixth and seventh decades
    • Approximately one out of eight invasive breast cancers:
      • Will be found in women younger than 45 years
    • Approximately two-thirds of invasive breast cancers:
      • Are found in women older than 55 years
• Personal and Family History of Breast Cancer:
  • A strong family history of breast cancer:
    • Has been recognized to increase a woman’s risk of breast cancer
  • The overall risk depends on:
    • The number of relatives with breast cancer
    • Their ages at diagnosis
    • Whether the disease was unilateral or bilateral
  • The highest risk is associated with:
    • A young first-degree relative with bilateral breast cancer
  • Overall, the risk of developing breast cancer is increased approximately:
    • 1.5- to 3-fold if a woman has a first-degree relative (mother or sister) with breast cancer
  • A personal history of breast cancer:
    • Is a significant risk factor for the development of cancer in the contralateral breast:
      • With an estimated risk of approximately 0.4% to 1% per year of follow-up (depending on the source)
• Genetic Predisposition:
  • Hereditary breast cancer secondary to genetic mutations:
    • Accounts for 5% to 10% of all breast cancer
  • Several mutations have been identified to have an increased association with breast cancer risk:
    • Although to varying degrees:
      • These include BRCA1, BRCA2, PALB2, CHEK2, p53 (Li–Fraumeni syndrome), PTEN (Cowden disease), ATM, CDH1, STK11 (Peutz–Jeghers syndrome), and Lynch syndrome
  • Expanded panel genetic testing:
    • Is becoming increasingly common although the penetrance of these mutations and relative risk of breast cancer may vary:
    • Testing of an affected family member:
      • Is recommended to identify and direct testing for a specific genetic loci mutation in unaffected family members
  • Genetic testing:
    • Should be preceded by genetic counseling
  • The most widely studied and known mutations are in the BRCA1 and 2 genes:
    • BRCA1 mutations:
      • Have an estimated lifetime risk of breast cancer of 57% to 65%
      • Have an estimated lifetime risk of ovarian of 10% to 40%
      • They have an increase risk if fallopian tube, peritoneal, pancreatic cancers, and melanoma
    • BRCA2 mutation carriers:
      • Have an estimated breast cancer lifetime risk of 45% to 55%
      • Have an estimated lifetime risk of ovarian of 10% to 20%
      • They and an increase risk of pancreatic, prostate, and higher association with male breast cancers (lifetime risk approximately 5% to 10%) in addition to Fanconi anemia, a syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia
    • BRCA1 and 2 mutation carriers are encouraged to undergo high-risk screening:
      • With annual mammogram alternating with breast MRI or prophylactic mastectomy for risk-reduction
• Proliferative Breast Disease:
  • Nonproliferative breast diseases:
    • Such as adenosis, fibroadenomas, apocrine changes, duct ectasia, and mild hyperplasia:
      • Are not associated with an increased risk of breast cancer
  • Proliferative breast diseases:
    • Are associated with and increase breast cancer risk to various degrees (RR is 1.5 to 2)
      • Moderate or florid hyperplasia without atypia, papilloma, and sclerosing adenosis carry a slightly increased risk of breast cancer:
        • 1.5 to 2 times that of the general population
      • Atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH):
        • Is associated with a four- to fivefold increased risk of developing breast cancer in either breast
      • Lobular carcinoma in situ (LCIS):
        • Is associated with up to an 8- to 10-fold risk of breast cancer
  • Risk factor modification with chemoprevention in the setting of high-risk lesions:
    • Is highly effective as evidenced by the findings of the NSABP P2 trial:
      • This study found chemoprevention with tamoxifen or raloxifene was associated with a significant decrease in the incidence of invasive and noninvasive breast cancer in the setting of ADH and LCIS:
        • Therefore, consideration of chemoprevention and risk assessment strategies for patients with high-risk lesions should be strongly encouraged
• Radiation Exposure:
  • Therapeutic radiation exposure to treat disease:
    • Can be a significant cause of radiation-induced carcinogenesis
  • The highest associated risk is seen with higher doses of radiation and radiation treatment given at a young age:
    • Particularly before age 30:
      • Relative risk is 5.2
    • This has been observed in women receiving mantle irradiation for treatment of Hodgkin disease:
      • Given the elevated lifetime risk of breast cancer in this population:
        • High-risk screening with annual mammography and breast MRI is recommended
• Endogenous Hormone Exposure:
  • The hormonal milieu at different times in a woman’s life may affect her risk of breast cancer:
    • The total duration of exposure to endogenous estrogen:
      • Is an important factor in breast cancer risk
  • Increased risk has been associated with:
    • Early age at menarche
    • Early establishment of regular ovulatory cycles
    • Nulliparity
    • Advanced age at first childbirth
    • Late menopause
  • Interestingly, women who have their first child between ages 30 and 34:
    • Have the same risk as nulliparous women:
      • Whereas women older than 35 years have a greater risk than nulliparous women
  • Obesity can also contribute to endogenous estrogen exposure:
    • Given higher rates of conversion of androgenic precursors through peripheral aromatization in adipose tissue
  • Lifestyle modification:
    • With healthy diet and regular physical activity is beneficial
• Exogenous Hormone Exposure:
  • Exogenous hormone replacement therapy is a known risk factor for breast cancer:
    • The Women’s Health Initiative, a large-scale prospective study, was abruptly halted in 2002:
      • After interim analysis indicated hormonal replacement therapy (HRT) was associated with:
        • A 26% increase in the risk of breast cancer over a 5-year period
        • As well as an increased risk of stroke and coronary artery disease
    • HRT was found to be associated with increased bone density and fewer menopausal symptoms:
      • Which makes the ongoing use of HRT attractive to many woma
  • A meta-analysis from the Mayo Clinic by Benkhadra et al:
  • Looked at 43 randomized controlled trials and found no association between the use of HRT and cardiac death or stroke
  • Estrogen plus progesterone use:
    • Was associated with a likely increase in breast cancer mortality (relative risk [RR] 1.96 [95% confidence interval (CI) 0.98–3.94])
  • The use of estrogen alone:
    • Did not increase this risk
  • In women who started HRT at less than 60 years of age:
    • There was a reduction in all-cause mortality including cardiovascular and cancer deaths:
      • Overall, the current evidence suggests that HRT does not affect the risk of death from all causes, cardiac death, and death from stroke or cancer
    • Therefore, treating physicians should thoroughly discuss the risks and benefits of this therapy with their patients