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• 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

• The INSEMA trial:
  • Citation:
    • Reimer T, et al. New England Journal of Medicine, 2024/2025 (INSEMA Investigators).
• According to a study published in The New England Journal of Medicine:
  • In this trial involving patients with clinically node-negative, T1 or T2 invasive breast cancer (90% with clinical T1 cancer and 79% with pathological T1 cancer):
    • Omission of surgical axillary staging was noninferior to sentinel-lymph-node biopsy:
      • After a median follow-up of 6 years
• The trial also demonstrated that omission of SLNB resulted in:
  • Lower rates of lymphedema
  • Better arm mobility
  • Less pain with arm or shoulder movement compared to SLNB:
    • As confirmed by both clinical and patient-reported outcomes
• However, a slightly higher – but still low – rate of axillary recurrence was observed in the omission group:
  • 1.0% vs. 0.3%:
    • With no impact on overall survival
• These findings support the safety of omitting SLNB in carefully selected patients with early-stage, clinically node-negative breast cancer:
  • Particularly those with favorable tumor biology:
    • When the absence of nodal status will not alter adjuvant therapy decisions
• The INSEMA trial (Intergroup‑Sentinel‑Mamma, often abbreviated “INSEMA”):
  • A large European randomized study (5,500+ patients):
    • Evaluating whether sentinel lymph node biopsy (SLNB) can be safely omitted in selected patients with early-stage breast cancer
• Background and Design:
  • Population: 
    • Clinically node-negative invasive breast cancer (cT1 to cT2, ≤ 5 cm), mostly hormone receptor–positive, HER2-negative tumors
    • Patients candidates for breast‑conserving surgery and whole‑breast radiation
    • All had negative axilla by clinical exam:
      • Most centers used axillary ultrasound (AUS) as standard triage
  • Trial Type:
    • Prospective, randomized non‑inferiority study:
      • Germany and Austria; 2015 to 2019
    • Randomized in a 4 : 1 ratio:
      • ~ 962 patients omitted SLNB versus ~ 3,896 who underwent standard SLNB
    • Primary Endpoint:
      • 5‑year invasive disease–free survival (iDFS):
        • With non‑inferiority margin HR ≤ 1.271 and lower bound ≥ 85% iDFS
• Key Results (Median Follow‑up ≈ 73.6 months ≈ 6 years):
  • Invasive Disease‑Free Survival (iDFS):
    • No‑SLNB group:
      • 5‑year iDFS ≈ 91.9% (95% CI: 89.9–93.5)
    • SLNB group:
      • 91.7% (95% CI: 90.8–92.6)
    • Hazard Ratio:
      • 0.91 (95% CI: 0.73–1.14), within non‑inferiority margin
  • Overall Survival (OS):
    • No‑SLNB group:
      • 98.2% (95% CI: 97.1–98.9)
    • SLNB group:
      • 96.9% (95% CI: 96.3–97.5) 
  • Axillary Recurrence:
    • Slightly higher in no‑SLNB group:
      • ≈ 1.0% vs. ≈ 0.3%:
        • But still very low clinically 
• Secondary Outcomes:
  • Quality of Life and Morbidity:
    • Lower rates of lymphedema, better arm mobility, and less pain with arm / shoulder movement in the no‑SLNB group
  • Patient‑reported outcomes consistently favored omission:
    • Better arm symptom scores (BRAS) and overall quality of life scales (EORTC) 
• Clinical Implications:
  • Omitting SLNB appears safe and non‑inferior for iDFS and OS:
    • In carefully selected cN0 patients undergoing breast‑conserving therapy
  • Best suited for:
    • ≥ 50‑year‑old patients with low-risk tumors:
      • ≤ 2 cm, grade 1 to grade 2, HR-positive, HER2-negative
  • Underrepresented groups (younger, grade 3, HER2‑positive or larger tumors):
    • Were under‑powered for definitive recommendations
• Trial required whole‑breast radiation:
  • No partial‑breast or omission of radiation was allowed, limiting generalizability
• Although non‑SLNB led to slightly higher axillary recurrence (1% vs 0.3%):
  • The absolute rates remained extremely low (< 1%), with meaningful improvements in arm morbidity and quality of life
• Limitations and Cautions:
  • Under‑powered subgroups:
    • T2 tumors, younger patients, grade 3, or HER2+ disease:
      • Had low representation and thus results may not apply
  • No SLNB omission in the context of mastectomy, neoadjuvant therapy, or partial breast radiation:
    • These settings were excluded
  • Patient selection remains critical:
    • Omitting nodal staging may impact systemic therapy decisions:
      • Chemotherapy, genomic testing
• The INSEMA trial:
  • Demonstrates that in clinically node-negative women with early-stage, low-risk invasive breast cancer:
    • Who are undergoing breast-conserving therapy with whole breast radiation:
      • Omitting sentinel lymph node biopsy is non‑inferior for disease‑free and overall survival:
        • While significantly reducing lymphedema risk and improving arm function and patient quality of life
  • This de‑escalation strategy is particularly appropriate for:
    • Patients over age 50 with:
      • T1, grade 1 to grade 2, hormone receptor‑positive / HER2‑negative tumors
    • However, broader application to younger patients, higher‑risk tumors, or non‑lumpectomy contexts should be approached with caution and discussed in a multidisciplinary setting
• References:
  • Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. Reimer T, Stachs A, Veselinovic K, et al. The New England Journal of Medicine. 2025;392(11):1051-1064. doi:10.1056/NEJMoa2412063.
  • Sentinel Lymph Node Biopsy Omission in Early-Stage Breast Cancer: Current Evidence and Clinical Practice. Huang T, Wang W, Sun X. Frontiers in Oncology. 2025;15:1598730. doi:10.3389/fonc.2025.1598730.
  • Patient-Reported Outcomes for the Intergroup Sentinel Mamma Study (INSEMA): A Randomised Trial With Persistent Impact of Axillary Surgery on Arm and Breast Symptoms in Patients With Early Breast Cancer. Reimer T, Stachs A, Veselinovic K, et al. EClinicalMedicine. 2023;55:101756. doi:10.1016/j.eclinm.2022.101756.
  • Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. Reimer T, Stachs A, Veselinovic K, et al. The New England Journal of Medicine. 2024;. doi:10.1056/NEJMoa2412063.

• Atypical ductal hyperplasia (ADH):
  • Proliferative breast lesions:
    • Such as ADH confer a substantial increase in breast cancer risk of:
      • 4 to 5-fold when compared to the general population (RR 3.7-5.3)
• In post-menopausal women a higher BMI and / or peri-menopausal weight gain:
  • Is associated with a higher risk of breast cancer
  • In the Nurses’ Health Study:
    • Women who gained 10 kg or more after menopause had a greater risk of developing breast cancer compared to those who maintained their weight (RR 1.18, 95% CI 1.03-1.35)
• After an average of 10 years of follow-up in the Women’s Health Study:
  • Higher daily alcohol consumption was associated with an increase in invasive breast cancer risk (RR 1.43, 95% CI 1.02-2.02 for ≥ 30g alcohol (2 to 3 drinks vs. none)
• Based on epidemiological data from 52 studies, risk ratios for breast cancer increase with the number of affected first-degree relatives:
  • 1.8 (99% CI 1.7-1.9), 2.9 (2.4-3.6), and 3.9 (2.0-7.5) respectively for one, two, and three or more affected relatives vs. none
• There is no definitive evidence that caffeine intake is associated with breast cancer risk
• References
  • Smart CE, Furnival CM, Lakhani SR. Chapter 17: High-Risk Lesions: ALH/LCIS/ADH. In: Kuerer HM, ed. Kuerer’s Breast Surgical Oncology. New York, NY: McGraw-Hill; 2010.
  • Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296(2):193-201.
  • Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE. Alcohol consumption and breast cancer risk in the Women’s Health Study. Am J Epidemiol. 2007;165(6):667-676.
  • Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet. 2001;358(9291):1389-1399.
  • Ganmaa D, Willett WC, Li TY, et al. Coffee, tea, caffeine and risk of breast cancer: a 22-year follow-up. Int J Cancer. 2008;122(9):2071-2076.