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• 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.

• Recent high-quality randomized trials have provided strong evidence supporting the:
  • Omission of sentinel lymph node biopsy (SLNB) in select patients with:
    • Early-stage, clinically node-negative breast cancer
• The SOUND and INSEMA trials both demonstrated that:
  • In patients with small tumors (≤ 2 cm in SOUND; ≤ 5 cm in INSEMA) and negative axillary imaging:
    • Omission of SLNB is noninferior to SLNB in terms of:
      • Invasive disease-free survival (INSEMA) and distant disease-free survival (SOUND):
        • With very low rates of axillary recurrence and improved quality of life due to fewer surgical complications such as lymphedema and reduced arm mobility
• Guidelines from the American Society of Clinical Oncology (ASCO) and Ontario Health (Cancer Care Ontario):
  • Now recommend omitting SLNB in women aged 70 or older with:
    • Clinically node-negative, hormone receptor–positive, HER2-negative tumors who will receive endocrine therapy:
      • As supported by the Society of Surgical Oncology Choosing Wisely campaign
  • For younger or higher-risk patients:
    • SLNB remains standard unless ongoing or future trials further expand the eligible population
• According to a study published in JAMA Oncology, the following conclusion was reached:
  • In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small breast cancer (BC) and a negative result on ultrasonography of the axillary lymph nodes
  • These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan
• In summary:
  • Omission of SLNB is now supported for older women with low-risk, node-negative breast cancer and for select patients with small tumors and negative axillary imaging, provided that the lack of nodal pathological information does not alter adjuvant therapy decisions
  • Ongoing trials:
    • BOOG 2013-08, NAUTILUS:
      • Will further clarify the boundaries of safe omission
• 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. 2024;. doi:10.1056/NEJMoa2412063.
  • Sentinel Lymph Node Biopsy vs No Axillary Surgery in Patients With Small Breast Cancer and Negative Results on Ultrasonography of Axillary Lymph Nodes: The SOUND Randomized Clinical Trial. Gentilini OD, Botteri E, Sangalli C, et al. JAMA Oncology. 2023;9(11):1557-1564. doi:10.1001/jamaoncol.2023.3759.
  • Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline. Brackstone M, Baldassarre FG, Perera FE, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2021;39(27):3056-3082. doi:10.1200/JCO.21.00934.
  • Omitting Axillary Staging in Selected Patients: Rationale of Choosing Wisely in Breast Cancer Treatment. Grossi S, Le J, Armani A. Surgery. 2023;174(2):413-415. doi:10.1016/j.surg.2023.03.023.

• ConCERT Phase III Trial (ASCO 2022):
  • Design:
    • Randomized, multicenter, definitive treatment of locally advanced HNSCC
  • Findings:
    • Weekly 40 mg/m² was non-inferior to 100 mg/m² every 3 weeks in 2-year locoregional control:
      • 60.9% vs 57%, within a 10% non-inferiority margin
    • Better tolerance:
      • Fewer severe toxicities
      • Fewer hospitalizations
      • Fewer treatment interruptions with the weekly regimen
    • No significant differences in OS or PFS after ~ 26 months follow-up
• Earlier Small Randomized and Retrospective Studies:
  • Tsan et al. (2012) (Phase III, ~ 55 patients):
    • 100 mg/m² every 3 weeks had higher compliance (more patients achieved ≥ 200 mg/m² cumulative dose) and lower acute toxicity than weekly 40 mg/m²
  • Mashhour et al. (2020):
    • Compared weekly 30 mg/m² vs 100 mg/m² every 3 weeks:
      • Weekly arm:
        • Less acute toxicity
        • Improved compliance
        • However, loco‑regional control was lower in weekly arm (57.6% vs 72.8%)
  • Singh et al. (2022, retrospective):
    • 3‑weekly arm achieved better OS and DFS, higher completion of cumulative dose:
      • But had more toxicities and treatment breaks
  • Meta‑Analysis and Cumulative Dose Importance
    Pooled analysis (Canada / Italy):
    • Higher cumulative cisplatin exposure (≥ 200 mg/m²) correlated with significantly better overall survival, especially in HPV-negative HNSCC:
      • 3-year OS:
        • 72% vs 60% vs 52%, p < 0.001
  • Ongoing and Investigational Trials:
    • NRG‑HN009 (Phase II/III, recruiting):
      • Comparing toxicity and non-inferiority in OS between weekly 40 mg/m² vs 100 mg/m² every 3 weeks, stratified by HPV status
    • CISLOW Trial (Netherlands, protocol published 2023):
      • Focuses on patients with low skeletal muscle mass, comparing compliance and
        Cisplatin Dose-Limiting Toxicity (CDLT) risk between weekly and triweekly regimens
    • Fractionated cisplatin schedules (2024) are also being explored, e.g., splitting 100 mg/m² over 4 days to improve tolerability

• Bottom Line (as of August 2025):
  • High-dose (100 mg/m² q 3weeks):
    • Remains the standard based on long-term efficacy, especially where achieving ≥ 200 mg /m² is feasible and toxicities can be managed
  • Weekly 40 mg/m² has emerged as a viable alternative:
    • Not inferior in locoregional control per ConCERT, with better tolerability, particularly for patients with comorbidities or reduced treatment tolerance
  • Maintaining an adequate cumulative cisplatin dose (≥ 200 mg/m²) is crucial for optimal oncologic outcomes
• Ongoing randomized trials (e.g., NRG-HN009, CISLOW) should provide clearer guidance soon

• Sentinel Lymph Node Biopsy Omission in Early Breast Cancer:
  • Insights from the INSEMA Trial
• Recent findings from the INSEMA trial offer robust evidence supporting the omission of sentinel lymph node biopsy (SLNB) in select patients with low-risk, early-stage invasive breast cancer undergoing breast-conserving surgery (BCS).
• Presented by Toralf Reimer, PhD, at the 2024 San Antonio Breast Cancer Symposium (SABCS) and published in the New England Journal of Medicine, the trial demonstrates no significant compromise in survival outcomes when SLNB is omitted in these patients.
• Among clinically node-negative women with stage T1 or T2 breast cancer, the 5-year invasive disease-free survival (DFS) rates were comparable:
  • 91.9% in patients omitting SLNB and 91.7% in those who underwent SLNB (HR: 0.91; 95% CI: 0.73–1.14).
• Overall survival (OS) rates were also similar, estimated at 98.2% without SLNB and 96.9% with SLNB.
• Trial Design and Key Results:
  • The INSEMA trial enrolled 5,502 patients with clinically node-negative, hormone receptor-positive, HER2-negative invasive breast cancer (T1 / T2, tumor size ≤ 5 cm). Following BCS and whole-breast irradiation, patients were randomized to SLNB or no axillary surgery.
    • Median follow-up: 73.6 months
    • Axillary recurrence:
    • Slightly higher in the no-SLNB group (1.0% vs. 0.3%):
      • Though the absolute numbers were low
    • Distant relapse rates:
      • Identical at 2.7% in both groups
    • Morbidity:
      • Omitting SLNB significantly reduced rates of lymphedema (5.7% vs. 1.8%), arm mobility restrictions (3.5% vs.
        and pain with arm or shoulder movement (4.2% vs. 2.0%).
        • Context Within Ongoing De-Escalation Trials
          • The INSEMA trial is one of four ongoing studies exploring the omission of axillary surgery in select patients with early-stage breast cancer. These include:
            • SOUND trial: Published results demonstrated no difference in 5-year DFS or OS between patients undergoing or omitting axillary surgery for small (≤ 2 cm) breast tumors.
            • BOOG 2013-08 and NAUTILUS trials: Expected to further validate and refine patient selection criteria for omitting axillary surgery.
          • Clinical Implications
          • The INSEMA trial strengthens the case for omitting SLNB in carefully selected patients, particularly for tumors ≤ 2 cm. However, the continued role of SLNB as a staging tool in certain patients and the need for shared decision-making with multidisciplinary teams.
          • This trial represents a key milestone in an ongoing paradigm shift, aligning with earlier data (e.g., Danish Breast Cancer Cooperative Group studies from the 1980s) that suggested no survival benefit from extensive axillary node removal.
          • Conclusion:
            • The findings from the INSEMA trial provide compelling evidence supporting deescalation of axillary surgery in early-stage breast cancer, with a significant reduction in morbidity and no compromise in survival outcomes.
            • Further results from ongoing trials such as BOOG 2013-08 and NAUTILUS will likely cement this strategy as standard practice for patients with low axillary disease burden.
              
              
              
              
              
              
              

• Title:
  • Axillary Surgery in Breast Cancer Patients With Negative Axillary Ultrasound: The SOUND Randomized Clinical Trial
    
• Published:
  • 2023 in JAMA Oncology
    • ClinicalTrials.gov ID: NCT02167490
• Location:
  • Italy, Spain, Switzerland, Chile (18 hospitals)
• Study Objective:
  • To evaluate whether sentinel lymph node biopsy (SLNB):
    • Can be safely omitted in women:
      • With early-stage, clinically node-negative breast cancer with negative axillary ultrasound (AUS), without compromising oncologic outcomes
• Patient Population:
  • Women with:
    • Unifocal invasive breast cancer:
      • Tumor ≤ 2.0 cm (cT1)
    • Clinically and ultrasound-negative axilla
    • Undergoing breast-conserving surgery
    • No neoadjuvant therapy
  • Tumor types:
    • Majority were hormone receptor-positive, HER2-negative
• Study Design:
  • Randomized, phase 3, non-inferiority trial
  • Two arms:
    • SLNB group:
      • Underwent sentinel lymph node biopsy
    • Observation group:
      • No axillary surgery
  • Primary endpoint:
    • 5-year distant disease-free survival (DDFS)
  • Secondary endpoints:
    • Overall survival (OS)
    • Disease-free survival (DFS)
    • Axillary recurrence
    • Quality of life

• Non-inferiority was met for the primary endpoint (DDFS)
• Clinical Implications:
  • In women with small tumors (≤ 2 cm) and negative axillary ultrasound:
    • SLNB can be omitted without compromising distant disease-free or overall survival
  • Supports a less invasive approach and aligns with the de-escalation of axillary surgery trend in breast cancer care
• Leads to fewer surgical complications:
  • Lymphedema, seroma, pain
• Limitations:
  • Results apply only to women with:
    • Negative axillary ultrasound and early-stage, low-risk tumors
  • Not applicable to:
    • Mastectomy patients
    • Multifocal tumors
    • Patients receiving neoadjuvant therapy
• Conclusion:
  • The SOUND trial confirms that routine sentinel lymph node biopsy can be safely omitted in selected patients with early-stage breast cancer and negative axillary ultrasound:
    • Supporting a shift toward minimally invasive surgical strategies in modern breast cancer management