Nuclear Medicine in Breast Cancer

1. The clinical problem

Breast cancer is the most commonly diagnosed cancer in women worldwide. About 75–80% of invasive cancers are of no special type (NST), formerly called invasive ductal carcinoma, and 10–15% are invasive lobular carcinoma (ILC). Treatment depends as much on biology as on anatomy: oestrogen and progesterone receptors (ER, PR), human epidermal growth factor receptor 2 (HER2) and proliferation define the subtypes that decide systemic therapy.

What the oncologist needs from imaging

• Local extent: mammography, ultrasound and, selectively, MRI; nuclear medicine plays a minor role (molecular breast imaging, section 9).
• Axilla: ultrasound with needle biopsy of suspicious nodes, then sentinel lymph node biopsy (SLNB) in the clinically node-negative patient. Lymphoscintigraphy is a nuclear medicine procedure at the centre of this step.
• Extra-axillary nodes and distant disease: the question that decides curative versus palliative intent in higher-stage disease. This is where FDG PET/CT changes management.
• Receptor status across sites: metastases can differ from the primary; ¹⁸F-FES PET shows ER expression at every site at once.
• Response: early response during neoadjuvant therapy, and response of bone-predominant metastatic disease that CT cannot measure.

Staging system in force: AJCC 8th edition

The American Joint Committee on Cancer (AJCC) 8th edition remains current for breast cancer; breast has not yet been released in AJCC Version 9. It has two parts. The anatomic stage uses tumour (T), node (N) and metastasis (M) categories. The prognostic stage adds grade, ER, PR, HER2 and, for T1–2 N0 ER-positive HER2-negative cancers, a multigene assay result (a low Oncotype DX recurrence score assigns prognostic stage IA). Imaging defines the clinical anatomic stage, and guideline recommendations for PET use the clinical anatomic stage.

Clinical anatomic stage groups (AJCC 8th) and what they mean for nuclear medicine.

• Nodal categories that PET changes: N2b is internal mammary nodes without axillary nodes; N3a is infraclavicular (level III); N3b is internal mammary plus axillary; N3c is ipsilateral supraclavicular.
• What is metastatic, not nodal: contralateral axillary, internal mammary or supraclavicular nodes and any cervical node are M1.

Subtypes and why they matter for tracer choice

HR, hormone receptor. Luminal-like tumours are about 65% of cases, HER2-positive 15–20% and triple-negative 10–15%.

2. Tracers and why they work

• ¹⁸F-FDG: uptake reflects glucose transporter 1 (GLUT1) and hexokinase activity, viable tumour cell density and hypoxia-driven glycolysis. NST is more avid than lobular cancer, triple-negative more than ER-positive, and grade 3 more than lower grades. High uptake carries a worse prognosis.
• ¹⁸F-FES (fluoroestradiol): a radiolabelled oestrogen that binds functional ER. Uptake correlates with ER immunohistochemistry. It does not image PR or HER2.
• Bone tracers (⁹⁹ᵐTc-MDP/HDP, ¹⁸F-NaF): show osteoblastic reaction, not tumour. NaF PET has higher sensitivity and resolution than planar bone scintigraphy.
• Radiocolloids for sentinel nodes: ⁹⁹ᵐTc-nanocolloidal albumin (5–100 nm, preferred in most of Europe), filtered ⁹⁹ᵐTc-sulphur colloid (mostly 100–220 nm; unfiltered mean about 305–340 nm), ⁹⁹ᵐTc-antimony trisulphide (3–30 nm) and the receptor-targeted ⁹⁹ᵐTc-tilmanocept (about 7 nm), which binds mannose receptors on macrophages.

When FDG fails and what replaces it

• Small lesions: lesions of 10 mm or less (about 4–5 mm with digital PET) and micrometastatic nodes are missed. This is why PET cannot replace SLNB.
• Low-avidity histology: lobular, tubular, mucinous, low-grade ER-positive and in situ disease. In stage III, PET/CT revealed unsuspected distant metastases in 22% of NST patients but 11% of ILC patients; sclerotic, sometimes miliary, lobular bone metastases may be visible only on the CT component.
• Sclerotic bone metastases: may be faint on FDG; read the CT windows and consider bone-specific imaging.
• Replacement: ¹⁸F-FES for ER-positive disease (approved in the USA and France); bone scan or NaF PET for purely sclerotic disease; fluciclovine and fibroblast activation protein inhibitor (FAPI) PET are investigational (section 9).

3. Indications by clinical scenario

The joint EANM–SNMMI guideline on FDG PET/CT in NST breast cancer (Vaz et al., 2024; endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR and EUSOMA) graded its recommendations by level of evidence (I–IV) and NICE grade (A–D). It applies to NST cancer; the panel explicitly did not extend it to lobular cancer.

Sources: Vaz et al. 2024; comparison with NCCN, ESMO and ABC guidelines from Groheux et al. 2024.

Where the guidelines disagree

• The EANM–SNMMI guideline recommends FDG PET/CT more widely than NCCN, ESMO or the Advanced Breast Cancer (ABC) consensus. NCCN and ESMO mainly use it to resolve equivocal conventional imaging, although ESMO and ABC accept it instead of CT and bone scan in high-risk and metastatic disease.
• For neoadjuvant response, EANM–SNMMI supports early FDG assessment in triple-negative and HER2-positive disease; NCCN and ESMO give PET no role there.
• For bone, EANM–SNMMI accepts FDG PET/CT alone; NCCN still asks for concordant PET and CT findings or a separate bone scan or NaF PET/CT.

The axilla: sentinel node biopsy and its de-escalation

• Clinically node-negative (cN0): SLNB is the staging standard. FDG PET/CT cannot exclude small-volume nodal disease, and an FDG-avid axillary node still needs tissue.
• One or two positive sentinel nodes: ACOSOG Z0011 (891 women, T1–T2, breast-conserving surgery with whole-breast radiotherapy) showed no survival loss without axillary dissection: 10-year overall survival 86.3% versus 83.6%. AMAROS (1,425 randomised) showed axillary radiotherapy is an alternative to dissection with less lymphoedema (11.9% versus 24.5% at 5 years) and 10-year axillary recurrence of 1.82% versus 0.93%.
• Omitting SLNB altogether: SOUND (1,405 analysed; tumours up to 2 cm with a negative axillary ultrasound) found 5-year distant disease-free survival of 98.0% without axillary surgery versus 97.7% with SLNB. INSEMA (5,502 randomised 1:4; T1–T2 up to 5 cm, clinically node-negative, breast conservation) found 5-year invasive disease-free survival of 91.9% versus 91.7% (hazard ratio 0.91), with axillary recurrence 1.0% versus 0.3%.
• ASCO 2025: clinicians should not recommend routine SLNB in postmenopausal patients aged 50 or over with a negative axillary ultrasound and a grade 1–2, 2 cm or smaller, HR-positive HER2-negative cancer treated with breast-conserving therapy. SLNB may be offered in clinically node-negative cT3–T4c or multicentric tumours, in pregnancy, obesity and men, and after previous breast or axillary surgery.
• After neoadjuvant therapy in node-positive disease: SLNB alone is less reliable. In ACOSOG Z1071 (cN1 disease, two or more nodes removed) the false-negative rate was 12.6%. Removing the biopsy-proven, clipped node as well (targeted axillary dissection, localised with an ¹²⁵I seed in the original series) cut the false-negative rate to 2.0%.

Internal mammary drainage

Deep (peritumoral or intratumoral) injection is needed to map internal mammary nodes (IMNs). They are seen in about one-third of patients; 63–92% can be harvested, and 11–27% of harvested IMNs contain metastases. IMN involvement worsens prognosis, and mapping causes stage migration and changes radiotherapy and systemic treatment, but survival benefit from IMN biopsy is unproven, so practice varies. The nuclear medicine task is to report the drainage accurately and localise it.

4. Evidence at a glance

pCR, pathological complete response; SLN, sentinel lymph node; TAD, targeted axillary dissection.

5. Patient preparation and acquisition

FDG PET/CT: what differs in breast cancer

• Standard preparation: fast at least 4 h, hydrate, blood glucose below 200 mg/dL (11.1 mmol/L), rest warm for an uptake time of 60 ± 5 min, arms up, skull base to mid-thigh.
• Timing after therapy: metabolic flare occurs 7–10 days after starting endocrine therapy (tamoxifen, fulvestrant or aromatase inhibitors). The panel suggests scanning at least 10 days (15 if possible) after the last dose of chemotherapy or endocrine therapy; this is expert opinion. Do not interrupt targeted therapy for a scan.
• After radiotherapy: wait at least 3 months before looking for recurrence in the radiotherapy field.
• Record: biopsy and surgery dates, radiotherapy fields, growth factor injections, corticosteroids and recent vaccinations (with the arm used).
• Options: contrast-enhanced CT helps in metastatic disease and makes later CT comparison easier; prone hanging-breast images and a flat table top help breast assessment and radiotherapy planning.
• Response studies: baseline, interim and final scans on the same accredited scanner.

¹⁸F-FES PET/CT

• Activity and timing: the US label recommends 222 MBq (range 111–222 MBq) with imaging 80 min after injection (range 20–80 min); the SNMMI/EANM standard describes 111–280 MBq with about 60 min uptake. Effective dose is about 4.9 mSv for 222 MBq, plus the CT.
• Drug interactions: tamoxifen and other ER modulators, and fulvestrant, block FES binding for up to 8 and 28 weeks respectively. Image before these drugs start; do not delay indicated therapy for a scan. Aromatase inhibitors do not block the receptor and were allowed in the registration studies.
• Other preparation: the label asks for good hydration and frequent voiding, a pregnancy check, and interruption of breastfeeding for 4 hours.

Breast lymphoscintigraphy (EANM–SNMMI 2013)

Tracer uptake in a node does not predict whether it is the sentinel node, so no quantification is needed; report location and number.

6. Interpretation and reporting

Reading the staging FDG study

• Nodes by station: name axillary level I–II, level III (infraclavicular), internal mammary and supraclavicular nodes, because each changes the N category (N1 to N3c). Contralateral nodes are M1.
• Bone: FDG is sensitive for lytic and marrow disease; sclerotic lesions can be faint. In 102 patients with newly diagnosed metastatic disease, FDG PET found 87% of bone lesions, bone scan 26% and contrast CT 39%, and FDG changed management in 16%.
• Lung: PET is less sensitive than dedicated CT for small nodules; read the CT lung windows.
• Brain: not assessed reliably by FDG; MRI if symptoms or in high-risk subtypes.
• Incidental focal breast uptake: found in 0.61% of women having PET/CT for other reasons, and 38.7% of these are malignant. Recommend diagnostic mammography and ultrasound.
• Quantify: report SUVmax, and where possible metabolic tumour volume (MTV) and total lesion glycolysis (TLG). They are prognostic, but no validated cut-offs exist.

Reading FES

• Uptake reflects ER density and function. Positivity is judged against background outside high-uptake organs; quantitative SUV helps when visual reading is equivocal (an SUV of 1.5 separated likely non-responders in one prospective study), but scanner calibration matters.
• Physiological uptake: liver, gallbladder and bowel (hepatobiliary excretion), kidneys and bladder, uterus and ovaries. Liver metastases are hard to assess.
• A negative FES scan in a patient on tamoxifen or fulvestrant, or within 8 or 28 weeks of stopping, is not evidence of ER loss.
• FES-positive lesions predict endocrine sensitivity only in part; FES-negative lesions in a patient with ER-positive biopsy suggest heterogeneity, and pathology should take precedence over a discordant negative scan.

Normal variants, pitfalls and mimics

G-CSF, granulocyte colony-stimulating factor.

Reading the lymphoscintigram

• A sentinel node is one on a direct lymphatic drainage pathway from the tumour, not simply the hottest node; nodes that appear later along the same channel are second-echelon nodes.
• Report each node basin (axilla, internal mammary with interspace, intramammary, infraclavicular, supraclavicular, contralateral) and mark the skin.
• Watch for contamination and for a node hidden by the injection site in upper outer quadrant tumours; an oblique view or SPECT/CT resolves both.

Wording the conclusion

• State the stage consequence: for example, "ipsilateral supraclavicular node, cN3c" or "FDG-avid bone lesions in keeping with M1; biopsy of the iliac lesion is advised if it will change treatment intent".
• Say when a negative result is weak: "low FDG avidity of the primary (lobular histology) limits the sensitivity of this study".
• Separate treatment effects from disease: "uptake in the right chest wall corresponds to the radiotherapy field (completed 6 weeks ago)".

7. Response assessment and follow-up

Keep uptake time within 15 min of baseline and use the same scanner. The EANM–SNMMI guideline accepts either system; use immunotherapy-specific criteria when checkpoint inhibitors are given.

• Neoadjuvant therapy: in four meta-analyses, early FDG response predicted pathological complete response with sensitivity 80–85% and specificity 66–79%. Cut-offs vary with subtype and regimen, so use the trial protocol. Luminal tumours rarely reach complete response and early PET adds little. At the end of treatment PET underestimates residual tumour: MRI is better for the breast, and no imaging test reliably identifies complete axillary response.
• Metastatic disease: FDG detected progression first in half of 87 patients in the MESTAR study, a mean of 6 months earlier than contrast CT, and PET response predicted survival. Use the same modality at baseline and follow-up.
• Bone-only or bone-predominant disease: RECIST cannot measure most bone lesions. A fall in FDG uptake with increasing sclerosis on CT indicates response. Early FDG at 4 weeks of endocrine therapy predicted outcome in a prospective study of 23 women, and is being tested in the ECOG-ACRIN EA1183 (FEATURE) trial.
• Flare: on bone scan, more or brighter lesions within the first months of effective therapy can represent healing; on FDG, a transient rise 7–10 days after starting endocrine therapy is a flare, not progression.
• Surveillance: no guideline recommends PET, bone scan or CT in asymptomatic patients after curative treatment; annual mammography and clinical review are standard.

8. Theranostics and emerging tracers

No radioligand therapy is approved for breast cancer.

• FES in practice: the SNMMI appropriate use criteria rate FES as most appropriate to assess ER function when endocrine therapy is considered at first diagnosis of metastatic disease or after progression on endocrine therapy, to assess lesions that are difficult or dangerous to biopsy, and when other tests are inconclusive. Staging of lobular and low-grade ER-positive cancer may also be appropriate. In seven patients with metastatic lobular cancer imaged with both tracers, FES showed 254 lesions and FDG 111, and FES found more metastases in five of seven.
• Molecular breast imaging: in 1,585 women with dense breasts, adding sestamibi imaging (300 MBq, effective dose 2.4 mSv) to mammography raised cancer detection from 3.2 to 12.0 per 1,000, at the cost of more recalls (11.0% to 17.6%) and biopsies (1.3% to 4.2%). There are no outcome or randomised data.
• HER2 imaging: HER2-targeted PET can show HER2-positive metastases in patients with HER2-negative primaries and may help select patients for HER2-directed drugs, a question sharpened by treatments for HER2-low disease. It remains a research tool.

9. Structured report example

10. Take-home points

1. Use clinical anatomic stage (AJCC 8th): FDG PET/CT from stage IIB (including T3N0) through III and inflammatory disease, instead of CT plus bone scan; not in stage I.
2. PETABC doubled detection of stage IV disease in locally advanced cancer; biopsy a solitary PET-only lesion before changing treatment intent.
3. Know the N categories: internal mammary and ipsilateral supraclavicular nodes are regional (N2b–N3c); contralateral nodes are M1.
4. Lobular and low-grade ER-positive cancers are often FDG-poor: read the CT and consider FES.
5. FES is blocked by tamoxifen (up to 8 weeks) and fulvestrant (up to 28 weeks), not by aromatase inhibitors; liver assessment is poor.
6. Lymphoscintigraphy: superficial injection for the axilla, deep injection for internal mammary nodes; SPECT/CT for unusual drainage. PET never replaces SLNB, and SLNB itself may now be omitted in selected low-risk patients.
7. Report response with PERCIST or EORTC criteria, and expect flare early in endocrine therapy and in healing bone.

Test yourself

5 quick questions. Pick an answer to see the explanation.

References

1. Vaz SC, Woll JPP, Cardoso F, et al. Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). Eur J Nucl Med Mol Imaging. 2024;51(9):2706-32.
2. Groheux D, Vaz SC, Poortmans P, et al. Role of [18F]FDG PET/CT in patients with invasive breast carcinoma of no special type: literature review and comparison between guidelines. Breast. 2024;78:103806.
3. Giuliano AE, Connolly JL, Edge SB, et al. Breast cancer: major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290-303.
4. Dayes IS, Metser U, Hodgson N, et al. Impact of 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography versus conventional staging in patients with locally advanced breast cancer. J Clin Oncol. 2023;41(23):3909-16.
5. Han S, Choi JY. Impact of 18F-FDG PET, PET/CT, and PET/MRI on staging and management as an initial staging modality in breast cancer: a systematic review and meta-analysis. Clin Nucl Med. 2021;46(4):271-82.
6. Hildebrandt MG, Gerke O, Baun C, et al. [18F]Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in suspected recurrent breast cancer: a prospective comparative study of dual-time-point FDG-PET/CT, contrast-enhanced CT, and bone scintigraphy. J Clin Oncol. 2016;34(16):1889-97.
7. Coudert B, Pierga JY, Mouret-Reynier MA, et al. Use of [18F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [18F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial. Lancet Oncol. 2014;15(13):1493-502.
8. Pérez-García JM, Cortés J, Ruiz-Borrego M, et al. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Lancet. 2024;403(10437):1649-59.
9. Ulaner GA, Mankoff DA, Clark AS, et al. Summary: appropriate use criteria for estrogen receptor-targeted PET imaging with 16α-18F-fluoro-17β-fluoroestradiol. J Nucl Med. 2023;64(3):351-4.
10. Mankoff D, Balogová S, Dunnwald L, et al. Summary: SNMMI procedure standard/EANM practice guideline for estrogen receptor imaging of patients with breast cancer using 16α-[18F]fluoro-17β-estradiol PET. J Nucl Med. 2024;65(2):221-3.
11. Cerianna (fluoroestradiol F 18) injection, for intravenous use. Prescribing information (initial US approval 2020; revised 05/2020). US Food and Drug Administration, application 212155.
12. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of 18F-FES and 18F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62(3):326-31.
13. Linden HM, Stekhova SA, Link JM, et al. Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer. J Clin Oncol. 2006;24(18):2793-9.
14. Giammarile F, Alazraki N, Aarsvold JN, et al. The EANM and SNMMI practice guideline for lymphoscintigraphy and sentinel node localization in breast cancer. Eur J Nucl Med Mol Imaging. 2013;40(12):1932-47.
15. Giuliano AE, Ballman KV, McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA. 2017;318(10):918-26.
16. Bartels SAL, Donker M, Poncet C, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer: 10-year results of the randomized controlled EORTC 10981-22023 AMAROS trial. J Clin Oncol. 2023;41(12):2159-65.
17. Gentilini OD, Botteri E, Sangalli C, et al. 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. JAMA Oncol. 2023;9(11):1557-64.
18. Reimer T, Stachs A, Veselinovic K, et al. Axillary surgery in breast cancer: primary results of the INSEMA trial. N Engl J Med. 2025;392(11):1051-64.
19. Park KU, Somerfield MR, Anne N, et al. Sentinel lymph node biopsy in early-stage breast cancer: ASCO guideline update. J Clin Oncol. 2025;43(14):1720-41.
20. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455-61.
21. Caudle AS, Yang WT, Krishnamurthy S, et al. Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary dissection. J Clin Oncol. 2016;34(10):1072-8.
22. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S-50S.
23. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer. 1999;35(13):1773-82.
24. Van den Wyngaert T, Strobel K, Kampen WU, et al. The EANM practice guidelines for bone scintigraphy. Eur J Nucl Med Mol Imaging. 2016;43(9):1723-38.
25. Rhodes DJ, Hruska CB, Conners AL, et al. Molecular breast imaging at reduced radiation dose for supplemental screening in mammographically dense breasts. AJR Am J Roentgenol. 2015;204(2):241-51.