PET/CT in Breast Cancer

Transcription

1 PET/CT in Breast Cancer Hossein Jadvar, MD, PhD, MPH, MBA Associate Professor of Radiology and Vice Chair of Research Associate Professor of Biomedical Engineering President, Society of Nuclear Medicine and Molecular Imaging

2 Outline Breast Cancer Demographics Conventional Diagnosis Brief overview of PET/CT and FDG Clinical Applications of FDG PET/CT in BrCa Clinical Impact on Management Summary Jadvar

3 Breast Cancer Demographics 2015 Prevalence (2012): 2,975,314 Incidence: 231,840 (14.0% of all new cancer cases) Estimated Deaths: 40,290 (6.8% of all cancer deaths) Lifetime Cancer Risk: 12.3% (1 of 8); Median age: 61 y %Cases by Stage: 61%local; 32% regional; 6% distant 5-year Survival: 89.4% 5-y survival by stage Jadvar

4 Breast Cancer Histopathologic types and Metastases Weigelt B et al. Nat Rev Cancer 2005 Jadvar

5 Breast Cancer: Diagnosis Physical examination (self breast exam) Mammography overall sensitivity: 54-81%, specificity:25-40%, PPV: 10-35% difficult to biopsy small lesions non-palpable lesion equivocal findings (ultrasonography) dense breasts, augmentation mammoplasty, treated breast MRI sensitivity: %, specificity: < 85% 99m Tc-MIBI (Breast-Specific Gamma Cameras) lesions >1.5 cm palpable: sensitivity 91-95%; non-palpable: sensitivity 65-72% specificity: ~75-90%

6 Breast Cancer: Subtypes Luminal A ER+ and/or PR+, HER2-, Ki-67 low (<14%) Luminal B (HER2-) ER+ and/or PR+, HER2-, Ki-67 high (>14%) Luminal B (HER2+) ER+ and/or PR+, any Ki-67 index HER2+, ER-, PR- Triple Negative: ER-, PR-, HER2- Inflammatory BrCA (IBC): no establsihed molecular criteria for differentiating from non-inflammatory ca; poor prognosis 12 th Intl. Breast Conf. Goldhirsch A, Ann Oncol Jadvar

7 Breast Cancer: Staging Locally advanced breast cancer T3 = Primary > 5 cm T4 = Any size with skin or chest wall invasion N2 = Fixed axillary LN Lee JH et al. J Nucl Med 2009.

8 Breast Cancer: Axillary Nodal Staging 20-30% nodal metastasis at early BrCa Predictor of recurrence and survival Five-year DFS 75% - no nodal involvement 45% - involvement of 1-3 nodes 20% - involvement of 4 nodes Surgical staging (ALND vs. ALND if SLN+) is SOC 70-80% of patients with negative nodes chronic lymphedema (8-25%), wound complications (8%), shoulder dysfunction (2%) Sentinel LN localization and biopsy

9 Hallmarks of Cancer Hanahan D, et al. Cell 2000; Cell 2011; Cancer Cell self-sufficiency in growth signals insensitivity to anti-growth signals evasion of apoptosis limitless replicative potential sustained angiogenesis tissue invasion and metastasis evasion of tumors from the immune system increased glucose metabolism (Warburg effect)

10 Tumor FDG Uptake

11 Breast Cancer Biologic Correlates of FDG Uptake in Tumor Cell type (Ductal > Lobular) and tumor volume (necrosis) Histologic grade Glut-1, Hexokinase Microvessel density; Mitotic activity index P53 mutation; upa/pai1 protein ER, PR, HER2-neu status (higher uptake with ER- and triple negative tumors) High uptake high risk of mets, poor prognosis Decline in uptake after Rx predictive of favorable response upa=urokinase-type plasminogen activator PAI1=plasminogen activator inhibitor 1 HER2/neu=ERBB2=epidermal growth factor receptor 2 (15-20% tumors; trastuzumab) Grover-Mckay, 1998; Brown, NMB 2002; Bos, JCO 2002; Weigelt, Nat Rev Cancer 2005; Osborne, JNM 2010; Jadvar, JNM 2009; Wang, AJR 2011; Morris, Cancer 2012 Jadvar

12 Breast Cancer FDG Uptake Variants FP Fibroadenoma, dysplasia; ductal ectasia, infection, inflammation (mastitis); silicon leak; fact necrosis FN Small lesions (< 1 cm); carcinoma-in-situ; lobular ca; tubular ca, mucinous ca Variable Menstrual cycle; lactation; dense breasts Jadvar

13 Normal Breast and FDG Uptake Dense Vranjesevic et al. JNM 2003 Mixed Fatty Jadvar

14 Lactating Breast Courtesy of Dr. Dominique Delbeke (Vanderbilt) Jadvar

15 Breast Cancer: FDG PET/CT Clinical applications Incidental FDG uptake Detection of Primary Tumor Staging Restaging after Therapy Monitoring Therapy Response Prognostication Jadvar

16 J Nucl Med 2009

17 Breast Cancer FDG PET/CT Jadvar

18 Breast Cancer: Subtypes and SUV Groheux D et al. EJNMMI 2011.

19 Breast Cancer: Subtypes and SUV Kitajima K et al. EJNMMI 2015.

20 Primary Infiltrating Ductal Breast Adenocarcinoma Jadvar

21 Breast Cancer FDG PET/CT: Multifocal Tumors Couretesy of Dr. Dominique Delbeke (Vanderbilt)

22 Breast Cancer: FDG PET/CT Luminal A invasive ductal CA, ER 100%, PR 50%, HER2 0, nuclear grade 1, 2 cm left breast SUVmax = 2.72 Kitajima K et al. EJNMMI 2015 Jadvar

23 Breast Cancer: FDG PET/CT HER2+ invasive ductal CA, ER 0%, PR 0%, HER2 3+, nuclear grade 2, Ki-67 50%, 3.2 cm right breast SUVmax = Kitajima K et al. EJNMMI 2015 Jadvar

24 Breast Cancer: FDG PET/CT 27 yo F with BRCA1 after bilateral mastectomy Courtesy of P. Colletti Jadvar

25 Breast Cancer: FDG PET/CT Staging PET may be useful for >T2 (> 2 cm) lesions may modify stage and change management (Bernsdorf, Ann Oncol 2012; Groheux, JNCI 2012) Detect previously unsuspected distant disease (Alberini, Cancer 2009; Carkaci, JNM 2009)

26 Breast Cancer: FDG PET/CT Staging PET- axilla does not exclude involvement (SLN mapping) Meta Analysis: pooled sensitivity 69%, pooled specificity 88% (Quan A, JCO 2005) Size: Sens. (<5mm:20%; 6-10mm:80%; >10mm:90%) PET+ often stages the axilla (needs verification) extra-axillary basin (e.g. IM) Wahl R. JNM 2003 Eubank, JCO 2001; Vernonesi, Ann Oncol 2007;Pritchard, JCO 2012 Jadvar

27 Breast Cancer: FDG PET/CT Postop scan of a pt with preop clinical stage determined by CI as stage I; underwent R breast-conserving surgery and SLNB (neg). Postop pathology revealed TN invasive ductal carcinoma; restaged as IV and systemic Rx started Gunalp, Exp Ther Med 2012

28 Breast Cancer FDG PET for Axillary Nodal Staging Study N Sensitivity Specificity Comments Wahl, % 80% Multi-center, mostly T1 Keleman, % 94% vs SLNB Barranger, % 100% vs SLNB Fehr, % 93% vs SLNB Kumar, % 95% Mostly SLNB FDG PET has low sensitivity compared to SLNB

29 Ann Nucl Med 2007

30 75 yo F with breast cancer: pre-operative breast MRI identifies L breast lesion; FDG PET/CT shows liver and pleural metastases Iagaru A et al. Ann Nucl Med 2007

31 43 yo F with breast cancer; post-operative FDG PET-CT shows cervical and lumbar spine metastases; breast MRI was neagtive Iagaru A et al. Ann Nucl Med 2007

32 46 yo F with R breast DCIS: post-operative MRI showed non-specific changes and FDG PET/CT demonstrated residual disease (confirmed on histopathology) Courtesy of A. Iagaru (Stanford)

33 Breast Cancer: FDG PET and MRI 40 patients with 42 lesions (23 benign, 19 CA) PET and MRI complementary poss. reduce bx 55% 17% Breast Cancer Sensitivity Specificity MRI 89% 74% PET 63% 91% Walter, Eur Radiol 2003; Courtesy D. Delbeke Jadvar

34 Breast Cancer: Integrated PET/MRI (Siemens Biograph mmr) 52 yo F with 3 invasive ductal carcinomas Kong, Hell JNM 2014 Jadvar

35 NCCN Guidelines: FDG PET/CT for Breast Cancer (v ) Early stage ( I, IIA): PET or PET/CT scanning NOT recommended Stage some IIB (locally advanced) IIIA (T3, N1, M0) or IIIB and Stage IV: CT C/A/P, bone scan, abdominal MRI or FDG PET may be considered unsuspected regional nodal disease and/or distant metastasis in locally advanced breast equivocal standard imaging results

36 Breast Cancer: Monitoring Therapy Response Chemotherapy Most studies with heterogeneous tumor phenotypes, assessment time after start of chemotherapy, response criteria, verification standard overall results similar to other cancers Prediction of CR after 1 st chemo cycle: Sens 90%, Spec 74% (Schelling M. J Clin Oncol 2000) significant decline in tumor uptake is associated with favorable response and improved patient outcome Tateishi, Radiology 2012; Martoni, Cancer 2010 Jadvar

37 Breast Cancer: Monitoring Therapy Response Hormonal Therapy Women with ER+ disease Metabolic flare ~1-2 week(s) after tamoxifen Metabolic flare favorable response Metabolic response may be correlated with outcome Mortazavi-Jehanno, EJNM 2012; Mortimer, JCO 2001 Jadvar

38 Breast Cancer: Therapy Response Assessment Lee JH et al. J Nucl Med 2009;50: Lee JH et al. J Nucl Med 2009.

39 53 y F w/ poorly differentiated ductal R BrCA treated w/ R mastectomy + chemo Pre-Rx PET: extensive metastases Post-Rx PET: no evident disease Pre-Rx Post-Rx Jadvar

40 Breast Cancer: Monitoring Therapy Response 51 yo F w/ R IBC (HER2+, Ki-67 68%), ALN+, & pulmonary infection A) Pre-chemotherpay B) Post-chemotherapy (CR) Champion L et al, JNM 2015

41 Breast Cancer: Monitoring Therapy Response 35 yo F w/ R IBC (Ki-67 30%), ALN+ A) Pre-chemotherpay B) Post-chemotherapy (PR) Champion L et al, JNM 2015

42 Breast Cancer: Therapy Response Assessment FDG SUV P <.001 Responders P = NS Non- Responders Day 0 Day 63 Wahl RW et al. J Clin Oncol 1993.

43 Breast Cancer: Therapy Response Assessment Responder Non- Responder Baseline 1st Course 2nd Course Schelling et al. J Clin Oncol 2000.

44 Breast Cancer: Metabolic Flare after Estradiol Predicts Hormonal Rx Response and Survival Dehdashti F et al. Br Ca Res Treat. 2008

45 Breast Cancer FDG PET/CT Restaging after Therapy Similar to most other cancers, PET more useful than CI for differentiation post-rx change from recurrence Highly sensitive (>90%) and specific (>85%) May change clinical anagement Not recommended routinely for clinically asymptomatic surveillance (unless high suspicion) Radan, Cancer 2006; Manohar, Nucl Med Commun 2012; Dirisamer, EJR 2010; Khatcheressian, JCO 2012; Yap, JNM 2001; Kamel, J Cancer Res Clin Oncol 2003 Jadvar

46 Breast Cancer FDG PET/CT: Unsuspected Nodal Metastasis Eubank et al JCO 2001; Courtesy of D. Delbeke

47 Breast Cancer: FDG PET/CT Osseous Metastatic Disease 89 patients with FDG PET and planar/spect MDP Overall FDG and MDP complementary but may start with FDG PET/CT first; useful for f/u therapy monitoring (Nakai, EJNM 2005; Bombardieri E. QJNM 2001) Bone lesion FDG 99mTc-MDP (radiographic) Osteoblastic 56% 100% Osteolytic 100% 70% Mixed 95% 84% none 88% 25% Jadvar

48 Breast Cancer: Meta-analysis for Bone Metastses FDG PET vs. Bone Scintigraphy Shie P et al. Clin Nucl Med 2008.

49 Breast Cancer: Bone Metastases 18F-NaF 18F-FDG 18F-FDG Blastic Marrow 18F-FDG Lytic Cook JRC, 2006; Habibian MR, et al. 2008

50 Breast Cancer: Prognosis Son SH et al. AJR 2015

51 Breast Cancer: FDG Uptake Predicts Outcome of Bone-Dominant Breast Cancer Time to Progression % Decline in FDG SUV c) Percentage SUV Change < 41% diff 41% mg/ml diff> 41% mg/ml > 41% p= Time to Skeletal-Related Event Initial SUV a) Initial Standardized Uptake Value (SUV) SUV1 5 SUV1 > 5 > 5.1 p proportion without SRE < 5.1 mg/ml mg/ml = Courtesy Specht et al. Br of Ca D. Res Delbeke Treat Courtesy of David Mankoff

52 PET in Oncology: Breast Cancer Impact 254 patients with clinical stages II and III BrCa unsuspected N3 disease (infra-, supra-clavicular, IM nodes) in 16% Change in clinical stage 30.3% (95%CI: 25-36%) unsuspected mets overall 21% 2.3% stage IIA, 10.7% stage IIB 17.5% stage IIIA, 36.5% stage IIIB, 47.1% stage IIIC Groheux, JNM 2011; J Natl Cancer Inst 2012 Jadvar

53 PET in Oncology: Breast Cancer Impact 125 women with recurrent or metastatic disease Retrospective chart review and PET comparison to CI Sensitivity 94%, Specificity 91% Extent of disease: increase by 43%; decrease by 24% Therapy plan change in 27% PET contributes significantly to defining the extent of disease and clinical management of patients with advanced breast cancer Eubank, AJR 2004 Jadvar

54 PET in Oncology: Breast Cancer Diagnostic and Therapeutic Impact (Survey) Standard questionnaires mailed to referring physicians 31% response rate Change in clinical stage 36% (28% upstage, 8% downstage) Change in intermodality management 28% Change in intramodality management 30% Major impact on staging and management (~30% of patients) Yap C et al. J Nucl Med Jadvar

55 Positron Emission Mammography (PEM) mean spatial resolution at center of FOV 2.01 mm radial, 2.04 mm tangential, 1.84 mm axial x ray x-ray γ ray γ-ray camera γ-ray γ-ray camera Compression paddles compression paddles Levine EA et al. Ann Surg Oncol 2003;10: Courtesy of Lee Adler, M.D. Tafra L et al. Am J Surg 2005;190 (4): *Berg WA et al. The Breast J. 2006;12 (4): Glass & Shah. Proc (Bayl Univ Med Cent) 2013; Raylman R, Phys Med Biol 2008

56 J Nucl Med 2012 Jadvar

57 Positron Emission Mammography (PEM) TP FP TP TN Jadvar

58 PEM-MRI Directed Breast Biopsy (PEM Flex Solo II by Naviscan PET Systems, Inc) PEM spatial resolution FHWM: 2.4 mm MacDonald L et al. J Nucl Med 2009.

59 Breast Cancer: FDG PET -- Meta Analysis Incidental Uptake 13 articles, prevalence 0.82% (95%CI: %) 60% IDC (95% CI: 53-66%) Bertagna, Jpn J Radiol 2014; Shin, J Breast Cancer 2015; Dunne, Br J Radiol 2013; Kim, Acta Radiol 2012; Kang, AJR 2011 Cancer Screening Program (Japan) 62,054 asymptomatic women 473 possible cases (0.8% prevalence) 161 breast cancer (34% cancer incidence) Sensitivity 84%, PPV 42% USA: ACR AUC for br. ca. screening insufficient evidence Mainiero, JACR 2013; Minamimoto, Clin Breast Cancer 2015 Jadvar

60 Breast Cancer: FDG PET -- Meta Analysis Primary Tumor 144 patients, Detection rate: 68% (pt1) vs. 92% (pt2), FN rate: 24% (ductal CA) vs. 65% (lobular CA) - Avril, JCO articles (23,255 cancers), higher FDG uptake with HER2 overexpression -- Elias, Cancer Epidemio,l Biomarkers Prev 2014 PEM 8 articles (873 patients) Caldarella, Clin Breast Cancer 2014 pooled sensitivity 85% (95% CI: 83-88%) pooled specificity 79% (95% CI: 74-83%) PEM vs. WB PET/CT Kalinyak, EJNMMI pre-surgical patients; size: cm ( cm) tumor detection: 95% PEM, 87% PET/CT Jadvar

61 Breast Cancer: FDG PET -- Meta Analysis Axillary Node Status 26 studies (2591 patients) pooled sensitivity 63% (95% CI: 52-74%) pooled specificity 94% (95%CI: 91-96%) mean sensitivity 11% (<2mm), 57% (>2mm) Cooper, Eur J Surg Oncol 2011 Detection of Distant Metastases Hong, Surg Oncol articles (748 patients) pooled sensitivity 96% (95%CI: 90-98%) pooled specificity 95% (95% CI: 92-97%) Jadvar

62 Breast Cancer: FDG PET -- Meta Analysis BS vs. PET/CT Rong, Surg Oncol studies (668 patients) BS pooled sens/spec 81%, 96% PET/CT pooled sens/spec 93%, 99% BS vs. MRI vs. PET/CT Liu, Skeletal Radiol articles; per patient basis BS pooled sens/spec 87%, 88% PET/CT pooled sens/spec 83%, 95% MRI pooled sens/spec 97%, 97% MRI better on per patient-basis; PET/CT higher specificity (at cost of lower sensivity) on per-lesion-basis. Jadvar

63 Breast Cancer: FDG PET -- Meta Analysis Neoadjuvant Chemotherapy Response Cheng, Acta Radiol studies (781 patients) Pooled sensitivity 84% pooled specificity 71% Mohanga, Clin Breast Cancer articles (745 patients) pooled sensitivity 81% pooled specificity 79% Jadvar

64 FDG PET/CT in Breast Cancer Summary Limited utility: detection of small primary tumors; in staging the axilla (micromets); blastic bone mets [PROBLEM-SOLVING TOOL] SUV: ductal CA > lobular CA > dense breast higher tumor SUV associated with poorer prognosis no need for SLN bx in PET + axilla Good diagnostic performance for recurrent/met disease Impact on clinical management Useful in therapy monitoring; metabolic flare with hormonal Rx is predictive of response Tumor extent and uptake level are predictive of outcome Positron emission mammography-guided biopsy Jadvar

65 Acknowledgement Patrick Colletti MD (USC) Dominique Delbeke, MD, PhD (Vanderbilt) Andrei Iagaru, MD (Stanford) David Schuster, MD (Emory) USA National Institutes of Health R01-CA R21-CA R21-EB P30-CA014089