1. Massimo Cristofanilli, MD, FACP
Massimo Cristofanilli, Knight of the Order of the Star of Italian Solidarity (born March 11, 1960) is an
Italian oncologist, internationally known for his contributions on the detection of micrometastatic
disease in breast cancer and the research and treatment of inflammatory breast cancer (IBC), the most
aggressive and deadly form of breast cancer. He currently serves as the Deputy Director of Translational
Research and Director of the Jefferson Breast Cancer Center at the Sidney Kimmel Cancer Center,
Thomas Jefferson University [1]
Contents
1 Early life and education
2 Early Career
3 Transformative Research
4 Tackle the impossible: IBC
5. Shaping the future: A bloody revolution
6 References

2. 1. Early life and education
A native of Nettuno (Italy), Cristofanilli obtained high-school graduation from the Scientific Liceum
“Innocenzo XII” in Anzio and subsequently his degree in Medicine and Surgery from the University of
Rome “La Sapienza”in (1986). He completed 2 years of laboratory training with Professor Luigi
Mingazzini (Department of Experimental Pathology) preparing his final gradation thesis “Mesenteric
fibromatosis in the Gardner’s syndrome”. During the same period he attended the Medical Oncology
ward in the Department of Experimental Medicine under the direction of Professor Alberto Pellegrini.
That experience convinced him to dedicate his professional activity to the study and treatment of breast
cancer. He was a Clinical Research Fellow in Oncology in the same department focusing his research in
clinical trial design and assuming increasing responsibilities in patients’ care, research and education of
trainees and medical students. In 1988, because his hard work, productivity and dedication he was
selected by Professor Pellegrini to join his group practice at the Villa Margherita Hospital in Rome.
Following completion of his Medical Oncology training he pursued additional training in Clinical
Pathology understanding the importance of molecular diagnostics in the future management of cancer
patients. Dr. Cristofanilli frenetic clinical and research activity during those years brought him close to
the established Italian oncology leaders including Professor Gianni Bonadonna and his team. He quickly
understood that his strong research interest in translational research in breast cancer could have been
only accomplished by an extended training experience in the US. In 1993 he moved to New York for
medical residency training at the Cabrini Medical Center (NY Medical College). He served as Chief
Medical Resident gaining additional experience as educator and administrator. Under his leadership, for
the first time the medical residency program was recognized for both excellence in patients care and
clinical research interest. In 1996 he was accepted for a Medical Oncology fellowship at the University of
Texas, M D Anderson Cancer Center (Director, Richard Pazdur, MD) and moved to Houston.
2. Early career
Dr. Cristofanilli completed two years of Medical Oncology Fellowship and distinguished himself among
the most scientifically productive trainee. He elected to spend clinical rotations with Drs. Gabriel
Hortobagyi and Aman Buzdar learning the importance of rigorous approach to breast cancer clinical
research and the exemplary multidisciplinary care at the Nellie B. Connally Breast Center. During those
years he was exposed to a large number of locally advanced and inflammatory breast cancers (LABC,
IBC) and soon became responsible for the clinical trials devoted to those patients. He analyzed data
from previous IBC trials performed at the Institution, developed and led his first prospective study in IBC
testing neoadjuvant weekly paclitaxel and started a number of retrospective biomarkers analysis
presented at National and International meetings and subsequently published in peer-review journals
[2-4]. This initial experience convinced him of the need of a more comprehensive and focused approach
for IBC as a unique and rare clinical and biological entity. This disease will later become one of his major
research focuses. He successfully competed for his first Susan G Komen Grant dedicated to the
evaluation of breast MRI in comparison to clinical exam and breast sonogram for the assessment of
clinical response to neoadjuvant therapy in patients with LABC. Furthermore, he spent last year of his
training in the laboratory of Dr. Mien-Chi Hung developing an approach to cancer cells sorting and single

3. cell molecular analysis with the intention to understand the role of micrometastatic disease in breast
cancer patients.
3. Transformative Research
In 1998 Dr. Cristofanilli joined the Department of Breast Medical Oncology led by Dr. Gabriel Hortogagyi
as an Assistant Professor. His first objective was to pursue an innovative concept to the detection of
micrometastatic disease in advanced breast cancer. He had just published a paper demonstrating that
dielectrophoresis can distinguish cancer cells from normal breast epithelium and other mononuclear
cells. Moreover, individual breast cancer cells could be further discriminated for the level of HER-2
protein expression [5]. He reasoned that the use of a sensitive enrichment method with the ability to
identify cancer cells in the peripheral blood of cancer patients could provide tremendous amount of
prognostic and predictive information. Moreover, there will be the theoretical potential to monitor
advanced and early disease by using a simple blood drawn. He presented his idea to a small
biotechnology companies, Immunicon (Drs. Terstappen and Doyle) and subsequently signed research
agreement and initiated and led a prospective study for the longitudinal study of circulating tumor cells
(CTCs) in metastatic breast cancer (MBC). The preliminary data demonstrating the prognostic value of
CTCs were presented as late-breaking abstract at the Annual meeting of the American Association of
Cancer Research (AACR) in 2003 in Washington. The final confirmatory analysis of the study was
published in 2004 in the New England Journal of Medicine [6]. This initial original paper was followed by
a series of subsequent analysis confirming the prognostic value of CTCs irrespective of disease subtype,
site of recurrence and type of therapy. In consideration of the results of this study the CellSearch® was
approved by the Food Drug Administration (FDA) for use in patients with MBC and the technology was
recognized with the Priex Gallen 2009 for technological innovation. A number of other investigators
subsequently confirmed the validity of these observations including a recent large pooled analysis of
almost 2000 patients with MBC [7,8]. Similar prognostic value has been recognized in primary breast
cancer and the detection of CTCs is now incorporated in the American Joint Committee on Cancer
Staging, 7th
edition [9]. The most important biological concept is that CTCs constitute seeds for
subsequent growth of additional tumors (metastasis) in vital distant organs, triggering a mechanism that
is responsible for the vast majority of cancer-related deaths, therefore the detection, monitoring and
molecular analysis of CTCs could inform not only about the generic risk of death but also the chance to
developing new metastasis providing opportunity for new treatment models [10]. The revolutionary
concept of “liquid phase” of solid tumors has stimulated research and investments in this diagnostic
field currently more focused on the molecular analysis of those cells for therapeutic targeting. Dr.
Cristofanilli’s more recent work is expanding the use of blood-based diagnostics to include circulating
tumor DNA (ctDNA) and circulating immune cells [11].
4. Tackle the impossible: IBC
In 2006 as faculty at the MDACC Dr. Cristofanilli started the first multidisciplinary Clinic and Research
program that focused mainly on IBC [12]. This was an example of team science applied to the research,
evaluation and treatment of this aggressive form of breast cancer. The team included epidemiologists,
scientists, diagnostic radiologists, physics, medical and surgical oncologists, radiation oncologists and

4. pathologists [13]. This tremendous effort translated in the immediate increase in the number of cases
referred to the Center with the possibility to establish a biobank and expand epidemiological and clinical
studies otherwise previously impossible. The clinic was dedicated to Morgan Welch, a young patient
with IBC diagnosed just a month after her marriage that died 18 months after diagnosis and this still
represent the only Clinical Program not named after a major donor. Drs. Cristofanilli and Robertson led a
Promise grant from American Airlines and the Susan Komen Foundation ($7.5M) resulting in a number
of discoveries and the development of IBC focused trials [14-18]. There was an incredible involvement of
breast cancer advocates that contacted elected officials demanding public attention to the needs of IBC
patients resulting in two major riders supporting the new research center. The New Mexico legislature
approved $3.2M to fund IBC research in collaborative efforts between the UNM and MDACC. The Texas
legislature provided $8M over four years for the same purpose at the MDACC. Understanding the need
for collaboration and education, Dr. Cristofanilli established the IBC International Conference of which
the first was held in Houston in 2008 and was attended by more than 200 physicians, scientists and
advocates. The conference has continued since and has been alternating between the US and Europe
and lend into the creation of an International IBC Consortium. Dr. Cristofanilli is also the co-founder of
the IBC Foundation, an advocacy organization dedicated to raise awareness of the disease through
increased education [19].
5. Drug development in Breast Cancer: Vision and Innovation
Dr. Cristofanilli’ s contribution in drug development has followed a clear path of innovation. He
performed the first and only gene replacement therapy for women with LABC consisting in the
intratumoral injection of adenoviral-p53 (AdMV-p53) associated with docetaxel and doxorubicin as
neoadjuvant systemic chemotherapy (20). AdCMV-p53 (ADVEXIN; Introgen Therapeutics Inc., Houston,
TX) is constituted of a nonreplicating adenoviral vector (Ad5) that contains the wt p53 transgene in an
appropriate expression cassette demonstrating promising preclinical activity combined with docetaxel
(Taxotere®). This trial enrolled 12 patients with HER-2 negative inoperable LABC and showed the safety,
efficacy (all patients achieved PR) and interesting immunomodulatory effects to such approach and
indicated biological effect of p53 gene replacement in cancer cells. I am among the recognized group of
experts defining standards and future directions for the use of neoadjuvant systemic therapy (20).
Another area of increasing research interest is represented by endocrine resistance in hormone-
receptor positive (HR+), postmenopausal breast cancer. Among the various mechanisms identified, this
study explored the bidirectional cross-talk between ER and receptor tyrosine kinase signaling. As
evidenced by the early observations, there seems to be a reciprocal expression of ER and members of
the EGFR (HER) family such as EGFR and HER-2. I conducted a prospective, multicenter Phase II,
randomized trial to compare anastrozole combined with gefitinib (Iressa®) or placebo in
postmenopausal women with hormone receptor-positive metastatic breast cancer. The study enrolled
enrolled only 50 patients but demonstrated the superiority in PFS of the combined therapy particularly
in women never previously exposed to any endocrine therapy (21). The data generated from this study
provided the rationale for a prospective randomized study of anastrozole +/- AZD8931 (inhibitor of
ErbB1, ErbB2 and ErbB3) in postmenopausal women with endocrine therapy naive breast cancer (MINT)
(http://clinicaltrials.gov/show/NCT01151215).

5. Moreover, as a recognized expert in the research and management of IBC, Dr. Cristofanilli played an
important role in the clinical development of Lapatinib in HER-2 overexpressing/amplified IBC [22]
6. Precision medicine in Oncology: Challenges and opportunities
Dr. Cristofanilli was among the first breast medical oncologist to understand the importance to use next-
generation sequencing (NGS) and subsequently other diagnostic technologies in the management of
patients with MBC. After initial established collaboration with the most advanced diagnostic entity,
Foundation Medicine, he performed initial studies demonstrating the clinical utility of NGS [23,24] and
was among the first to recognize ESR1 mutations associated with endocrine resistance [25].
Subsequently, he collaborated with Lance Liotta and Chip Petricoin in testing reverse-phase proteoin
array (RPPA). He described the overexpression of the Anaplastic Lymphoma Kinase (ALK) in IBC
proposing this new therapeutic target [26]. Furthermore, he contributed to the launch of TheraLink™ for
the prediction of clinical benefit and response to endocrine therapy or HER-2 targeted treatment in
advanced disease. Most recently he designed the first study comparting the additive value of NGS and
RPPA in ER+ MBC. He is also the PI of a prospective clinical study evaluating the clinical utility of RPPA.
His expertise expanded to expression profiling platforms/test in primary breast cancer. He is among the
few clinicians with collaborations and funded research with several diagnostic companies in this space
[27,28]
7. Shaping the future: A bloody revolution
Precision medicine has already started transforming our approach to predicting risk for disease,
response and toxicity of treatments. In oncology the use of advanced molecular diagnostics is
revolutionizing risk stratification, treatment selection and outcome prediction in a much more dramatic
way compared to other diseases or medical conditions. There are still practical limitations to the
universal application of tissue based analysis including quality and processing of specimens, potential to
perform multiple tests using different platforms on same specimens, possibility of longitudinal
molecular monitoring and the costs of testing. The development of blood-based testing offers the
advantage of providing “real-time” assessment of disease molecular status with the chance of a dynamic
approach to treatment selection and monitoring [29]. The preliminary results indicate that over time
patients become resistant to standard and targeted therapies acquiring new molecular abnormalities
requiring early change in treatment [30]. This “molecularly adaptive” solution can be used to introduce
novel therapies before the irreversible status of progression and have a much more significant impact
on cancer survival. Moreover, Cristofanilli recently demonstrated that the blood can be used to identify
components of the innate immunity, e.g. Cancer Associate Macrophage-Like Cells (CAMLs) that can be
used to further define risk of progression, detect early disease and possibly monitor the effects of
immune modulators [ 11]

6. 8. References
1. http://hospitals.jefferson.edu/find-a-doctor/c/cristofanilli-massimo/
2. Cristofanilli M, Buzdar AU, Sneige N, Smith T, Wasaff B, Ibrahim N, Booser D, Rivera E, Murray JL,
Valero V, Ueno N, Singletary ES, Hunt K, Strom E, McNeese M, Stelling C, Hortobagyi GN.
Paclitaxel in the multimodality treatment for inflammatory breast carcinoma. Cancer. 2001 Oct
1;92(7):1775-82.
3. Gonzalez-Angulo AM, Sneige N, Buzdar AU, Valero V, Kau SW, Broglio K, Yamamura Y,
Hortobagyi GN, Cristofanilli M. p53 expression as a prognostic marker in inflammatory breast
cancer. Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6215-21.
4. Resetkova E, Gonzalez-Angulo AM, Sneige N, Mcdonnell TJ, Buzdar AU, Kau SW, Yamamura Y,
Reuben JM, Hortobagyi GN, Cristofanilli M. Prognostic value of P53, MDM-2, and MUC-1 for
patients with inflammatory breast carcinoma. Cancer. 2004 Sep 1;101(5):913-7.
5. Cristofanilli M, De Gasperis G, Zhang L, Hung MC, Gascoyne PR, Hortobagyi GN. Automated
electrorotation to reveal dielectric variations related to HER-2/neu overexpression in MCF-7
sublines. Clin Cancer Res. 2002 Feb;8(2):615-9.
6. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard
WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in
metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91.
7. Bidard FC, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with
metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014
Apr;15(4):406-14. doi: 10.1016/S1470-2045(14)70069-5.
8. Cristofanilli M. Circulating tumour cells: telling the truth about metastasis. Lancet Oncol. 2014
Apr;15(4):365-6. doi: 10.1016/S1470-2045(14)70091-9.
9. Rack B, Schindlbeck C, Jückstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R,
Tesch H, Fasching PA, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann MW, Friese K, Pantel
K, Janni W; SUCCESS Study Group. Circulating tumor cells predict survival in early average-to-
high risk breast cancer patients. J Natl Cancer Inst. 2014 May 15;106(5). pii: dju066. doi:
10.1093/jnci/dju066.
10. Giuliano M, Giordano A, Jackson S, De Giorgi U, Mego M, Cohen EN, Gao H, Anfossi S, Handy BC,
Ueno NT, Alvarez RH, De Placido S, Valero V, Hortobagyi GN, Reuben JM, Cristofanilli M.
Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with

7. limited metastatic dissemination. Breast Cancer Res. 2014 Sep 16;16(5):440. doi:
10.1186/s13058-014-0440-8.
11. Adams DL, Martin SS, Alpaugh RK, Charpentier M, Tsai S, Bergan RC, Ogden IM, Catalona W,
Chumsri S, Tang CM, Cristofanilli M. Circulating giant macrophages as a potential biomarker of
solid tumors. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3514-9. doi:
10.1073/pnas.1320198111.
12. http://www.newswise.com/articles/m-d-anderson-establishes-clinic-research-program-for-
inflammatory-breast-cancer
13. Robertson FM, Bondy M, Yang W, Yamauchi H, Wiggins S, Kamrudin S, Krishnamurthy S, Le-
Petross H, Bidaut L, Player AN, Barsky SH, Woodward WA, Buchholz T, Lucci A, Ueno NT,
Cristofanilli M. Inflammatory breast cancer: the disease, the biology, the treatment. CA Cancer J
Clin. 2010 Nov-Dec;60(6):351-75. doi: 10.3322/caac.20082.
14. http://www.aaevents.com/index.php?page=the-cause-ibc
15. Robertson FM, Chu K, Boley KM, Ye Z, Liu H, Wright MC, Moraes R, Zhang X, Green TL, Barsky
SH, Heise C, Cristofanilli M. The class I HDAC inhibitor Romidepsin targets inflammatory breast
cancer tumor emboli and synergizes with paclitaxel to inhibit metastasis. J Exp Ther Oncol.
2013;10(3):219-33.
16. Robertson FM, Petricoin Iii EF, Van Laere SJ, Bertucci F, Chu K, Fernandez SV, Mu Z, Alpaugh K,
Pei J, Circo R, Wulfkuhle J, Ye Z, Boley KM, Liu H, Moraes R, Zhang X, Demaria R, Barsky SH, Sun
G, Cristofanilli M. Springerplus. 2013 Oct 1;2:497. doi: 10.1186/2193-1801-2-497. eCollection
2013. Fernandez SV,
17. Robertson FM, Pei J, Aburto-Chumpitaz L, Mu Z, Chu K, Alpaugh RK, Huang Y, Cao Y, Ye Z, Cai KQ,
Boley KM, Klein-Szanto AJ, Devarajan K, Addya S, Cristofanilli M. Inflammatory breast cancer
(IBC): clues for targeted therapies. Breast Cancer Res Treat. 2013 Jul;140(1):23-33. doi:
10.1007/s10549-013-2600-4.
18. Dawood S, Merajver SD, Viens P, Vermeulen PB, Swain SM, Buchholz TA, Dirix LY, Levine PH,
Lucci A, Krishnamurthy S, Robertson FM, Woodward WA, Yang WT, Ueno NT, Cristofanilli M.
International expert panel on inflammatory breast cancer: consensus statement for
standardized diagnosis and treatment. Ann Oncol. 2011 Mar;22(3):515-23. doi:
10.1093/annonc/mdq345.
19. http://www.eraseibc.com/
20. Cristofanilli M, Krishnamurthy S, Guerra L, Broglio K, Arun B, Booser DJ, Menander K, Van Wart
Hood J, Valero V, Hortobagyi GN. A nonreplicating adenoviral vector that contains the wild-type
p53 transgene combined with chemotherapy for primary breast cancer: Safety, efficacy, and
biologic activity of a novel gene-therapy approach. Cancer 107(5):935-44, 2006.

8. 21. Cristofanilli M, Valero V, Mangalik A, Royce M, Rabinowitz I, Arena FP, Kroener JF, Curcio E,
Watkins C, Bacus S, Cora EM, Anderson E, Magill P. Phase II, randomized trial to compare
anastrozole combined with gefitinib or placebo in postmenopausal women with hormone
receptor-positive metastatic breast cancer. Clin Cancer Res 16(6):1904-1914, 2010.
22. Boussen H, Cristofanilli M, Zaks T, DeSilvio M, Salazar V, Spector N. Phase II study to evaluate
the efficacy and safety of neoadjuvant lapatinib in combination with paclitaxel in patients with
newly diagnosed inflammatory breast cancer. J Clin Oncol 28(20):3248-3255, 2010.
23. Ali SM, Alpaugh RK, Downing SR, Stephens PJ, Yu JQ, Wu H, Buell JK, Miller VA, Lipson D, Palmer
GA, Ross JS, Cristofanilli M. Response of an ERBB2-mutated inflammatory breast carcinoma to
human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol. 2014 Sep
1;32(25):e88-91. doi: 10.1200/JCO.2013.49.0599.
24. Ali, SM, Alpaugh R.K., Buell JK, Stephens PJ, Qin J M, Wu H., Hiemstra CN, Miller VA, Lipson D,
Palmer GA, Ross JS, Cristofanilli M. Antitumor response of an ERBB2 Amplified inflammatory
breast carcinoma with EGFR mutation to the EGFR-TIKI Erlotinib. Clinical Breast Cancer Oct 2013.
25. Jeselsohn R; Yelensky R., Guchwalter G., Frampton G.M., Meric-Bernstam F., Gonzalez-Angulo
A.M., Ferrer-Lozano J., Perez-Fidalgo A., Cristofanilli M., et al. Emergence of constitutively active
estrogen receptor-a mutations in pretreated advanced estrogen receptor positive breast cancer.
Clinical Cancer Research 12.13.2013. online
26. Robertson FM, Petricoin EF, Van Laere SJ Bertucci F., Chu K, Fernandez SV, Mu Z., Alpaugh K, Pei
J, Circo R.., Wulfkuhle J, Ye Z., Boley KM., Liu H., Moraes R., Zhang X, DeMaria R., Barsky S, Sun
G., Cristofanilli M. Presence of anaplastic lymphoma kinase in inflammatory breast cancer.
SpringerPlus 2013, 2:497.
27. http://hospitals.jefferson.edu/news/2014/10/jefferson-offers-new-fda-approved-prognostic-
genomic-test-for-breast-cancer-patients/
28. Stork-Slods L., Yao K., Turk M, Kaul K., Weaver J., Cristofanilli M., et al. Molecular subtyping
using MammPrint and Blue Print as an outcome predictor in 180 U.S. breast cancer (BC)
patients. 2012 ASCO annual meeting. J Clin Oncol 30, 2012(suppl; abstr 577).
29. http://www.ascopost.com/issues/september-15,-2014/potential-of-liquid-biopsies-in-detecting-
cancer-and-establishing-prognosis.aspx
30. Austin LK., Fortina P., Sebisanovic D., Stew L., Zapanta A., Talasaz AA., Cristofanilli M. Circulating
tumor DNA (ctDNA) as a molecular monitoring tool in metastatic breast cancer (MBC). 2014
ASCO annual meeting. . J Clin Oncol 31, 2013(suppl;abstract 11093).