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Abstracts 2010



BREAST AND GYNECOLOGICAL CANCER REGISTRY IN EGYPT
Prof. Ibrahim Abd El-Bar
Professor of Surgical Oncology
Tanta Cancer Institute (Egypt)


Gharbia Population Based Cancer Registry (GPBCR) , is the 1st and only population based cancer registry in Egypt. It has been successfully functioning, since jan.1999, covering a population of 4.1 million (8 districts and 318 villages). Gharbia Population Based Cancer Registry, is the source of the data presented
Breast and gynaenocological malignancies together constitutes 44.9% of female cancers in Egypt, Gharbiah. Breast cancer is the most frequent cancer among Egyptian females. Over the three years 2000-2002, 1831 breast cancer cases were registered; 1810 females and 21 males with an average of 603 cases of female breast cancer per year. Breast cancer accounts for 35.7 % of all newly diagnosed female cancers (5070 cases). The crude incidence rate for females was 33.1/100,000 female population. Standardized for age using world population, the rate was 41.9/100,000. Mean age at diagnosis in females was 49.3 years ranging between 18:93 years with a median of 49 years. Compared to published worldwide rates, Egypt, Gharbiah occupies the 27th percentile rank . Rates lower than that of Egypt are reported from 50 registries allover the world. These re¬markably large geographical differences are potentially explicable based on genetics or the influence of lifestyle and environment. Urban-Rural differences in breast cancer incidence across 8 years (1999-2006) in Egypt, Gharbiah showed 3-4 times higher rates in urban, (the more developed population). This higher rates in urban could be due to exposure to unknown risk factors like xenoestrogen , a hypothesis that needs further studies. Eight years study (1999-2006) of TNM staging of breast cancer in Egypt, Gharbiah showed minimal increase in stage I, mild decrease in stage IV & marked increase in stage II, which necessiates more advocacy for awareness among females. Over the three years 2000 - 2002, 225 ovarian cancer cases were registered with an average of 75 cases per year. They represented 2.2% of all incident cancer accounting for 4.4% of all newly diagnosed female cancers. Ovarian cancer ranked fourt in females. Crude incidence rates was 4.1/100,000 female population. The ASR (world) was 5.2/100,000 female population .Mean age at diagnosis was 47.2 years ranging between 8-90 with a median of 49 years. . The risk of epithelial tumors increases with age occurring predominantly in pre and post menopausal women. The highest rate was observed in the age group 65-69 years. Incidence of uterine cancer in urban is striking & almost 6 times higher than rural supporting the theory of xenoestrogen exposure.Cancer of cervix is relatively uncommon in Egypt, ranking third in gynaecological cancer (after ovary & uterus) & 15th among all females cancers.

GENETIC COUNSELING IN BREAST AND GYNECOLOGICAL MALIGNANCIES
Prof. Banu Arun
Professor of Breast Medical Oncology
Co-director Clinical Cancer Genetics
University of Texas, MD Anderson Cancer Center, (USA)

10-15% of breast cancers are due to mutations in hereditary genes. The majority of these mutations are in the BRCA1 or BRCA 2 gene. Since genetic testing has become clinically available a large number of women with a significant risk for carrying this mutation have been tested. The results of BRCA testing might help high risk individuals to manage their risk; for example consider increased surveillance or preventive surgeries. Positive results can also be used to perform predictive testing for family members. BRCA genetics testing could also have implications on an affected patient. A breast cancer patient with a BRCA mutation for example might opt to have bilateral mastectomy performed. The availability of new targeted drugs, such as PARP inhibitors, can also be considered in clinical trials settings for these patients. This session will discuss hereditary breast cancer risk assessment, genetic testing procedures, risk management and other related issued to genetic testing.

FERTILITY PRESERVATION IN BREAST CANCER PATIENTS
Prof. Amit Bahl
Professor of Clinical Oncology
University Hospitals Bristol (UK)

The diagnosis and treatment of cancer often poses a threat to fertility. Methods of fertility preservation are evolving quickly, yet little has been published in the medical oncology literature regarding this topic. Studies suggest that the ability to have biological children is of great importance to many people diagnosed with cancer, and that infertility resulting from cancer treatment may be associated with psychosocial distress. Some evidence suggests that patients may choose a less efficacious treatment strategy in order to avoid greater toxicity and long-term complications.Many patients are now diagnosed with breast cancer at a younger age and some of these young women are planning to have children or contemplating the possibility. Any oncologist seeing reproductive-aged patients for consideration of cancer therapy should be addressing potential treatment-related infertility with them. Fertility preservation options in females depend on the patient’s age, type of treatment, diagnosis, whether she has a partner, the time available and the potential that cancer has metastasized to her ovaries.Current available options include embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation and ovarian suppression. Embryo cryopreservation is considered an established fertility preservation method as it has routinely been used for storing surplus embryos after in vitro fertilization for infertility treatment. Cryopreservation of unfertilized oocytes is another option for fertility preservation, particularly in patients for whom a partner is unavailable, or who have religious or ethical objections to embryo freezing. Ovarian tissue cryopreservation is an investigational method of fertility preservation but has the advantage of requiring neither a sperm donor nor ovarian stimulation.Ovarian suppression through gonadotropin-releasing hormone (GnRH) agonist or antagonist treatment during chemotherapy is controversial as a method to maintain fertility. At this time, since there is insufficient evidence regarding the safety and effectiveness of GnRH analogs and other means of ovarian suppression on female fertility preservation, women interested in ovarian suppression for this purpose are encouraged to participate in clinical trials. Because GnRH analogues are readily available, this strategy has been used widely without clear evidence for efficacy or full understanding of the potential risks and benefits, especially in women with hormone sensitive tumours.Review of the fertility preservation literature reveals a paucity of large and/or randomized studies. Most data come from cohort studies, case series, small nonrandomized clinical trials or case reports. Fertility preservation methods are still applied relatively infrequently in the cancer population, limiting greater knowledge about success and effects of different potential interventions.

THE USE OF GENOMICS IN DISSECTING NEW ENTITIES IN HUMAN CANCERS
Prof. Thomas Tursz
Director of Institute Gustave Roussy (France)

Targeted agents are expected to be effective in patients who present genetic alteration leading to cell transformation or drug resistance. As an illustration, Her2 inhibitors are effective in patients exhibiting ERBB2 amplification. In the same setting, it has been shown that activation of the mTOR pathway through PTEN loss or PI3KCA mutations mediates resistance to trastuzumab, and that mTOR inhibition could reverse resistance.

High throughput technologies allow us to identify which gene is dysregulated in a single specimen. As an illustration, CGH array is evaluating the gene copy number at the whole genome level. Applied to patients, these technologies could identify which pathway is abnormal and therefore which protein should be targeted. At Institut Gustave Roussy, we have developed a strategy for profiling breast cancer from patients who present refractory disease. These profilings allow us to drive patients into early phase trials according to molecular alterations. The presentation will report the impact of genetic dissection of cancers in daily practice based on ongoing programs.

TARGETING ANGIOGENESIS: BEVACIZUMAB AND BEYOND
Prof. David Khayat
Ex-Head of NCI, (France)

Laboratory and clinical evidence supports the central role of angiogenesis in progression of breast cancer. Molecular targeted therapies have been developed in this setting leading to the approval of bevacizumab in association with paclitaxel as first line therapy for metastatic breast cancer. The story just begins since many questions are still pending. Is there a place for anti-angiogenic therapies for non-metastatic cancer or for more advanced metastatic disease? Should other chemotherapy agents be considered in association with bevacizumab? The place of antiangiogenic tyrosine kinase inhibitors has also to be discussed and associations between molecular targeted therapies may represent the next major step in the future. These treatments are costly and have toxic side effects. The identification of predictive factors of response represents therefore an urgent need in order to propose the right treatment to the right patient.

Multiple answer questions concerning this lecture (correct answer in bold)

1. Bevacizumab is approved in breast cancer

• as neoadjuvant therapy for inflammatory breast cancer
• as adjuvant therapy (one year of treatment)
• as first line therapy for metastatic breast cancer in association with paclitaxel
• in metastatic setting, regardless the line but only in association with paclitaxel
• bevacizumab is not approved yet


2. What is the best predictive factor of response for antiangiogenic therapies?
• pretherapeutic levels of VEGF-A in the serum
• decrease of VEGF-1 levels under therapy
• pretherapeutic vascular density in the tumor
• level of hypertension under therapy
• none of this factors can be considered as validated


BREAST RECONSTRUCTION AFTER BREAST CONSERVING SURGERY
Prof. Omar Zakria
Professor of Surgical oncology, NCI, (Egypt)

Modern breast surgery appeared at the beginning of the 20th century, when Halsted described radical mastectomy for treatment of breast cancer.Throughout the first 65 years of the 20th century, radical mastectomy was the treatment of choice for breast cancer.Then, breast surgery evolved dramatically in the 1970s, and became more and more less radical and less aggressive. Nowadays, breast conserving surgery (BCS) is becoming the optimal surgery for early breast iaacancer. The importance of optimal local excision has been studied by several researchers and they all concluded that optimal resection with wide safety margins is as equal as mastectomy (1-2) However, it is sometimes difficult to achieve good cosmetic results, particularly in patients with large, ill-defined, or poorly situated tumors, for which clear margins are difficult to achieve without leaving deformed and asymmetrical breasts (3) There is a clash of interest between resecting large breast volume to achieve wide negative margins and cosmetic outcome following resection. This dilemma was solved by Audretsch et al (4) who proposed oncoplastic surgery, which is integrating plastic surgical techniques in breast conserving surgery, hence allowing wide excision and preventing breast deformities by immediate reconstruction of large defects. There are two fundamentally different types of approach to breast-conserving reconstruction; The first is volume displacement where the resection defect is reconstructed from pedicles that are raised within the breast tissue itself. The second is volume replacement; the defect caused by the tumor resection is reconstructed, usually with autologous tissue from outside the breast, to be sutured in the defect. (5). Conclusion:Oncoplastic surgery adds to the oncological safety of BCS. A much larger volume of breast tissue can be excised, wider margins can be achieved and improving cosmetic results. (6)

References:
1. Veronesi U, Cascinelli N, Mariani L et al.: Twenty-Year Follow-up of a Randomized Study Comparing Breast-Conserving Surgery with Radical Mastectomy for Early Breast Cancer. N Engl J Med 347:1227, October 17, 2002: 1227-1232
2. EBCTCG Meta-Analysis, Lancet 2005, p2087
3. Clough KB, Lewis JS, Couturand B, et al. Oncoplastic techniques allow extensive resections for breast-conserving therapy of breast carcinomas. Ann Surg 2003;237:26–34.
4. Audretsch W, Rezai M, Kolotas C, et al. Tumor-specific immediate reconstruction in breast cancer patients. Perspect Plast Surg 1998;11:71–100.
5. Dick Rainsbury, e-grand round in Cancer World; March/April 2009
6. Kaur N, Petit JY, Rietjens M et al. Comparative Study of Surgical Margins in Oncoplastic Surgery and Quadrantectomy in Breast Cancer: Ann. Surg. Oncol. Vol. 12, No. 7, 2005; 1-7


VALUE OF HEPATIC METASTATECTOMY IN BREAST CANCER
Prof. Mehra Golshan
Director of Breast Surgical Services Dana Farber Cancer Institute
Brigham and Women’s Hospital
Harvard Medical School (USA)

In general, surgery has no role in the curative treatment of metastatic breast cancer. Metastatic breast cancer is considered incurable with an average of 18-24 month survival. Certain factors such as hormone receptor negativity, Her2/neu positive disease, and short disease free interval portend to a poor prognosis. The liver is not usually a site of initial failure, less than 15% of patients fit this pattern.1 Even fewer are candidates for surgical resection due to extrahepatic disease. Eventually over half of patients with metastatic disease will have liver metastasis during their clinical course. With the advent of newer chemotherapeutic agents, endocrine therapy and targeted therapy, prolonged survival and delayed disease progression have been shown in some patients. Recently chemotherapy trials of hepatic only metastasis (EORTC 10923 and 10961) revealed median survival of 22.7 and 27 months respectively.2 Most studies have been small with a heterogeneous group of patients included in their reports, patients with and without breast cancer. Earlier experience reported dismal outcomes with very poor five and ten year survival rates. With the improvement in surgical and anesthetic technique, more recent studies have shown acceptable morbidity and mortality with surgical resection of liver metastasis. A few small studies with R0 resections in patients free of measurable extraheptic disease have revealed reasonable and improved median survival.3,4 A second avenue of interest is the use of intraoperative or percutaneous ablation techniques. Some groups have shown reasonable success in cytoreduction and ablation, although curative ablation is still controversial for most metastatic tumors. The ablative methods have also been tried in breast cancer only hepatic metastasis in a small number of patients and are an emerging area of interest. What should be carefully pointed out is that these are small studies, not prospective and not randomized. Selection bias is inevitable in the studies published to date and concluding that carefully selected patients with liver only metastasis should undergo resection is a route we are not ready to endorse. Looking at ways to study these patients in multi-institutional randomized prospective studies would better answer the question of surgical therapy in liver only metastasis. In terms of the ablative technology, initially ethanol and cyroablation were used and now radiofrequency ablation has become the preferred technique. These ablative techniques in general are used for non-resectable tumors and thus an oncologic ablation has not been proven. With the improvement of surgical technique and critical care anesthesia combined with chemotherapy, hormonal therapy and targeted therapies, surgical resection of isolated intrahepatic metastasis from breast cancer should be explored. Since hepatic only metastasis is a fairly uncommon event, the resources of multiple centers would need to be combined to adequately explore this question. With the increased use of novel imaging techniques such as PET/CT and the development of other molecular imaging techniques, patients with extrahepatic disease not seen on conventional imaging could be removed from consideration, further stratifying patients that would be amenable to surgical resection. It is not unreasonable to think that there will be a day when selected patients with metastatic disease to the liver can be offered surgical or ablative resection and may expect improved survival. However, we believe that day is not yet upon us.

References:
• Jardines L, Callans LS, Torosian MH. “Recurrent breast cancer: presentation, diagnosis and treatment” Semin Oncol; 1993:20;538-47.
• Atalay G, Biganzoli L, Renard F. et al. “Clinical outcome of breast cancer patients with liver metastases alone in the anathracycline-taxane era: a retrospective analysis of two prospective, randomized metastatic breast cancer trials.” Eur J Canc 2003:39;2439-2449.
• Vlastos G, Smith DL, Singletary SE, et al. “Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases.” Ann Surg Oncol 2004;11:869-874.
• Sakamoto Y, Yamamoto J, Yoshimito M, et al. “Hepatic resection of metastatic breast cancer: Prognostic analysis of 34 patients.” World J Surg 2005


AROMATASE INHIBITORS: WHAT’S THE BEST STRATEGY?
Prof. Ian Smith
Head of the Breast Unit
Royal Marsden Hospital (UK)

Data continue to mature showing a small but significant efficacy benefit for aromatase inhibitors over tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. An overview of the two main upfront trials (ATAC and BIG1-98) involving over 10,000 women confirm a significant reduction in the risk of recurrence with anastrozole or letrozole (HR 0.77) and an overall 5 year gain over tamoxifen of 2.9% and an 8 year gain of 3.9%. No overall survival benefit has so far emerged (HR 0.94 and with an 8 year non-significant gain of 0.5%). In the most recent BIG1-98 update analysis however a survival benefit in the intention to treat analysis emerged with an HR of 0.87 which was almost significant (p0.08) and probably would have been without a significant crossover effect from tamoxifen to letrozole. In the AI overview analysis of switch therapy after 2-3 years of tamoxifen to an AI versus around 5 years of an AI a significant reduction in recurrence was seen in favour of the switch approach (HR 0.71) and a 6 year absolute survival gain of 3.5%. The switch approach was also associated with an overall absolute 6 year survival gain of 1.6% (p0.02). In the BIG1-98 trial the randomised policy of switching from tamoxifen after 2 years to letrozole compared with letrozole upfront showed no benefit and was numerically inferior with a 5 year disease free survival of 86.2% versus 87.9% (HR 1.05). The switch to tamoxifen after 2 years letrozole showed no significant difference from letrozole upfront. Finally data on extended adjuvant aromatase inhibitor therapy after around 5 years of tamoxifen continue to show a highly significant benefit for this approach based on the NSABPB33 and the ABCSG-6a trials.

CANCER TREATMENT DURING PREGNANCY
Prof. Salah T Fayed, MD
Prof. Gynecologic Oncology
Ain-Shams University, Cairo (Egypt)

Malignant tumors are not uncommon during pregnancy. Breast cancer, cervical cancer and germ cell tumors of the ovary are the most common gynecologic cancers seen during pregnancy. Surgical treatment of breast cancer is considered safe throughout pregnancy. Conservative surgery for ovarian tumors is a relatively safe procedure if performed after the first trimester. Surgery for cervical cancer almost always sacrifices the pregnancy as it extirpates the uterus. Pelvic irradiation is incompatible with pregnancy at all times. Chemotherapy is allowed after the first trimester with relative safety both to the mother and to the fetus. For a nursing mother on chemotherapy lactation should be avoided. Long term effect on the neonate is not yet clear.

OVARIAN GERM CELL TUMORS AFFECTING YOUNG WOMEN.
A CLINICOPATHOLOGICAL STUDY OF THIRTY CASES
Prof. Sobhi Abou Louz
Prof. of Gynecological Oncology
Ain Shams University (Egypt)

Germ cell tumors of the ovary are uncommon but aggressive tumors seen, principally affecting young women and are generally curable if found and treated early. They are derived from primitive germ cells of the embryonic gonad, and may undergo germinomatous or embryonic differentiation .They differ in clinical presentation, histology and biology and include both benign (Predominantly) and malignant subtypes. Approximately 20% of all ovarian tumors are of germ cell origin, with only 2% to 3% of these being malignant. Malignant germ cell tumors account for less than 5% of ovarian cancers.

Roughly 70% to 80% of all germ cell tumors occur before age 20 . This study included 30 cases of germ cell tumors (7 cases of yolk sac tumor, 8 of dysgerminoma, 4 immature teratoma and 11 of mature teratoma). The mean patient age was 13 years (range: 8 to 20 y). The main complaint was abdominal swelling and pain. Workup included tumor markers: (B – HCG, AFP &LDH), CBC and liver functions, Chest X – ray, C.T scan to assess organ metastases and retroperitoneal lymphadenopathy.

All patients underwent laparotomy and conservative surgery (Ipsilateral adenectomy and omental sampling). Postoperatively, patients with malignant germ cell received chemotherapy and followed by clinically and by tumor markers.

THE ROLE OF ROBOTIC SURGERY IN GYNECOLOGIC CANCER
Magdy Nour, MD, MPH1 and Achim Schneider, MD, MPH2

1. Clinical Assistant Professor, Indiana University School of Medicine, Terre Haute, Indiana. (USA)
2. Professor and Chairman, Gynecology Oncology, Charite Hospital, Berlin, (Germany)

Background: Robotic surgery is the latest development in minimal invasive surgery. It provides superb visualization and superior hand dexterity. This allows the surgeon to perform complex tasks that would exceed his/her abilities with conventional laparoscopy and would be associated with an increased morbidity if performed by laparotomy. In this study we summarize our experience with Robotics in a two year period. We also compare the recent data from University of North Carolina, Mayo Clinic, and The Charite Hospital in Berlin.

Methods: We did a retrospective systematic chart review of all our cases since the installation of the DaVinci Robot Surgical System at our institution. We had 60 patients from September 2009 to November 2009. The types of surgeries performed ranged between hysterectomy and myomectomy. Patients demographics, comorbidities, operative and postoperative complications will be reviewed. A review of the literature on Robotics in Gynecology will be included. Preliminary data from the first randomized control trial of Robotic Vs Laparoscopic surgery in gynecologic malignancies will be presented.

Conclusion: Current evidence demonstrates the feasibility and safety of this technology in gynecology oncology. The cost, lack of haptic feedback, and the bulky size of the equipment make robotics less attractive to others. The projected cost of robotic surgery remains one of the main sources of controversy. It is expected to come down with further developments of the technology and the emergence of new Robots. If evidence-based long-term outcome evaluations show the superiority of robotic surgery in comparison to conventional laparoscopic and open surgery, this technology will have a major impact on gynecological oncology.

FERTILITY SPARING SURGERY IN GYNECOLOGIC ONCOLOGY
Prof. Maged Abouseeda
Head of Gyne-Oncology Unit
Ain Shams University (Egypt)

Following advances in the management of malignancies, cancer patients can hope for cure and long term survival. Cytotoxic drugs or radiation therapy are administered in order to control or destroy cancer cells. Surgery for gynecologic malignant tumors may affect the future fertility potential in these patients.

While the overall aim of the treatment regime is for maximal anti-cancer effect, damage to other body cells may occur. The ultimate goal of the oncologist is to permit not only survival but quality survival.

One such common side effect concerns the fertility and reproductive issues for these patients especially among young patients before or during the reproductive years. The purpose of this work is to review the different surgical techniques used to spare fertility among these patients.

CINICOPATHOLOGICAL EVALUATION OF PELVIC & PARA-AORTIC
LYMPHADENECTOMY IN GYNECOLOGIC MALIGNANCIES
Hussein Fakhrya, Gamal Amirab, Ikuo Konishic, Shiozawa Tanric

a Surgical Oncology Department, South Egypt Cancer Institute, Assiut University, (Egypt).b Surgical Oncology Department, National Cancer Institute, Cairo University, (Egypt). CObstetric and Gynecology Department, School of Medicine, Shinshu University (Japan) Methods: Our objectives were to study the various clinico-pathologic variables including a lymph node metastasis in cervical, endometrial, and ovarian cancer, to evaluate the incidence, distribution, and number of pelvic and aortic lymph node metastases in gynecologic malignancies and to study the impact of pelvic and paraaortic lymph node dissection on postoperative treatment plan. Methods: In this prospective study, Pelvic and paraaortic lymphadenectomy was done for 86 patients with cervical, endometrial and ovarian malignancies that were admitted to Department of Obstetric and Gynecology, Shinshu University Hospital, Japan and South Egypt Cancer Institute, Assiut University, Egypt between June 2005 and May 2008.
Results: For cervical cancer, Paraaortic LNs metastasis from cervical carcinoma occurs secondarily to extensive lymphatic metastasis in the pelvic area. Cervical stromal invasion, vaginal invasion and parametrial invasion were significantly correlated to pelvic and paraaortic lymph nodes metastases. Postoperative treatment plan tailored according to PLN and PALN dissection. For endometrial cancer, the most commonly involved PLN groups were internal iliac and obturator groups so that the principal connections are between the uterine corpus and the external iliac and obturator basins. Pelvic or paraaortic lymph nodes metastasis in advanced stage was significantly higher than early stage carcinoma. Myometrial invasion, cervical invasion, adnexal metastasis and lymph-vascular invasion were significantly correlated with PLN metastasis, while myometrial invasion, adnexal metastasis, lymph-vascular invasion were significantly correlated with PALN metastasis. For ovarian cancer, aortic nodal metastases are commonly understood as the initial route for the spread of EOC, with the pelvic nodes constituting a second metastatic site. Lymph nodes metastasis was only detected in advanced stage disease (stage III or IV). Peritoneal metastasis, omental involvement and presence of ascites were significantly correlated with PALN metastasis. Conclusions: In early stage cervical carcinoma, formal paraaortic lymphadenectomy can be avoided in patients with small early stage tumors. Complete pelvic and para-aortic lymphadenectomy should be done in all patients with endometrial carcinoma this can eliminate the need for adjuvant treatment in low-risk patients with negative nodes. Formal pelvic and paraaortic lymph node dissection is necessary for accurate staging in early stage ovarian cancer and optimal surgical debulking and in tailoring subsequent adjuvant treatment in advanced stage.

BREAST CANCER IMAGING AND SCREENING
IMAGE-DETECTED BREAST CANCER
Dr. Hanan Gweefle
Consultant Radiology, (Egypt)

Mammography currently remains the only imaging modality that is recommended for screening for breast cancer in general population. There are two categories for mammography , either screening or diagnosis. Screening mammography should be done on regular basis to detect breast cancer in an earlier stage than encountered in clinical practice, where as diagnostic mammography is a solving problem examination , necessitate presence of radiologist on site. In 2001 and 2005, a conference panel comprised of an interdisciplinary group of physicians specializing in the diagnosis and treatment of breast disease met to discuss their experiences with image-detected breast cancer and draft a report detailing points of consensus. A third, similar group (composed of approximately 50% of the members of the first and second groups and 50% new attendees) met in June 2009 to reassess some of the issues debated by the earlier panels, discuss the available evidence and implications of new and ongoing investigations, and develop current recommendations for diagnosis and treatment of image detected breast cancers. Consensus was reached by the Panel on a number of the challenging issues faced by patents and physicians. Five basic concepts arrived at during the 2001 conference were reaffirmed in 2005 and were again accepted. These include describing disease using objective measures, such as size, grade, nodal status, biologic markers, etc; the ability of screening mammography to reduce breast cancer mortality, at the price of requiring additional tests and possible overtreatment of some women; the progressive nature of breast cancer and the value of early detection in widening treatment options and improving outcomes; the highly variable growth rate and phenotypic evolution of breast cancers; and the benefits of early recognition and adequate treatment of ductal carcinoma in situ (DCIS).

Screening mammography
To be successful in reducing breast cancer mortality, screening mammography must be performed on a regular basis, as shown in numerous randomized controlled trials. The Panel supports the current recommendation of the American Cancer Society that women of average risk undergo screening mammography on a yearly basis, beginning at age 40. The upper age limit for undergoing screening mammography should be based on comorbidity. Screening ultrasonography
Routine screening with breast ultrasonography is not currently recommended. The American College of Radiology Imaging Network (ACRIN) trial 6666 demonstrated that, among a group of high-risk women with dense breast tissue, the addition of screening ultrasonography to routine screening mammography increased the detection of breast cancer from 7.6 to 11.9 per 1,000. Screening magnetic resonance imaging
A number of international clinical trials support the use of MRI as a screening modality for patients at high risk of developing breast cancer. The Panel endorsed the American Cancer Society guidelines regarding screening MRI. Appropriate candidates include:


1. Women with a lifetime breast cancer risk of 20% to 25% or higher based on predictive models;

2. Those with BRCA 1 or 2 mutations or those having a first-degree relative with a BRCA 1 or 2 mutation who have not yet been tested themselves; 3. Individuals who have had radiation therapy to the chest between ages 10 and 30; and

4. Women with Li-Fraumeni syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and their first-degree relatives.

REFERENCES
1. International Breast Cancer Consensus Conference. Imagedetected breast cancer: state of the art diagnosis and treatment. J Am Coll Surg 2001;193:297–302.
2. Silverstein MJ, Lagios MD, Recht A, et al. Image-detected breast cancer: state of the art diagnosis and treatment. J Am Coll Surg 2005;201:586–597.
3. American College of Radiology. BI-RADS® – Ultrasound, first edition. 2003. Available at: http://www.acr.org/SecondaryMainMenuCategories/quality_safety /BIRADSAtlas/BIRADSAtlas excerptedtext/BIRADSUltrasoundFirstEdition.aspx. Accessed June 13, 2009.
4. Berg WA, Blume JD, Cormack JB, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA 2008;299: 2151–2163.
5. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007;57:75–89.
6. American College of Radiology. ACR practice guideline for the performance of contrast-enhanced magnetic resonance imaging (MRI) of the breast. 2008. Available at:http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guidelines/breast/mri_breast.aspx. Accessed July 5, 2009.
7. American College of Radiology. BI-RADS® – MRI, first edition. 2003. Available at: http://www.acr.org/SecondaryMain .
8. Consensus Conference Committee. Consensus conference on the classification of ductal carcinoma in situ. Cancer 1997;80: 1798–1802.
9. Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Arch Pathol Lab Med 2009;133:15–25.

HI-TECH IN BREAST SURGERY
"EARLY DETECYTION, EARLY TREATMENT AND PHOBIA COMPLEX IN BREAST CANCER"
Prof. Fateen Anouss
Professor of Surgical Oncology
Ain Shams University (Egypt)

Type of breast biopsy, needle biopsy with and without suction was a matter of controversy for long time. A streotactic, ABBI and mammotome were all used and evaluated.

Radiofrequency thermal ablation was used as a method of minimal invasive breast surgery in cancer, as well as sentinel L.N biopsy intead of total axillary dissection.The gap between incidental discovery of breast lump, visiting doctor, biopsy and decision for surgery either by mastectomy or lumpectomy is crucial in overall management of breast cancer.

LOCAL RECURRENCE AFTER CONSERVATIVE
BREAST SURGERY: RETROSPECTIVE STUDY
A.M. El Anwar1, M.D., M. Shinawi1, M.D., M. Alaa Osman1, M.D.,
Hany Abd El Aziz2, M.D., Hisham El Ghazaly M.D.,
Department of General Surgery1, Faculty of Medicine – Ain Shams University
Department of Radiotherapy2 Faculty of Medicine – Ain Shams University

Breast conservative therapy (BCT) is the preferred treatment for early breast cancer and carries low local recurrence rates (LRR). Proper follow up is mandatory and includes periodic clinical examination, mammography and ultrasound to detect early recurrence. This study aims at evaluating the results of breast conservative therapy especially as regard local recurrence. Methods: Between January 2000 and July 2008, 241 consecutive female patients with early breast cancer were surgically treated by conservation surgery plus radiotherapy. Two patients had bilateral breast cancer and were subjected to preservation surgery on both sides in the same setting. The median age of patients was 48 years (range 23-76). Two hundred twenty four cases were treated by wide local excision and axillary clearance (level I&II) and 19 cases utilized neoadjuvant chemotherapy followed by preservation procedure. Patients were followed after surgery from one to 9 years (average 5.5yrs).Those who developed suspicious lesions on mammography or ultrasound were subjected to magnetic resonance imaging (MRI) and then all suspicious lesions were subjected to biopsy and histopathologic examination. Results: During follow-up, 62 out of 241 cases showed abnormal mammographic findings were all of them subjected to magnetic resonance imaging (MRI) and then biopsy for all suspicious lesions.
Local recurrence (LR) was detected in 12 of them (4.9%). For 11 cases, LR was the only event and one case showed coincident LR and distant metastasis. The recurrences detected were true (n=7) or marginal (n=3), which arise within or adjacent to the excision area, respectively. Only 2 recurrences were located elsewhere in the breast (n=2). Also patients with large breast where found to have a lower risk of local recurrence compared to patients with small breast, highly statistically significant relation (p<0.01). Statistically significant relation was also found between young age and the risk of LR (p<0.05). Patients with tumor size <2 cm were found to have a lower risk of local recurrence compared to patients with tumor size >2 cm, statistically significant relation (p=0.017). Statistically significant relation was also found between positive lymph nodes (+ve LNs) and the risk of LR (p<0.01).Four patients with LRs underwent salvage mastectomy, and the other 8 patients received wider local excision and adjuvant therapy. No mortalities were detected in patients with LR.conclusion, breast conserving therapy is an appropriate primary therapy for early breast cancer, surgeons should be aware of the mammographic findings following such a surgery. Young age, breast size, tumor size and lymph status should be considered in planning optimal treatment for breast cancer. Detection of biological risk factors for types of LR would be fruitful to distinguish unfavorable LRs that need systemic therapy from favorable LRs which could be treated only locally.

DUCTAL CARCINOMA IN SITU (DCIS) AXILLARY STAGING AND LOCAL MANAGEMENT
Prof. Mehra Golshan
Director of Breast Surgical Services Dana Farber Cancer Institute
Brigham and Women’s Hospital
Harvard Medical School (USA)

In the United States there will be approximately 60,000 cases of DCIS in 2010. This is largely due to the implementation of widespread screening mammography. The natural history of DCIS is impossible to predict and not all cases will go on to become invasive breast cancer. Regardless of local therapy, survival is outstanding at over 99%. Local therapy patterns revolve principally around three modalities: mastectomy, lumpectomy with radiation and lumpectomy alone. Local recurrence rates for breast conserving therapy are low with the addition of radiation and can be diminished further with endocrine therapy. Some groups advocate wide excision alone, although prospective data is lacking to support this method of treatment. Local recurrence after mastectomy is under 1%. The role of margins and the definition of clear margins is one that continues to evolve over time. Several studies are looking at the role of adjunct imaging such as MRI in its role in disease extent and surgical planning.In general axillary staging is not necessary of DCIS outside of women undergoing mastectomy, in those cases consideration may be made for sentinel lymph node biopsy. Some groups advocate axillary staging because the risk of upgrading to invasive breast cancer on final pathology; however the morbidity of the procedure is outweighed by any benefit in undergoing this procedure in a prophylactic fashion. As we see an increased incidence of DCIS around the world, further studies are underway looking at risk reduction, imaging and treatment.

AN UPDATE OF THE WIN-WIN INITIATIVE: SCIENTIFIC
APPROACHES FOR RESOURCE SPARING AND AFFORDABLE BREAST
CANCER TREATMENT
Prof. Ahmed Elzawawy
President of ICEDOC & ICEDOC’s Experts in Cancer without Borders
Director of SEMCO South and East Mediterranean College of Oncology
Chairman of Clinical Oncology Department., Suez Canal University (Egypt)

By the end of the year 2007, the win-win initiative was proposed by ICEDOC’s Experts in Cancer without Borders ( ICEDOC: is the International Campaign for Establishment and Development of Oncology Centers ), followed in the year of 2008 with preparatory communications, brain storming meetings and publications [1,2]. We don’t claim neither invention or leadership. But, the win-win initiative calls for enhancing the scientific efforts and constructive collaboration to increase the affordability of cancer treatment in the world particularly in the Low and Middle Income Countries (LMCs), mainly via exploring the scientific avenues. As a model for other cancers, the initiative started with breast cancer systemic therapy (BCST), then with breast cancer radiotherapy (BCRT).

We assume that there would be increasing of problems of affordability novel cancer treatment in the next decade in LMCs. The overall and disease-free survival rates, scores of quality of life, cost effectives and cost utility are not increasing in a measure commensurate with the expenses of cancer treatment.

In this presentation, we update the win-win initiative with more examples of the recent scientific published and ongoing researches and approaches that could lead to lower costs of BCST and BCRT, without significant evidence of compromising the overall outcome. We introduce the terms of “ The Non relevant oncology and The Relevant oncology” that consider the variability in biologic and pharmacologic factors among the human hosts and nature of tumors, cost effectiveness and cost utility as well as the real socio-economic conditions and respecting the expectations and priorities of the human beings of each community. REFERENCES
1. Elzawawy AM: Breast Cancer Systemic Therapy: The Need for More Economically Sustainable Scientific Strategies in the World. Breast Care 2008;3:434–438
2. Elzawawy A: The "Win-Win" initiative: a global, scientifically based approach to resource sparing treatment for systemic breast cancer therapy .World Journal of Surgical Oncology 2009, 7;44

COMPARISON BETWEEN MAMMOSITE AND IMRT IN PARTIAL
BREAST IRRADIATION
Prof. Amit Bahl
Professor of Clinical Oncology
University Hospitals Bristol (UK)

The standard of care for adjuvant radiation therapy of early breast carcinoma includes whole breast irradiation in case a breast conserving strategy is applicable. The purpose of the irradiation is to minimise the risk of local failure and thus improve disease-specific survival. This strategy includes irradiating the breast and in node-positive patients also loco-regional lymph nodes. The latest Early Breast Cancer Trialists Collaborative Group (EBCTCG) systematic review confirmed a 75% reduction in local recurrence risk after radiotherapy, and showed that the prevention of 4 local recurrences prevents 1 cancer-related death at 10 years, corresponding to 1–5 fewer deaths per 100 node-negative patients and 5–10 fewer deaths per 100 node-positive patients treated [1].During the last decade an alternative to the well-documented whole breast irradiation has been investigated, the so-called partial breast irradiation (PBI) where only a limited volume of the mammary gland is irradiated. The rationale for this are:Local recurrence rate after breast conserving strategy have decreased steadily over the last decade due to a combination of different factors: improved surgery techniques focusing on achieving negative surgical margins, more effective chemotherapy and hormonal therapy and CT-based radiotherapy assuring that the right target is hit.As a result of better awareness and screening programmes, incidence of early breast cancer has peaked in the USA, and since 2002 also in Europe, and adjuvant breast radiotherapy has became a heavy burden in the radiotherapy facilities.Most local recurrences appear close to the tumour cavity and a wish to spare the patient late radiation morbidity. Taken together the question emerges if it is possible to select patients to be offered radiotherapy to only a limited volume around the tumour bed and to increase the dose per fraction (since the treated volume is smaller) and provide the therapy in fewer fractions than standard.A meta-analysis of studies comparing treatment outcomes in patients with breast cancer treated with partial breast irradiation and of those treated with whole breast radiation therapy was presented at the American Society of Clinical Oncology (ASCO2009) 45th Annual Meeting.(2) The study identified 3 trials with pooled total of 1,140 patients and found no statistically significant difference between partial and whole breast radiation arms as regardstg death, distant metastasis or supraclavicular recurrences. However, partial breast irradiation was statistically significantly associated with an increased risk of both local and regional disease recurrences compared with whole breast radiation. (2).Approaches to Partial Breast Radiotherapy including Interstitial implant brachytherapy, Intra-Operative Radiotherapy, Intensity modulated radiotherapy and MammoSite brachytherapy will be discussed. REFERENCES
1. Abe O, Abe R, Enomoto K, Kikuchi K, Koyama H, Masuda H, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106.
2. A. Valachis, D. Mauri, N. P. Polyzos, D. Mavroudis, V. Georgoulias and G. Casazza, Partial breast irradiation or whole breast radiotherapy for early breast cancer: A meta-analysis of randomized controlled trials, Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings, Vol 27, No 18S (June 20 Supplement), 2009: CRA532.

3-D PLANING IN GYN BRACHYTHERAPY
Prof. Mervat Elnaggar
Professor of Radiation Oncology
National Cancer Institute (Egypt)

With the development of image guided techniques in radiation therapy,3 D planning concepts was exrended to brachytherapy.In GYN malignancy carcinoma of the uterine cervix is a good example of changing concepts.

Evaluation of CT and MRI findings in different stages of treatment is usefull in delineation of target,pathoanatomic structures and organs at risk.

Recommendations from the Gynaecologic (GYN)GEC-ESTRO Working groups as regard concepts and terms in 3-D image based 3-D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV will be presented

CANCER BREAST IN YOUNG WOMEN: RADIATION THERAPY
Prof. Samy El-Badawy, FRCR
Professor of Radiation Oncology Department
National Cancer Institute (Egypt)

Breast cancer rarely occurs in very young women .About 2% of the patients with the disease are less than 35 years old at diagnosis. Below the age of 20 years , the incidence is estimated to be 0.1 per 100.000 women increasing to 1.4 for women 20-24 years old, 8.1 for women 25-29 years old , and 24.8 for women 30-34 years old. Breast cancer at young age has a more aggressive biological behavior and is associated with a more unfavorable prognosis compared with the disease arising in older premenopausal patients. Specifically , tumors in younger women present with a higher grade and have a higher proliferating fraction and more vascular invasion the those occurring in older patients . Information from older series indicated that more positive axillary lymph nodes are detected in younger , compared with older , patients .Recent observations at the European Institute of Oncology, Milan Italy, showed that the proportion of patients with lymph node-positive disease among 185 patients below 35 years of age was similar to that for 1242 patients 35-50 years old treated at the institute between April 1997 and August 2000. Changes in the attention paid to axillary lymph node involvement related to sentinel lymph node work-up might explain this finding. Results from the same study indicated that patients under 35 years of age had a higher grade and higher expression of Ki67 , a higher percentage of vessel invasion , and less expression of estrogen receptor (ER) and progesterone receptor but similar overexpression of HER2/neu in the primary tumor.
Results from two population-based studies indicate that the risk of death is highest among the youngest and the oldest cohorts when compared with the patients of intermediate age even when the analysis allows for differences in initial tumor stage. A review of the National Cancer Institute data base reveals that patients younger than 35 years of age have more advanced disease at diagnosis and a poorer 5-year survival than older premenopausal patients. Similar findings have been reported from the National Cancer Institute SEER data base , from the Finnish Cancer Registry , from the South West Oncology (SWOG) data base , and from a recent Danish study on young patients who did not receive adjuvant therapy as well as from several series described from single centers.

NEO ADJUVANT RADIOTHERAPY WITH HIGH FRACTION FOR
BREAST CANCER: RESULTS OF CYBERKNIFE STUDY
Prof. Pierre-Yves Bondiau
Professor of Radiation Oncology (France)

CyberKnife (CK) allows stereotaxic irradiation for thoracic tumors it has never been used for breast tumors but may have a real potential. To define this interest, we have conducted a .5-phase 1 dose escalation study (19.5 Gy, 21.5 Gy x 25.5 Gy 28.5 Gy in 3 fraction) with a breast-conservating approach by using neoadjuvant chemotherapy (NACT) and a CK neoadjuvant tumor boost.

Patients and Methods: We perform a clinical examination made by two independent observers, at 36 days (DE1) at 56 days (DE2) after the NACT treatment onset, and prior to surgery (DE3).Surgery is performed 4 to 8 weeks after the last chemotherapy with pathology examination.

Results: 13 patients are includes in this study. All patients tolerated CK with no fatigue, 2 patients have presented a small pain after the third fraction of the treatment, no treatment was needed. We notice 2 grade II axillary toxicity and 1 grade 3 skin toxicity.There were 11 clinical complete responses and 2 clinical partial responses at D56 and D85.There were 4 histological complete responses at D85 for the 2 levels of dose (25.5 Gy and 28.5 Gy). CK boost does not alter surgical resection. Breast conservative approach has been made on 12 patients. Post-operative irradiation (50 Gy) has been delivered without toxicity.

Conclusion: This study shows the feasibility of an irradiation by Cyberknife combined with chemotherapy for breast tumors. The surgical morbidity was not increased. Pathologic response was promising.

MANAGEMENT OF BRAIN METASTASES IN BREAST CANCER
Prof. Yasser Abdel Kader
Professor of Clinical Oncology
Cairo University (Egypt)

Breast cancer is the second most common cause of brain metastases (after lung cancer), occurring in 10- 15 % of patients with breast cancer. HER-2 overexpression is considered to be the most significant prognostic factor for development of brain metastases, occurring in about 9% of HER-2 overexpression and 1.9 % in HER-2 negative tumors.

Although considerable progress has been made in the treatment of this complication, supportive measures like steroids, anti-seizure medication and whole brain radiation remain the cornerstone of the management in the majority of patients.

Recently the HER-1/HER-2 targeted dual tyrosine kinase inhibitor (Lapatinib) has been found to have significant activity in these tumors. Clinical case presentation of metastatic breast cancer to brain treated by Lapatinib will follow the presentation

BONE METASTASIS IN BREAST CANCER : FROM EVULATION TO PREVENTION
Prof. Hamdy A.Azim
Professor of Clinical Oncology,
Faculty of Medicine, Cairo University (Egypt)

Breast cancer is associated with a significant morbidity in the skeleton. It is generally accepted that the process of bone destruction is mediated by osteoclasts, whose formation, function, and survival requires the receptor activator of NF-kB ligand (RANKL). There is a large body of evidence for a causal role of parathyroid hormone related protein PTHrP in the pathogenesis of human breast cancer–mediated osteolytic metastases. Preclinical models of bone metastases ,have shown that breast cancer cells can produce PTH-rP which is responsible for increased RANKL expression and decreased osteoprotegerin expression (endogenous RANKL inhibitor) by osteoblasts resulting in excessive osteoclastic resorption and establishment of osteolytic bone lesions. Many studies have suggested that in bone metastatic tumors, inhibition of the primary resorptive stage may be sufficient to inhibit tumor establishment and halt progression of the disease.

Targeting bone metastases : the role of Bisphosphonates Bisphosphonates ,which are potent inhibitors of osteoclastic bone resorption, are used in the treatment of nearly all types of bone metastases. Bisphosphonates inhibit osteoclast formation and migration, and osteolytic activity. Furthermore bisphosphonates promote osteoclast apoptosis and increase production of osteoprotogerin by osteoblasts. Bisphosphonates effectively reduce the release of bone derived growth factors and cytokines associated with osteoclastic bone resorption. Accordingly, bisphosphonates can inhibit physiologic and pathologic bone resorbtion. Moreover preclinical data suggest that bisphosphonates may have anti-tumor activity against many cancer cell lines including breast cancer. Importantly, experimental data indicate that these antiosteolytic agents reduce the occurrence of bone metastases but not the extraskeletal metastases suggesting that local concentration of bisphosphonates is sufficient to induce apoptosis of tumour cells only in the bone.
Other mechanisms by which bisphosphonates exert their effects to decrease bone metastases may involve impairment of tumor cell adhesion to bone. In-vitro and animal models data suggest that zoledronic acid is the most potent among other bisphosphnates as an anti-cancer drug. In addition to its confirmed anti-angiogenesis effects, zoledronic acid shows a sequence-dependent synergy with cytotoxic agents being significantly more effective in inducing apoptosis in breast cancer cells when given after rather than before doxorubicin). Such pharmacodynamic properties of zoledronic acid have not been fully explored in clinical trials
In the adjuvant setting, three randomized trials using oral clodronate have been reported. The German and British studies administered oral clodronate (1,600 mg/d) for two years to patients with primary operable breast cancer. In spite of the differences in eligibility criteria between the two studies, the addition of oral clodronate significantly reduced the occurrence of bone metastases during the 2 years of medication period, but this effect, was not maintained afterwards. The third trial (Finnish adjuvant clodronate study), was criticized for the imbalance between the 2 groups in the population of ER negative patients being higher in the clodronate group , compared to the control group . In this trial, bone metastases were detected at the same frequency in the clodronate and control groups: 32% vs. 29% respectively. However, a negative effect of clodronate on disease free survival (DFS) was seen due to a significant increase in visceral metastases especially among ER negative patients. However even in this negative study , bone as a first site of relapse was less frequent in the clodronate group than in the controls (14% vs. 30% respectively; p=0 .016). Important lessons should be drawn from the prevention studies using oral clodronate. The early reduction of bone metastases in the German and British studies might have been maintained if a longer medication period was adopted or should a more potent bisphosphonate (e.g. zoledonic acid) was used. A third suggestion is related to the population of breast cancer patients that may potentially draw the maximum benefit of preventive bisphosphonate therapy. It has been consistently reported that ER-positive tumours are more likely to be associated with the development of bone metastases. Patients with ER-positive tumours had bone metastases almost three times more often than patients with ER-negative tumours. Furthermore, in-vitro and in-vivo studies have shown that estrogen can suppress PTHrP production by breast cancer cells while tamoxifen and aromatase inhibitors can induce PTHrP overexpression. Since ER positive patients are always treated by hormonal therapy, therefore the relapsing cells residing within the bone matrix may show increased PTHrP expression under the effect of prolonged estrogen opposition attributed to hormonal therapy. In other words, inspite of the significant benefit of hormonal drugs in ER positive breast cancer, yet the surviving residual cells would express PTHrP which facilitates their progression as bone metastases. Importantly in the two studies that utilized a more potent bisphosphonate zoledronic acid in a homogenous population of ER positive patients produced a significant improvement in DFS in the treated patients. In the ABCSG-12 Trial, 1803 premenopausal patients with ER positive early breast cancer were randomized to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen or anastrozole with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. At a median follow-up of 47.8 months ,the addition of zoledronic acid to endocrine therapy, resulted in a 36% relative reduction of in the risk of disease progression (hazard ratio, 0.64; p= 0.01) compared to endocrine therapy alone.
The second study included 1065 postmenopausal patients with again ER positive early breast cancer. The patients were randomized to receive either letrozole with zoledronic acid (4 mg given intravenously every 6 months) for 5 years (upfront group) or letrozole alone with subsequent addition of zoledronic if bone mineral density scores declines (T-score <-2) or in case of clinical or asymptomatic fracture (delayed group) At a median follow-up period of 36 months, upfront zoledronic acid significantly decreased the risk of disease progression by 41% (HR= 0.588, P= 0.0314) compared to delayed group which is quite similar to the benefit reported in ABCSG-12 Trial.

SUPPORTIVE CARE IN PATIENTS WITH BREAST CANCER
Prof. Gloria Mattiuzzi
Assistant Professor of Medicine
Supportive Care Program
M.D. Anderson Cancer Center (USA)

Although the treatments for breast cancer have the potential to cure the disease, and to prolong the life of the patients, these treatments are associated with a wide range of physical and psychosocial problems. Among the treatment-related complications, anemia, emesis and menopausal symptoms emerge as significant problems with still several questions pending to be answered. We will review the latest findings in the search to prevent/control these complications.
Anemia: Approximately 30% of patients with breast cancer have anemia at the moment of diagnosis and as much as 70% will experience some degree of anemia during the course of chemotherapy. The need of frequent transfusions and the negative impact of anemia in the quality of life of such patients require prompt solutions. Two eythropoetic agents, darbepoetin alfa and epoetin alfa, are currently approved in the USA for the treatment of chemotherapy-associated anemia. Both products differ in the glycosylation patters but they share the same protein sequence. An important clinical question is to know if both agents are also comparable in efficacy. Few clinical trials have directly compared the two agents. We will present the data available in clinical trials evaluating the efficacy and safety of darbepoetin alfa and epoetin alfa in patients with breast cancer.
Emesis: Despite advances in the prevention and treatment of chemotherapy induced emesis, nausea and vomiting are still one of the most frequent and feared side effects of complications of breasts cancer treatment. The serotonin-receptor antagonists are the mainstay of antiemetic therapy. There are different agents in this class with distinct pharmacologic differences that may affect the potential for drug interactions. Neurokinin-receptor antagonists are the newest class of antiemetics but must be used in combination with a serotonin-receptor antagonist and corticosteroid. Several drug combinations have demonstrated similar efficacy in the prevention of chemotherapy-induced emesis, however, the potential of drug interactions and ultimately, patient’s adverse events needs to be considered.
Menopausal symptoms: Pre menopausal women who receive adjuvant chemotherapy for breast cancer may undergo premature menopause. The implications include loss of fertility, accelerated bone loss, hot flashes and night sweats which can be more severe than in natural menopause women. Menopausal symptoms are an important source of morbidity and discomfort and are associated to reduced health-related quality of life. For these patients, hormonal therapy is contraindicated, therefore, given the increasing number of survivor from breast cancer, it is imperative to explore safe and effective treatment options.

PAIN MANAGEMENT IN METASTATIC BREAST CANCER
Prof. Samy Alsirafy, MBBCh, MSc, MD, ABHPM, Dip Pall Med
Professor of Palliative Care Medicine Unit
Kasr Al-Aini Center of Clinical Oncology & Nuclear Medicine (NEMROCK)
Kasr Al-Aini School of Medicine, Cairo University (Egypt)

Pain is the most distressing symptom among breast cancer patients. Sixty two percent of breast cancer patients in all stages experience pain and the prevalence is higher among those with metastatic disease. Pain may be caused by the disease itself or by the different treatment modalities directed at breast cancer. Some pain syndromes specific for breast cancer patients may cause significant suffering like the post-mastectomy pain syndrome, which occurs in up to 50% of patients.

Pain is controllable in the majority of patients using the simple World Health Organization (WHO) guidelines for cancer pain management. These guidelines are “by mouth”, “by the clock”, “by the ladder”, “for the individual” and “attention to detail”. Ideally, pain management is multidisciplinary and should address the psychological, social and spiritual components of pain in addition to the physical one.

Although guidelines and tools for adequate cancer pain control are available for decades, it remains largely uncontrolled worldwide. This is because of many barriers like lack of education, drug unavailability and unsupportive government policy. There is a need to implement the WHO strategy to improve pain control and palliative care provision for metastatic breast cancer patients and other advanced cancer patients in Egypt. The strategy is based on promoting education of health care professionals, the public and others, improving drug availability and changing government policy. Special attention should be paid to change the restrictive regulations that limit accessibility of cancer patients to opioids in Egypt.

SURGICAL TREATMENT OF BONE METASTASES TO THE SPINE
Dr. Micheal Gebhart
Orthopedic Surgeon
University of Brussel (Belgium)

The most frequent neoplastic involvement of bone is caused by metastatic disease. The number of metastatic disease increases currently especially with aging of the population and longer life expectancy in the face of generalized neoplastic disease due to better medical cancer management especially in breast and prostate cancer. Metastatic disease to the spine is by far the most frequent location. Bone metastases to the spine affects 50% of all cancer patients, causes intractable pain and disability and causes a huge part of medical expenses of global health cost. Axial skeletal lesions should be treated preferentially by initial radiotherapy.Under the following circumstances surgery may be required: 1) to obtain a clear histological diagnosis of metastatic lesions from an unknown, sometimes known primary tumor (unique lesion or unusual clinical presentation); 2) to stabilize a compression fracture of the vertebra and 3) to reconstruct bone defects of the spinal column. The indications to proceed with a rather aggressive surgery are related to the Tomita Score for survival. Instability of the spinal chord is evaluated by either criteria developed by De Wald or a scoring system according to White and Panjab. Epidural involvement and neurological status are evaluated respectively by the Denis Pain Scale and the Frankel Grading Scale.Surgical treatment may be considered. Epidural involvement may be treated by either anterior (lesion of the vertebral body) or posterior (lesion of the posterior elements) = laminectomy. After resection, the vertebral body can be reconstructed by a cage injected with bone cement. Those techniques can be combined: posterior and anterior approach. In exceptional cases, especially in bone destructive lesions due to multiple myeloma or other very lytic bone metastases, vertebro-or kyphoplasty may lead to major pain relieve with simple cement injection into the vertebral body.

INFLAMMATORY BREAST CANCER: NEW INSIGHTS OF AN OLD DISEASE
Prof. Ricardo Alvarez
Assistant Professor of Medical Oncology
M. D. Anderson Cancer Center (USA)

IBC is the most aggressive manifestation of primary breast carcinoma. It is relatively rare, with an incidence of only 1% to 6% in the United States. Furthermore, a review of the Surveillance, Epidemiology, and End Results (SEER) program data comparing trends and patters for breast cancer revealed that the incidence of IBC increased from 0.3 to 0.7 cases per 100,000 person-years, a much larger increase than that observed for non-inflammatory forms of breast cancer.
The management of IBC has substantially evolved in the past three decades. Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with IBC remains poor. Therapies that target the vasculolymphatic processes –angiogenesis, lymphangiogenesis, and vasculogenesis- have shown potential in the treatment for IBC, as represented by bevacizumab. Although the therapeutic effect of targeting lymphangiogenesis and vasculogenesis requires further investigation, targeting of angiogenesis has potential, not only through true antiangiogenic effects, but also through antitumor effects in content with other pathways. Therapies that target human epidermal growth factor 2 (e.g., trastuzumab and lapatinib) have performed well in the clinical setting, leading to improved outcomes for patients with IBC. Metastatic pathways could have a unique, key role in the aggressiveness of the IBC phenotype. Further extensive work on the unique molecular characteristics of IBC is essential to ensure improved outcomes for patient with this disease.

On December 5-7, 2008 the First International Inflammatory Breast Cancer (IBC) Conference was held at M.D. Anderson Cancer Center in Houston, USA. Following the formal meeting, a consensus panel composed of experts from various disciplines identified common strengths and the IBC World Alliance was formed to foster international collaborations.

TARGETED THERAPY IN METASTATIC BREAST CANCER
Prof. Ian Smith
Head of the Breast Unit
Royal Marsden Hospital (UK)

Trastuzumab established proof of principle in the treatment of metastatic breast cancer, showing a significant survival advantage in combination with either Paclitaxel or Docetaxel compared with these drugs alone. Recent data have shown that patients with HER2 positive metastatic breast cancer now have a better prognosis than those with HER2 negative breast cancer since the introduction of trastuzumab, whereas before the prognosis was worse. Randomised trials data have established that trastuzumab continued beyond first relapse with capecitabine achieves better outcome than capectiabine alone and is therefore recommended for this indication. Pertuzumab, also targeted against HER2, has shown useful clinical activity when combined with trastuzumab in patients who have relapsed on trastuzumab alone. Lapatinib, an oral small molecule single transduction inhibitor acting against HER1 and HER2 is clinically effective in metastatic breast cancer and has shown improved activity in combination with trastuzumab compared with alone. Bevacuzimab, an anti-VEGF antibody, has shown improved clinical outcome in metastatic breast cancer when given with chemotherapy compared with chemotherapy alone. This has been established in 3 separate trials, E2100 (with paclitaxel), AVADO (with docetaxel) and RIBBON 1 (with taxanes or anthracycline or capecitabine). In these trials and in the large ATHENA trial with safety as a primary endpoint, Bevacuzimab has been shown to be well tolerated with a much lower incidence of hypertension than was initially thought (3% in ATHENA) and a very low incidence (less than 1%) of GI perforation, thromboembolism and other potentially serious side effects. Bevacuzimab and trastuzumab in combination have shown high clinical activity without chemotherapy (overall response rate around 54%). These trials demonstrate that single agent and combination targeted therapy are clinically effective in metastatic breast cancer and promise to be valuable new treatments providing costs can be accommodated.

APPROACH TO PERSONALISED MEDICINE WITH TARGETED
DRUGS IN BREAST CANCER
Prof. Thomas Tursz
Director of Institute Gustave Roussy (France)

The incidence of cancer is increasing with more than 14 million new cases each year worldwide. Despite real progress in recent years, many types of tumours (such as lung cancers) are diagnosed at a late stage, are inoperable and have poor outcomes with drug and radiation therapies. Early diagnosis is the most rational way to improve the overall efficacy of care for cancer patients, since early detection confers the highest chance of survival. The cornerstone will then become personalised treatment after curative surgery. Important questions such as whether or not patients should receive adjuvant treatments and if so, which type of therapy, are the questions that the medical community and the drug industry are trying to address worldwide. The conference will outline the major trends currently accepted by the medical community and will present the experience of the Institut Gustave Roussy in France in early diagnosis and tailored individualised treatments. These combine medical expertise and major efforts towards improving technologies, together with networking in Europe and worldwide, since such challenges can no longer be addressed by a single Institution. Only rational cooperation and synergistic efforts in the advancement of science and technology developments will bring significant improvements to the care of cancer patients. The conference will present examples of advances in personalised cancer care in the field of human breast and lung cancers.

PARP INHIBITORS IN BREAST MALIGNANCIES
Prof. Banu Arun
Professor of Breast Medical Oncology
Co-director Clinical Cancer Genetics
University of Texas, MD Anderson Cancer Center (USA)

Poly (ADP-ribose) polymerase (PARP) is an enzyme which repairs DNA damage. PARP inhibitors inhibit this function and studies have shown that they can enhance chemotherapy efficacy. Currently, there are 2 prospective clinical trials that have been completed with promising results. In one study the addition of the PARP inhibitor BSI-201 to chemotherapy in patients with triple negative metastatic breast cancer was studied. The other study evaluate Oleparib as a single oral agent in patients with metastatic breast cancer who also have BRCA mutations. This session will discuss the mechanism of action of PARP inhibitors, summarize current clinical trials and future directions.

TRIPLE NEGATIVE BREAST CANCER : IS IT REALLY A TARGETLESS TUMOR ?
Prof. Martine Piccart
President of the European Organization for Research & Treatment of Cancer (EORTC)
Head of Chemotherapy, Jules Bordet Institute, Brussels (Belgium)

Triple negative breast cancer (TNBC) accounts for 15% of diagnosed breast cancer patients, and is clinically represented by estrogen-, progesterone- and HER2-receptor negative tumors. Cases with this immuno-histochemical (IHC) phenotype show considerable heterogeneity but are most commonly high grade, highly proliferative, TP53 mutant and tend to metastasize preferentially to viscera and CNS. Approximately 85 % of TNBC is found to fall within the “basal-like” intrinsic gene expression cluster most closely identified by additional +ve IHC staining for cytokeratin 5/6 and/or EGFR. These features are shared with most tumours occurring in BRCA1 carriers. In a significant subgroup of non-familial sporadic cases of TNBC abnormalities in the BRCA1 regulated DNA damage response are suggested by low expression of BRCA1, a characteristic pattern of high genome instability. Different population series have demonstrated a higher incidence of TNBC tumors among premenopausal African American patients when compared to white women, which can, in part, explain the worse prognosis historically attributed to this patient group. The higher frequency of TNBCs clinically detected between interval-mammograms is probably related to its rapid growth pattern. Population-based studies have shown the likelihood of disease recurrence and death for TNBCs to be higher than for non-TNBC. This higher recurrence rate is typically observed in the first years after diagnosis, with a peak occurring in the third year. Aggressive disease behavior is usually observed at the moment of disease relapse, with a predilection for visceral, soft tissue and central nervous system metastasis. For TNBC no single marker is available to predict response to a particular treatment, and chemotherapy remains the main therapeutic option available. In the early disease setting, the optimal adjuvant chemotherapy schedule remains undefined although most guidelines recommend the use of the “third generation” regimens which include anthracyclines, cyclophosphamide and a taxane. In advanced breast cancer, some progress has been achieved by using antiangiogenic therapy. Bevacizumab is approved in combination with chemotherapy for the first-line treatment of HER2-negative metastatic breast cancer. Although bevacizumab was not specifically evaluated in the subset of TNBC in the pivotal clinical trials, the added benefit in terms of progression free survival was similar in the TNBC subset analysis. However, it is important to note that no overall survival could be demonstrated. Another important therapeutic strategy being developed to treat TNBC focuses on targeting the DNA repair machinery. It is known that BRCA-1 gene is important for maintaining genomic stability by promoting repair of double-strand breaks. Although the majority of triple negative tumors are sporadic and lack BRCA1 mutations, the integrity of BRCA1 pathway seems also compromised in these tumors. This compromised double-strand repair mechanism can render TNBCs sensitive to drugs that block the single-strand repair mechanism, such as PARP inhibitors. Highly potent PARP inhibitors (PARPi) have recently been developed and tested as single agents in phase I and phase II clinical trials. These have been found to be well tolerated with minimal toxicity. Two recent trials have examined the response to these agents in advanced breast cancer in two distinct contexts. The potent oral PARPi olaparib showed a single agent response rate of 41 % in BRCA1 and BRCA2 carriers with advanced breast cancer who had had a median of 3 prior chemotherapy regimens and where >90 % were taxane and anthracycline exposed. More than 50 % of patients had TNBC and this subpopulation had a similarly high response rate. The drug was well tolerated with main toxicities of mild nausea and fatigue. (Tutt et al). Olaparib is currently in phase I combination trials with the following relevant agents; paclitaxel, carboplatin, cisplatin, bevacizumab. Results are awaited from these studies but early indications suggest that it may be simpler to combine Olaparib with cisplatin than carboplatin. BSI-201 an intravenous PARPi has also completed phase I combination studies with temozolamide, topotecan, gemcitabine and with carboplatin AUC6 D1 when given with paclitaxel D1 Q21 combination. No additional toxicities were noted with these combinations over recognised toxicities of the chemotherapy drugs. BSI-201 was combined with gemcitabine 1000mg/m² D1, D8 and carboplatin AUC2 D1, D8 (GCP) chemotherapy and compared with the same chemotherapy (GC) regimen alone in a randomised phase II trial in women with advanced first or second advanced disease relapse. A significant improvement in response rate (48 % vs 16 %), PFS and OS (9.2 vs 5.7 mths) was noted for the PARPi GCP arm which was well tolerated with no additional toxicities compared with GC. (O’Shaughnessy et al). A randomised registration Phase III has commenced in N America testing the same GC + BSI-201 (GCP) regimen vs GC alone. The Breast International Group (BIG) will be launching 3 clinical trials which should help resolving some of the key questions relative to the use of PARP inhibitors in triple negative breast cancer.
References:
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