The European Breast Cancer Conference (EBCC 7) was held in Barcelona, Spain in March 2010. Following are some of the more interesting abstracts presented at the meeting.

Mammographic Screening

Mammographic screening has continued to be controversial in the United States, predominantly because older clinical trials have been evaluated on an “intent-to-treat” basis for those invited versus not invited to attend screening. The mortality reduction is magnified when evaluating breast cancer mortality on those who actually got screened versus those that did not. We continue to look for other newer databases from around the world to inform us on the benefit of mammographic screening in the more modern era.

Investigators from the Netherlands had previously noted a downward trend in Dutch breast cancer mortality rates in 2001, which appeared to occur after the initiation of mammography screening. They presented the results of a recently initiated case-control study to evaluate their program. The results that they presented were from the Southwest region of the Netherlands from 1990-2003. Screening was implemented in the period 1990-1996. Eligible women for the study were those aged 49 to 75 at the first invitation to be screened. They noted that the attendance rate at the initial screenings among eligible women varied between 59% - 88%. Cases used in the study were those women who were diagnosed with breast cancer after the first invitation and subsequently died from breast cancer. Five controls were then matched with each case based on age at the case’s last invitation, year of birth, year of first invitation, and number of invitations up to the diagnosis of breast cancer. All the controls were alive at the time of death of the matched case and were breast cancer-free at the time the case’s breast cancer was diagnosed. Results: There were 755 cases and 3739 matched controls. Thirty-six percent of the cases were never screened compared to 18% of the controls. Among the cases, the proportion of localized tumors (stage 0-1) was considerably higher in women with screen-detected tumors versus those never screened (34.1% vs 10.4%). The authors concluded that their study suggested reductions of 52% - 56% in breast cancer mortality among women who were invited and attended the mammography screening program in the Southwest region of the Netherlands between 1990-2003. Although these data don’t help us understand the correct interval for screening or the age at which to begin screening, they do further verify the very strong impact of mammographic screening on women who actually do attend screening on a regular basis. (Abstract 1N)

A CASE BASED REVIEW THAT WILL HELP YOU APPLY NEW DATA FROM THE ANNUAL ONCOLOGY MEETING July 10, 2010 New York, New York Westin New York at Times Square July 17, 2010 Tysons Corner, Virginia The Westin Tysons Corner   July 10, 2010 Los Angeles, California The Westin Bonaventure Hotel & Suites July 24, 2010 Dallas, Texas The Westin Galleria Dallas

Internal Mammary Lymph Node Radiation

Two different presentations were delivered back-to back-regarding the benefit of elective radiation of the internal mammary chain after breast surgery for those women undergoing radiation.

Romestaing presented data on behalf of a large multicenter French radiation oncology consortium. As an introduction to the study, it was noted that standard postoperative radiotherapy after mastectomy includes the supraclavicular area and the chest wall. Some groups have routinely also added the internal mammary chain (IMC) into the radiation field. The objective of this trial was to evaluate the impact of internal mammary chain radiation on the 10-year survival in patients with breast cancer who were treated with mastectomy. The authors reported on the early results of a multi-centric randomized phase III trial comparing chest wall, axillary, and supra-clavicular irradiation with or without IMC radiation in newly diagnosed patients with stage I and II breast cancer. The women were eligible if they were under the age of 76, had positive axillary nodes or internal/central tumor location in the breast, whatever the pathologic nodal (pN) status. Adjuvant chemotherapy or hormonal therapy was left to the discretion of the treating physician. They planned to include 1200 patients that would allow for the detection of a 10% difference in survival (observed arm, 40% versus 50% radiation therapy-arm). Results: 1334 women were randomized. Seventy-five percent of patients had positive lymph nodes, and 86% received chemotherapy and/or hormonal therapy. With a median follow-up of 10 years, 535 deaths were observed. Ten-year survival was 62.6% in those with and 59.5% in those without IMC radiation therapy (P = .88). Of the known causes of death, most were due to breast cancer. There was no difference in deaths from cardiac disease between the 2 groups, which has previously been a concern with older techniques of radiation to the internal mammary chain. Although the authors concluded that there appeared to be no beneficial effect of IMC radiation therapy, their study was likely underpowered to see a 10% improvement in survival, and that the event rate for women on this trial was much lower than anticipated, likely due to improvements in systemic therapy. Abstract 5N.

Immediately after this presentation, a second one on the same topic was delivered. Poortmans, et al presented data on a large European Organisation for Research and Treatment of Cancer (EORTC) trial investigating the additional benefit of IMC radiation therapy for women receiving chest wall radiation after a mastectomy. Women were eligible if they had involved axillary lymph nodes and/or a medially located primary tumor. They were randomly assigned to chest wall radiation therapy +/- IMC radiation therapy. The original trial design aimed at detecting a 5% increase in 10-year overall survival (from 50% - 55%) with a hazard ratio (HR) of 0.86. However, after reviewing the patient characteristics of the women on the trial and the increasing survival trends for early breast cancer, the protocol was modified in April, 2003 to target a 10-year overall survival (OS) benefit from 75% to 79% (HR = 0.82). Three analyses are planned at 10, 15, and 20 years of median follow-up. At years 5 and 10, toxicity assessments were performed for evidence of late pulmonary or cardiac toxicity. Results: Between 1996 and 2004, a total of 4004 patients were enrolled on the study. Thirty-four percent of patients were stage I and the remainder were either stage II or III. A majority (76%) of the patients were treated with breast conserving surgery. Nearly all the patients with node-positive disease and two-thirds of the patients with lymph node negative disease received adjuvant systemic therapy. At 3 years of follow-up there were more reports of pulmonary toxicity in the IMC radiation therapy arm (4.3 vs 1.3%). At the time of this report, and with a median follow-up of 7.3 years, 558 patients have died, giving an estimated 10-year OS to be within 79% - 82.5%. Data maturity for the first analysis is expected to be reached within another 3 - 4 years. Abstract 6N.

All of us await the mature results of these trials over the next several years to help define a population of women with breast cancer who may benefit from internal mammary radiation added to their other radiation fields.

Local Failure Patterns in Patients with BRCA 1 and 2 Mutations

The third compelling radiation oncology abstract was presented by Dr Lori Pierce from the University of Michigan on behalf of a consortium of radiation oncologists. Women with a BRCA 1 or 2 deleterious mutation are well-known to have a 55% to 85% cumulative risk of developing breast cancer. In addition, those women who do develop 1 cancer carry an approximately 50% chance of developing a second cancer in the contralateral breast. Women with a known BRCA 1/2 mutation who develop breast cancer must decide between mastectomy and breast conserving surgery. Six hundred fifty-five women with a deleterious BRCA 1/2 mutation diagnosed with operable breast cancer and who were treated with mastectomy or breast conserving surgery (BCS) were identified and underwent follow-up for evidence of local, regional, or systemic recurrence. Results: Local failure as the first site of failure was significantly more likely in those undergoing BCS versus mastectomy (cumulative estimated risks at 15 years were 23.5 versus 5.5%). The lack of chemotherapy was also associated with a significantly higher rate of ipsilateral in-breast events (HR = 5.4). Interestingly, the 15-year estimates of carriers treated with BCS and chemotherapy was 11.9%. Most of the in-breast recurrences appeared to be consistent with new primary lesions, rather than recurrences from the original cancer. The risk of contralateral breast cancer exceeded 40% in all groups and was not higher in those who received contralateral radiation. There were no significant differences in rates of systemic recurrence, breast cancer-specific, or overall survival between the BCS and mastectomy groups.

Although most women who are known to be carriers of a deleterious BRCA1 or 2 mutation will elect mastectomy when they develop a breast cancer, many women may undergo their definitive local therapy prior to being gene tested. This abstract gives us information regarding the natural history of new breast cancer events in these women. Abstract 7N

Update on Adjuvant Trials

HERA Trial
Dr De Azambuja presented data on the prognostic and predictive value of central and local hormone receptor assessment in the HERA trial on behalf of the HERA investigators. In this trial, 5080 women with HER2-positive early breast cancer were randomized to 1 of 3 arms after adjuvant systemic chemotherapy or concurrent with hormone therapy: observation, 1 year of trastuzumab, or 2 years of trastuzumab. The aim of this presentation was to establish whether the benefit of trastuzumab differed according to the status of hormone receptor expression for those on the trial. The investigators studied the estrogen receptor (ER) and progesterone receptor (PR) status, endocrine treatments, and disease-free survival (DFS) for women in the observation and 1-year trastuzumab groups. Hormone receptor status was assessed both locally and centrally. Results: 3401 patients were enrolled 1 of the 2 previously mentioned arms and had a median follow-up of 23.5 months. A central assessment of ER and PR was possible for 3002 out of the 3401 patients. Concordance evaluations were performed for the local and central assessment of hormone receptors. There was a 91% concordance for those with ER-negative tumors, and a 73% concordance for those with ER-positive tumors, while central PR concordance was 84% and 81%, respectively. There was a trend for patients with a higher HER2 copy number to have a lower central ER score. The authors pointed out that discordance rates for ER appear to be higher here compared to other studies done in patients with HER2-negative disease and may be reflective of the difficulty of local ER testing imposed by lower levels of ER in patients with HER2-positive disease. Abstract 435.

MINDACT Trial
Dr Rutgers updated the first results of the pilot phase of the MINDACT trial for compliance and feasibility. MINDACT is an acronym, which stands for MicroArray in Node negative, and 1-3 node positive lymph node Disease may Avoid ChemoTherapy. The study aims to enroll 6000 patients, all of whom will have their tumors assessed by the 70-gene (Mammaprint) profile. The study is testing whether the gene signature is equivalent or superior to clinicopathological assessment (as measured by Adjuvant! Online) with regards to the benefit of adjuvant systemic chemotherapy. Patients are assigned to 1 of 4 categories based on these features. The genomic testing profile categorizes patients as low-risk or high-risk. Adjuvant! Online defines low-risk as patients having a >88% 10-year breast cancer specific survival for ER-positive and >92% for ER-negative. Patients who are high-risk by both criteria are offered chemotherapy and are offered an anthracycline-based regimen or a combination of docetaxel and capecitabine. Patients who are low-risk by both genomic and clinical features do not receive chemotherapy. If they are ER-positive, they are offered hormonal therapy and are randomized between 2 years of tamoxifen followed by 5 years of letrozole, or to 7 years of letrozole. Discordant patients (high-genomic and low-clinical, or high-clinical and low-genomic) are randomized to chemotherapy or no chemotherapy. Patients with ER-positive disease, again, are offered the same hormonal therapy as described previously. This presentation was based on the first 800 patients enrolled. The investigators found that the trial indeed was logistically feasible in this multinational setting. Accrual is currently around 140 patients per month, and approximately half of the total numbers of patients have been enrolled. The current clinical/genomic risk allocations for these first 800 patients is as follows: clinical/genomic low-risk: 48%; clinical/genomic high-risk: 25%; clinical low/genomic high: 9%; clinical high/genomic low: 18%. We look forward to completion of both this MINDACT trial as well as the TAILORx trial being run in the United States using the Oncotype assay to better understand the contribution of genomic testing to our decision-making regarding adjuvant systemic chemotherapy. Abstract 444

PARP Expression
PARP (polyadenosine diphosphate [ADP]-ribose polymerase) is a family of multifunctional enzymes, of which PARP-1 is a key regulator of DNA damage repair processes, binds directly to DNA strand breaks, and is involved in DNA base-excision repair. Increased expression of PARP is thought to be associated with resistance to DNA damaging therapeutic agents. PARP inhibitors are currently being investigated in clinical trials either as single agents or in combination with chemotherapy agents. Von Minckwitz and his colleagues investigated PARP expression in the tumor specimens of patients who were undergoing neoadjuvant chemotherapy on the GeparTrio trial, and attempted to correlate PARP expression with pathologic complete response. The tumor specimens were centrally stained immunohistochemically for PARP, ER, PgR and HER2 expression. Both cytoplasmic and nuclear staining of PARP was assessed with regards to intensity and percentage of positive cells and was scored as low, medium, or high expression. Results: High expression was found in 20% of HR-positive/HER2-negative, 20% of HR-positive/HER2-positive, 36% of HR-negative/HER2-positive, and 35.6% of HR-negative/HER2-negative tumors. High PARP expression was significantly correlated with undifferentiated or non-lobular cancers, and negative HR status. Patients with a high PARP expression showed a pCR rate of 25.7% compared to 18.8% and 6.1% in patients with medium or low expression. No correlations were found regarding nuclear PARP staining. The authors suggested that cytoplasmic PARP expression can be detected by immunohistochemistry in all subtypes of early breast cancer, not just in triple-negative tumors and are correlated with an aggressive biologic tumor pattern. They stated that clinical investigation of PARP inhibitors should not be limited to triple-negative tumors alone. Abstract 443

Bevacizumab in Metastatic Breast Cancer
Three independent phase III trials have now shown the significant clinical benefit of combining bevacizumab with chemotherapy from multiple classes compared to chemotherapy alone. However, preclinical studies have suggested that the use of anti-angiogenic agents may increase the malignant potential of tumors, especially after the agents are stopped. This paper, delivered by Chan et al, is an exploratory analysis on the data from the AVADO trial. In that trial, patients with metastatic breast cancer were treated with docetaxel 100 mg/m2 every 3 weeks for a maximum of 9 cycles. Patients were randomized to 1 of 3 arms in combination with the docetaxel: placebo, bevacizumab 7.5 mg/kg, or bevacizumab 15 mg/kg given every 3 weeks until progression. Mortality rates were calculated every 30 days for up to day 210 after the discontinuation of the placebo or bevacizumab. For patients discontinuing either placebo or bevacizumab for toxicity, progression-free survival was analyzed. Results: 91 patients had discontinued their bevacizumab or placebo for toxicity. The median PFS from discontinuation was longer in the bevacizumab arms than the placebo arm. Mortality rates for patients stopping bevacizumab or placebo for any reason (n = 463) were similar or lower in the bevacizumab arms. The authors concluded that although preclinical data suggest that anti-angiogenic therapy may increase the malignant phenotype of a tumor that was not supported by the clinical outcomes of patients enrolled in the AVADO trial who discontinued their bevacizumab or placebo for toxicity, or for any other reason. Abstract 480

130th Meeting of the American Surgical Association:

ACOSOG Z0011
The first presentation at the American Surgical Association meeting in April 2010 was presented by Dr Armando Giuliano on behalf of the American College of Surgeons Oncology Group and the Z-0011 investigators. The title of the trial is as follows: Local and Regional Control in Breast Cancer After Sentinel Node Biopsy without Axillary Lymph Node Dissection: Results from a Randomized Trial. Sentinel lymph node biopsy has significantly improved the quality of life for women with a negative sentinel node by allowing them to avoid the morbidity of an axillary lymph node dissection. If the sentinel lymph node is found to be involved, the standard of care is to perform a completion axillary lymph node dissection for presumed improved loco-regional control of the cancer. The original objective of this Z11 trial was to determine whether axillary lymph node dissection improves survival in women with stage I or IIA breast cancer. In addition, the trial was to quantify and compare surgical morbidities associated with sentinel lymph node dissection with and without ALND in these patients. The trial was intended to accrue 1900 women. However, due to slow accrual, the trial was closed prematurely. The objective of this Z-0011 trial presentation was to evaluate the local and regional recurrence in hemotoxylin and eosin (H & E)–node-positive women after sentinel lymph node biopsy alone compared to those treated with an axillary lymph node dissection. Women were required to have a clinically staged T1-2, N0 invasive breast cancer, and subsequently underwent breast conserving surgery followed by radiation. The use of systemic therapy was left to the treating oncologist and was not dictated by the trial. Results: 446 women were randomized to sentinel lymph node biopsy alone, and 445 to sentinel lymph node biopsy plus axillary lymph node dissection. The 2 groups were similar with regards to age, grade, estrogen receptor status, the use of adjuvant systemic therapy (97% of patients in each arm), tumor type, T stage, and tumor size. The median number of lymph nodes removed was 2 versus 17 for those without versus those with an axillary lymph node dissection (ALND). Approximately 20% of the women undergoing the ALND were found to have involved non-sentinel lymph nodes. After a median follow-up of 5.9 years, there are no statistical differences in either local recurrence or regional recurrence between the 2 groups with an approximately 2% local recurrence rate. The authors concluded that despite the potential of residual disease in the axilla, sentinel node biopsy alone can offer excellent regional control and may be reasonable management for selected patients with breast cancer.

References
1. Otto S, Boer R, Broeders MJM, et al. Evaluation of the breast cancer screening programme in Southwest Netherlands: a case-control study. Eur J Cancer Suppl. 2010;8(3):53. Abstract 1N.

2. Romestaing P, Hennequin C, Bosset JF, et al. Elective irradiation of Internal Mammary Chain (IMC) after mastectomy has no impact on 10y overall survival in breast cancer - results of a randomized phase III study in France. Eur J Cancer Suppl. 2010;8(3):54. Abstract 5N.

3. Poortmans P, Fourquet A, Collette L, et al. Irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer: state of the day of EORTC phase III trial 22922/10925 with 4004 patients. Eur J Cancer Suppl. 2010;8(3):54. Abstract 6N.

4. Pierce L, Phillips K, Griffith K, et al. Local therapy options in BRCA1/2 carriers with operable breast cancer: the importance of adjuvant chemotherapy. Eur J Cancer Suppl. 2010;8(3):55. Abstract 7N.

5. De Azambuja E, Arfi M, Dowsett M, et al. Prognostic and predictive value of central and local hormone receptor assessment in the HERA trial. Eur J Cancer Suppl. 2010;8(3):185. Abstract 435.

6. Rutgers E, Piccart M, Delaloge S, et al. The EORTC 10041/BIG 03-04 MINDACT trial is feasible: first results of the pilot phase. Eur J Cancer Suppl. 2010;8(3):188. Abstract 444.

7. von Minckwitz G, Muller B, Loibl S, et al. PARP is expressed in all subtypes of early breast cancer and is a predictive factor for response to neoadjuvant chemotherapy. Eur J Cancer Suppl. 2010;8(3):188. Abstract 443.

8. Chan A, Miles DW, ten Bokkel Huinink D, et al. Evidence from the phase III AVADO study reveals no increase in tumour malignant potential following treatment of metastatic breast cancer (mBC) with bevacizumab (BV) and docetaxel (D). Eur J Cancer Suppl. 2010;8(3):199. Abstract 480.

9. Giuliano AE, McCall L, Beitsch P, et al. Local and regional control in breast cancer after sentinel node biopsy without axillary lymph node dissection: Results from a randomized trial. Abstract and presentation at: American Surgical Association 130th Annual Meeting; April 8 - 10, 2010; Chicago, IL.

To enhance the abstracts presented here from EBCC 7, there are 6 “Best of the Day” interviews with leading national and international oncologists that are available in the Imedex E-Learning Center.

I hope that you have enjoyed this edition of OncoFacts and will look forward to next month’s edition.

OncoFacts™ Editor:

Christy Russell, MD

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