Breast Cancer

Primary nonepithelial malignancies of the breast comprise an importantminority of breast neoplasms, including primary breast sarcomas,therapy-related breast sarcomas, the phyllodes tumors, and primarybreast lymphomas. With widespread mammographic detection ofbreast lesions, these tumors represent critical elements of the differentialdiagnosis of even benign-appearing lesions. Each has a distinctclinical profile, including presentation, available therapeutic options,and prognosis, further underscoring the importance of timely recognition.The increasing incidence of breast carcinomas and the subsequenttherapy thereof may be contributing to an increase in the numberof therapy-related breast tumors. This review discusses various featuresof these uncommon malignancies and their treatment, with thegoal of increasing understanding of their clinical behavior andmanagement.

SAN ANTONIO-The question of how much weight to give isolated bone marrow micrometastases in making breast cancer treatment decisions was the focus of three presentations at the 26th San Antonio Breast Cancer Symposium. Two of these studies confirmed that occult micrometastases are a warning sign of poor prognosis in many breast cancer patients. The third found that isolated tumor cells in the sentinel lymph node are not a major problem in patients with ductal carcinoma in situ (DCIS).

SAN ANTONIO-A new analysis of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial shows that the aromatase inhibitor anastrozole (Arimidex) was more effective in preventing relapses than tamoxifen in receptor-positive breast cancer patients (estrogen and/or progesterone positive [ER+ and/or PR+]), with the greatest effect seen in ER-positive/PR-negative (ER+/PR-) women, said Mitch Dowsett, PhD, professor of biochemical endocrinology, Royal Marsden Hospital, London, UK, on behalf of the ATAC Trialists’ Group.

SAN DIEGO-In a cohort of endometrial cancer patients at M.D. Anderson Cancer Center, those who had previously developed breast cancer and used tamoxifen did not have a higher incidence of high-risk histologic subtypes, compared with breast cancer patients not receiving tamoxifen, reported Brian M. Slomovitz, MD, at the Society of Gynecologic Oncologists 35th Annual Meeting (SGO abstract 24).

AN ANTONIO-Breast cancer patients with BRCA 1 or 2 mutations undergoing breast-conserving surgery plus radiotherapy do not have more in-breast recurrences or radiotherapy complications than their counterparts without the germ-line mutation, and they derive particular benefits from prophylactic bilateral oophorectomy, according to 10-year results from a large collaborative database reported at the 26th San Antonio Breast Cancer Symposium (abstract 5).

Locally advanced breast canceraccounts for up to 70% ofbreast cancer cases worldwide.[1] In the past decade, neoadjuvantsystemic therapy has emerged asa therapeutic option for early breastcancer. The main goal of neoadjuvanttreatment is to downstage breast tumors,rendering them operable or permittingbreast-conserving surgery.The therapy has been used increasinglyin patients who have large breasttumors and are candidates for mastectomy,but in whom tumor shrinkageallows for less extensive surgeryand better cosmetic results.[2] Thedegree of the tumor’s responsivenessto preoperative therapy could serveas a surrogate for the response ofmicrometastasis to therapy and theconsequent outcome.[3]

Breast cancer mortality has declinedin recent years due toadvances in screening and adjuvantsystemic therapy. Based on anoverall estimated risk of relapse foran individual woman, her age, comorbidities,and tumor characteristics,she may be offered adjuvant hormonetherapy, chemotherapy, or both.

For many oncologists, neoadjuvant treatment for breast cancer issynonymous with preoperative cytotoxic chemotherapy, regardless oftumor characteristics. Preoperative therapy with an endocrine agent isgenerally considered suitable only for the frail elderly or the medicallyunfit. However, favorable information regarding third-generationaromatase inhibitors in the treatment of all stages of breast cancerprompts a reconsideration of this bias. In light of the fact thatneoadjuvant therapy with aromatase inhibitors is restricted to postmenopausalwomen with strongly estrogen-receptor–positive tumors, the assumptionthat neoadjuvant combination chemotherapy is more efficaciousthan a third-generation aromatase inhibitor can be reasonablyquestioned. It is particularly remarkable that the outcome of a comparisonof adjuvant tamoxifen vs anastrozole (Arimidex)-the Arimidex,Tamoxifen Alone or in Combination (ATAC) trial-in more than 6,000patients was predicted by a neoadjuvant trial that showed an efficacyadvantage for a third-generation aromatase inhibitor (letrozole[Femara]) compared to tamoxifen in a sample of 337 patients afteronly 4 months of treatment. The potential of the neoadjuvant setting inefforts to identify new biologic agents that could build on the effectivenessof adjuvant aromatase inhibitors is therefore beginning to be appreciated.Finally, neoadjuvant therapy with an aromatase inhibitorcould be considered a sensitivity test of endocrine therapy that might beincorporated into strategies to individualize treatment according to response.For this possibility to be realized, however, a better understandingof the relationship between surrogates from the neoadjuvant settingand the long-term outcome of adjuvant aromatase inhibitor therapywill have to be established through practice-setting clinical trials.

SAN ANTONIO-Expression of a set of 21 genes can be analyzed from ordinary, paraffin-embedded tissue specimens and can predict which newly diagnosed, node-negative, tamoxifen-treated breast cancer patients are likely to have distant disease recurrence within 10 years, according to data reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 16). The assay is less useful in node-negative patients who have not been treated with tamoxifen.

This special "annual highlights" supplement to Oncology News International is a compilation of some of the major advances in the management of gastrointestinal cancers during 2003–2004, as reported in ONI. Guest editor Dr. James L. Abbruzzesecomments on the reports included herein and discusses advances in the clinical management of GI cancers, with a focus on developments in targeted therapy, newcombinations, adjuvant therapy, and what to watch for in 2004.

About 10% to 15% of patients who undergo breast-conservation surgeryand radiation therapy will subsequently develop ipsilateral breasttumor recurrence (IBTR). This paper reviews the biology, clinical management,and outcome of this entity. Risk factors for IBTR includeyoung age, positive microscopic margins, gross multifocality, an extensiveintraductal component, and lymphatic vessel invasion. The standardtherapy following IBTR has been mastectomy, but interest in furtherbreast-conservation approaches has recently arisen. Although theoutcome following salvage therapy is quite good, the risk of distantmetastases for patients with IBTR is three to five times greater than forthose without recurrence. The reason for this association has been controversial,but it now appears that IBTR is both a marker of the underlyingbiologic aggressiveness of the tumor and a source for furthertumor metastasis. Monitoring of patients following lumpectomy andradiation therapy, and aggressive therapy for IBTR when diagnosed,are clearly warranted. Prognostic factors at the time of IBTR and implicationsfor local and systemic therapy are discussed.

SAN ANTONIO-Docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) improved overall survival by 30% and disease-free survival by 28% at 5 years, compared with the standard combination of flu-orouracil, doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for women with node-positive, early-stage breast cancer, John R. Mackey, MD, reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 43).

SAN ANTONIO-Intensity of immunostaining for the gene BP1 (beta protein 1) correlates with breast cancer aggressiveness, and detection of BP1 in otherwise apparently normal tissue specimens may be a marker for early detection of breast cancer, Patricia E. Berg, PhD, said at the 26th San Antonio Breast Cancer Symposium (abstract 41).

The success of the National SurgicalAdjuvant Breast and BowelProject (NSABP) trial P-01at showing that we now have an effectivemeans to prevent breast cancerposes larger and more seriousquestions: Who should receivechemoprevention, and at what pointin life should this occur? The designof the P-01 study allowed many womento enroll who, according to Gailmodel calculations, were at a less than 1% per year risk of subsequent breastcancer during the expected 5-yeartreatment period. These lower-risk individualsseemed to have less benefitthan those patients at much higherrisk. Other similar prevention studiesseem to confirm this observation.

Ductal lavage is a procedure that can improve the stratification ofwomen with clinical evidence of increased breast cancer risk by thecytologic detection of atypia. The relative risk of future breast cancerin women harboring atypia is approximately 3 to 5, as demonstrated instudies of women harboring atypia within direct nipple aspirates, fineneedleaspiration biopsies, and histopathology from surgical specimens.It is intuitively reasonable and biologically plausible that atypia detectedin ductal lavage specimens would be associated with a comparablemeasure of association; however, documentation of this assumptionawaits maturation of prospectively accumulated data. The technologyof the ductal lavage procedure is also a promising translational researchtool, because of the relatively substantial yield of ductal cellularmaterial for analysis via a minimally invasive technique.

SALT LAKE CITY-Women who continue to smoke during treatment for early breast cancer have more than double the risk of death, compared with those who have never smoked or those who quit the habit before their treatment, according to a study presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO abstract 2024).

SAN ANTONIO-Neoadjuvant anastrozole (Arimidex, A) produced about the same rate of clinical responses as tamoxifen (T) or combined anastrozole/tamoxifen (AT) in estrogen-receptor-positive (ER+) breast cancer and was better than either for shrinking tumors enough to permit breast-conserving surgery, researchers reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 1).

SALT LAKE CITY-Physical examination of the breasts by a woman and her health care provider remains an important means of detecting breast cancer, especially in young women, according to a study reported at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (abstract 194). The study found that physical examination was the sole method of breast cancer detection in nearly half of women younger than 40.

Dr. Wood has provided a comprehensivebut succinct reviewof the clinical managementoptions available to women withan increased risk of breast cancer. Heclearly defines his approach to riskstratificationamong women likely tosee a breast surgeon with concernsabout their breast cancer risk basedon family history-ie, BRCA1/2 mutationcarriers, those who have not yetbeen tested for BRCA1/2 mutations, and those who have tested negativefor BRCA1/2 mutations but have sufficientfamily and personal history tohave ongoing concern despite the negativetest. In the past, breast surgeonsmight have seen a wider range ofwomen at risk, but many are now toobusy to see anyone who is not contemplatingbilateral mastectomies. It is evenmore important, therefore, that they befamiliar with the basic workings of genetictesting.

Women with any family history of breast cancer assume a high probabilityof risk. Counseling women involves ascertainment of an accuratefamily history and use of the best predictive models to assess boththe risk of a known mutation and the risk of breast cancer. This riskmust then be considered in the contexts of both the woman’s lifetimeand the next decade, in each instance carefully separating the risk ofdeveloping cancer from the risk of mortality. These two risks are oftenemotionally melded in women who have watched a loved one die ofcancer. The options for a woman at significantly increased risk of breastcancer include optimal surveillance, chemoprevention, and prophylacticsurgery. This entire field is in continuing evolution as better methodsof diagnosis, screening, and chemoprevention continue to enter clinicalpractice.

Dr. Wood has provided an excellentreview of the issuesfacing women at high risk fordeveloping breast cancer. In additionto emphasizing the significance of accuraterisk assessment, he describessurveillance techniques that enableearly detection of the disease and hasprovided a comprehensive review ofrisk-reduction options for women athigh risk.

Four newly created Breast Cancer and the Environment ResearchCenters will work together in a $35 million effort to investigatethe prenatal to adult environmental factors that may predisposewoman to developing breast cancer. The centers, jointly financed bythe National Cancer Institute and the National Institute of EnvironmentalHealth Sciences, will receive $5 million annually for 7 years.

SALT LAKE CITY-Women with breast cancer who have limited nodal involvement may be able to safely forego regional radiation therapy after lumpectomy, according to an analysis of data from 10 randomized trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP) presented at the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO abstract 74).

Both paclitaxel and gemcitabine (Gemzar) have shown activity andmanageable toxicity when used as single agents in heavily pretreatedpatients with metastatic breast cancer. This phase II study evaluatedtheir use in combination for metastatic breast cancer patients whosedisease recurred or progressed following treatment with anthracyclinecontainingregimens.

It is fair to say that combination chemotherapy is the standard of care inmetastatic breast cancer. In many ways, however, the burden of proof that it isthe standard of care remains with those who advocate combination therapy.Some of the push to consider combination therapy as the standard is provided by ameta-analysis of trials comparing single-agent and combination therapy in thissetting, which was reported by Fossati et al in 1998.[1] Although the vast majorityof individual trials included in the analysis did not show significant differences inhazard ratios for death, the meta-analysis showed a significant mortality advantagefor combination therapy. Yet the total population considered in this meta-analysis(990 patients in combination groups, 996 in single-agent groups) is not largecompared with some recent phase III trials in metastatic breast cancer, includingone reported by Sledge et al that showed that sequential doxorubicin and paclitaxelwas equivalent to the concurrent combination.[2] Further, no studies includingtaxanes are included in the meta-analysis, raising questions about the application ofits findings to contemporary oncology. In addition, the trials included did notexamine sequential single-agent treatment, an approach that clearly has merit andthat requires additional consideration and study.

Krag and Harlow believe thatsentinel lymph node biopsyfor breast cancer is still an experimentalprocedure because “longtermrandomized trials comparing thesurvival outcome of this procedurewith that of conventional axillary noderesection have not been completed.”Specifically, they are awaiting the resultsof the American College of SurgeonsOncology Group (ACOSOG)Z0011 trial and the National SurgicalAdjuvant Breast and Bowel Project(NSABP) B-32 trial before they makea determination about the “safety” ofthis procedure.[1] This is a commonmisconception, because these studieswill not prove whether sentinel nodebiopsy results in equivalent survivalcompared to standard level I/II axillarydissection in patients with clinicallynode-negative breast cancer. Thetime has come for clear thinking aboutthe design of these trials and precisereasoning about the interpretation oftheir ultimate results.

The biologic rationale for sentinellymph node biopsy, althoughit may ultimately stagethe axilla more accurately, is essentiallythat a positive lymph node representssystemic disease. Removal ofaxillary lymph nodes is of little, if any,therapeutic value, and most patients with tumors greater than 1 cm are offeredchemotherapy regardless ofnodal status. Thus, the risks of lymphedemaand neurologic deficit outweighany prognostic information derivedfrom an axillary node dissection whenthis same information can be accuratelyobtained in a less invasive, lessmorbid procedure.

Gemcitabine (Gemzar) and paclitaxel exhibit good activity and goodsafety profiles when used alone and together in the treatment of advancedbreast cancer. In a phase II trial, 45 patients with metastaticbreast cancer received gemcitabine at 1,200 mg/m2 on days 1 and 8 andpaclitaxel at 175 mg/m2 on day 1 every 21 days. Twenty-seven patients(60.0%) had prior adjuvant therapy. Objective response was observedin 30 patients (objective response rate 66.7%, 95% confidence interval[CI] = 52%–71%), including complete response in 10 (22.2%) and partialresponse in 20 (44.4%). Median duration of response was 18 months(95% CI = 11–26.7 months), median time to tumor progression for theentire population was 11 months (95% CI = 7.1–18.7 months), medianoverall survival was 19 months (95% CI = 17.3–21.7 months), and the1-year survival rate was 69%. Treatment was well tolerated, with grade3/4 toxicities being infrequent. Grade 3/4 leukopenia, neutropenia, andthrombocytopenia were each observed in six patients (13.3%). No patientwas discontinued from the study due to hematologic ornonhematologic toxicity. Thus, the gemcitabine/paclitaxel combinationshows promising activity and tolerability when used as first-line treatmentin advanced disease. The combination recently has been shownto be superior to paclitaxel alone as first-line treatment in anthracyclinepretreatedadvanced disease according to interim results of a phase IIItrial and it should be further evaluated in comparative trials in breastcancer.

Sentinel node surgery potentially increases the accuracy of identifyinglymph nodes that contain breast cancer and decreases morbiditycompared to conventional axillary lymph node resection. However, nolong-term comparisons of the two modalities have been carried out,and the survival benefit associated with one protocol vs the other remainsunknown. Although sentinel node surgery is not expected to increasethe cure rate of breast cancer patients, a significant reduction inthe incidence of permanent side effects associated with axillary noderesection will be a considerable advance. The completion of clinicaltrials establishing that no meaningful reduction in survival is associatedwith the decrease in side effects is important.

In patients with advanced breast cancer, treatment with paclitaxeland doxorubicin has been shown to produce impressive overall responserates (up to 94%) and to prolong overall survival significantly over acombination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide(Cytoxan, Neosar) in one prospective phase III clinical study.