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ScienceWeek
6. BREAST CANCER
HORMONE REPLACEMENT THERAPY AND BREAST CANCER
C-L. Chen et al (Fred Hutchinson Cancer Research Center Seattle, US) discuss hormone replacement therapy and breast cancer, the authors making the following points:
1) The possible association between the use of estrogen replacement therapy or combined estrogen-progestin replacement therapy and the incidence of breast cancer has been assessed in numerous studies. In 1997, the Collaborative Group on Hormonal Factors in Breast Cancer reported a pooling and reanalysis of data from 52,705 women with breast cancer and 108,411 women without breast cancer, that study reporting a modest increase in the risk of breast cancer associated with ever use of estrogen replacement therapy, with evidence of an increasing relative risk with increasing duration of use. The risk of breast cancer was increased among current users, but not among past users. It was also reported in that study that among women whose duration of current combination therapy was more than 5 years, the risk appeared to be increased relative to never users, but the evidence was imprecise. In addition, there is recent evidence that use of hormone replacement therapy may differentially affect the incidence of lobular cancer relative to other types of breast cancer.
2) The authors conducted a nested case-control study to examine the relationship between postmenopausal hormone replacement therapy and risk of breast cancer by histologic type among female enrollees of a group health cooperative in the Seattle area. The study involved 705 postmenopausal women, age 50 to 74 years, who had primary invasive breast cancer diagnosed between July 1, 1990 and December 31, 1995 (called "cases"), and 692 randomly selected aged-matched female members of the same health cooperative (called "controls").
3) The authors report their data add to the growing body of evidence that recent long-term use of hormone replacement therapy is associated with an increased risk of breast cancer, and that such use may by related particularly to lobular tumors.
J. Am. Med. Assoc. 2002 287:734
Related Background:
BREAST CANCER: ON RADICAL MASTECTOMY VS. CONSERVATIVE SURGERY
U. Veronesi et al (European Institute of Oncology Milan, IT) discuss breast cancer surgery, the authors making the following points:
1) The radical mastectomy introduced by Halsted(1) was the treatment of choice for breast cancer of any size or type, regardless of the patient's age, for 80 years. Apart from a few modifications, such as enlarging the extent of the dissection to include the internal mammary nodes or reducing it to spare the pectoralis muscles, the Halsted mastectomy was performed as originally described throughout this period. The possibility of attempting a surgical procedure that would conserve the breast was not widely considered during those years.(2,3)
2) In 1969, a randomized study to compare radical mastectomy with breast-conserving surgery, which was termed "quadrantectomy", was approved by the World Health Organization Committee of Investigators for Evaluation of Methods of Diagnosis and Treatment of Breast Cancer.(4) The recruitment of patients began at the Milan Cancer Institute in 1973, after the new procedure was standardized, and preliminary data showing that survival rates were equal after radical and breast-conserving surgery were published in 1977(5) and 1981.
3) The main criticism of the data was that they were too preliminary; patients with small breast cancers must be followed for a very long time, even decades, to ensure that the evaluation of the efficacy of any new treatment is accurate. The authors carefully monitored the 701 women in the trial for up to 29 years, and they now report the results.
4) Thirty women in the group that underwent breast-conserving therapy had a recurrence of tumor in the same breast, whereas eight women in the radical-mastectomy group had local recurrences (P < 0.001). The crude cumulative incidence of these events was 8.8 percent and 2.3 percent, respectively, after 20 years. In contrast, there was no significant difference between the two groups in the rates of contralateral-breast carcinomas, distant metastases, or second primary cancers. After a median follow-up of 20 years, the rate of death from all causes was 41.7 percent in the group that underwent breast-conserving surgery and 41.2 percent in the radical-mastectomy group (P=1.0). The respective rates of death from breast cancer were 26.1 percent and 24.3 percent (P=0.8).
5) The authors conclude: The long-term survival rate among women who undergo breast-conserving surgery is the same as that among women who undergo radical mastectomy. Breast-conserving surgery is therefore the treatment of choice for women with relatively small breast cancers.
References (abridged):
1. Halsted WS. A clinical and histological study of certain adenocarcinomata of the breast: and a brief consideration of the supraclavicular operation and of the results of operations for cancer of the breast from 1889 to 1898 at the Johns Hopkins Hospital. Ann Surg 1898;28:557-576.
2. Hirsch J. Radiumchirurgie des Brustkrebses. Dtsch Med Wochenschr 1927;53:1419-1421.
3. Keynes G. Conservative treatment of cancer of the breast. BMJ 1937;2:643-647.
4. Meeting of investigators for evaluation of methods of diagnosis and treatment of breast cancer: final report. Geneva: World Health Organization, December 1969.
5. Veronesi U, Banfi A, Saccozzi R, et al. Conservative treatment of breast cancer: a trial in progress at the Cancer Institute in Milan. Cancer 1977;39:Suppl:2822-2826.
New Engl. J. Med. 2002 347:1227
Related Background Brief:
CONSERVATIVE TREATMENT OF BREAST CANCER. A TRIAL IN PROGRESS AT THE CANCER INSTITUTE OF MILAN. The authors report a clinical trial on conservative surgery in progress at the National Cancer Institute of Milan, Italy. The randomized clinical trial compares radical mastectomy with a more conservative procedure consisting of mammary resection plus axillary dissection plus radiotherapy. The resection comprises an entire quadrant of the breast together with the overlying skin and the corresponding portion of the fascial sheet of the pectoralis major. The axillary dissection is performed in continuity with the resected breast quadrant except in cases with tumors of lower inner quadrants, who need two separate incisions. After surgery the patients receive 6000 rads to the residual breast tissue over five to six weeks, starting 15 days after operation. The cosmetic results are satisfactory in approximately 70% of cases. The trial is limited to cases with tumors less than 2 cm and no palpable axillary nodes (T1N0M0). Patients with histologically positive lymph nodes (N+) are submitted to adjuvant chemotherapy with CMF for one year. From September 1973, to October 1976, 331 cases entered the trial. One hundred sixty were treated with radical mastectomy and 164 with the conservative procedure. Axillary metastases were found in 23% of the radical and in 29% of the conservative surgery group. Four local-regional recurrences have occurred till now, two in each group. Five cases in the radical mastectomy group and one in the conservative group had distant metastases. The clinical trial will collect some 500 cases by the end of 1977 and significant preliminary results are expected to be available from 1978. U. Veronesi et al: Cancer 1977 39(6 Suppl):2822.
Related Background Brief:
COMPARING RADICAL MASTECTOMY WITH QUADRANTECTOMY, AXILLARY DISSECTION, AND RADIOTHERAPY IN PATIENTS WITH SMALL CANCERS OF THE BREAST. The authors report that from 1973 to 1980 they carried out a controlled study at the National Cancer Institute in Milan to consider the value of a conservative procedure in patients with breast cancer of small size. The authors randomized 701 patients with breast cancer measuring less than 2 cm in diameter and with no palpable axillary lymph nodes to Halsted radical mastectomy or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral residual breast tissue. The authors treated 349 patients with Halsted mastectomy and 352 with quadrantectomy. The two groups were comparable in age distribution, size and site of primary tumor, menopausal status, and frequency of axillary metastases. There were three local recurrences in the Halsted group and one in the quadrantectomy group. Actuarial curves showed no difference between the two groups in disease-free or overall survival. From these results, mastectomy appears to involve unnecessary mutilation in patients with breast cancer of less than 2 cm and no palpable axillary nodes. U Veronesi, et al: New Engl. J. Med. 1981 305:6.
Related Background Brief:
CUMULATIVE CAUSE-SPECIFIC MORTALITY FOR CANCER PATIENTS IN THE PRESENCE OF OTHER CAUSES: A CRUDE ANALOGUE OF RELATIVE SURVIVAL. A common population-based cancer progress measure for net survival (survival in the absence of other causes) of cancer patients is relative survival. Relative survival is defined as the ratio of a population of observed survivors in a cohort of cancer patients to the proportion of expected survivors in a comparable set of cancer-free individuals in the general public, thus giving a measure of excess mortality due to cancer. Relative survival was originally designed to address the question of whether or not there is evidence that patients have been cured. It has proven to be a useful survival measure in several areas, including the evaluation of cancer control efforts and the application of cure models. However, it is not representative of the actual survival patterns observed in a cohort of cancer patients. This paper suggests a measure for cumulative crude (in the presence of other causes) cause-specific probability of death for a population diagnosed with cancer. The measure does not use cause of death information which can be unreliable for population cancer registries. Point estimates and variances are derived for crude cause-specific probability of death using relative survival instead of cause of death information. Examples are given for men diagnosed with localized prostate cancer over the age of 70 and women diagnosed with regional breast cancer using Surveillance, Epidemiology and End Results (SEER) Program data. The examples emphasize the differences in crude and net mortality measures and suggest areas where a crude measure is more informative. Estimates of this type are especially important for older patients as new screening modalities detect cancers earlier and choice of treatment or even "watchful waiting" become viable options. K.A. Cronin and E.J. Feuer: Stat Med 2000 19:1729.
Relative Background Brief:
TWENTY-YEAR FOLLOW-UP OF A RANDOMIZED TRIAL COMPARING TOTAL MASTECTOMY, LUMPECTOMY, AND LUMPECTOMY PLUS IRRADIATION FOR THE TREATMENT OF INVASIVE BREAST CANCER. In 1976, the authors initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan Meier and cumulative-incidence estimates of the outcome were obtained. Results: The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P < 0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those who underwent total mastectomy, was 1.05 (95 percent confidence interval, 0.90 to 1.23; P=0.51). The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation, as compared with those who underwent total mastectomy, was 0.97 (95 percent confidence interval, 0.83 to 1.14; P=0.74). Among the lumpectomy-treated women whose surgical specimens had tumor-free margins, the hazard ratio for death among the women who underwent postoperative breast irradiation, as compared with those who did not, was 0.91 (95 percent confidence interval, 0.77 to 1.06; P=0.23). Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer. This decrease was partially offset by an increase in deaths from other causes. The authors conclude: Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained. B. Fisher et al: New Engl. J. Med. 2002 347:1233.
Related Background:
ON BREAST CANCER: CURRENT RESEARCH
L. Sivaraman et al (Baylor College of Medicine, US) discuss breast cancer. The lifetime risk of developing breast cancer among Western women is approximately 10 percent, and despite advances in therapeutic strategies, breast cancer remains the leading cause of cancer deaths in women in most developed countries. It is expected that ultimately prevention of breast cancer will be achieved with better understanding of the etiological factors contributing to the development of the disease. There is significant evidence that the timing of normal developmental events like menarche, menopause, and age of first full-term pregnancy (parity) have a significant impact on an individual's susceptibility to breast cancer. In particular, there is strong epidemiological evidence that women who experience a full-term pregnancy early in their lives have a significantly reduced risk for developing breast cancer. This is recapitulated in rat models that demonstrate that early full-term pregnancy confers resistance ("refractoriness") to chemical carcinogen-induced mammary tumorigenesis. This protection can be mimicked with the hormones estrogen and progesterone, or human choriogonadotropin given either before or immediately after carcinogen challenge to induce a refractory state (i.e., a state resistant to tumorigenesis). But despite a wealth of literature supporting the role of endocrinological processes in mediating parity-related refractoriness to tumorigenesis, the cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved.
Proc. Nat. Acad. Sci. 2001 98:12379
Related Background:
ALCOHOL AND BREAST CANCER
K.W. Singletary and S.M. Gapstur (University of Illinois Urbana-Champaign, US) alcohol and breast cancer. The association of alcohol consumption with increased risk for breast cancer has been a consistent finding in a majority of epidemiologic studies during the past 2 decades. The authors summarize information on this association from human and animal investigations, with particular reference to epidemiologic data published since 1995. Increased estrogen and androgen levels in women consuming alcohol appear to be important mechanisms underlying the association. Other plausible mechanisms include enhanced mammary gland susceptibility to carcinogenesis, increased mammary carcinogen DNA damage, and greater metastatic potential of breast cancer cells, processes for which the magnitude likely depends on the amount of alcohol consumed. Susceptibility to the breast cancer-enhancing effect of alcohol may also be affected by other dietary factors (such as low folate intake), life-style habits (such as use of hormone replacement therapy), or biological characteristics (such as tumor hormone receptor status). Additional progress in understanding the enhancing effect of alcohol on breast cancer will depend on a better understanding of the interactions between alcohol and other risk factors and on additional insights into the multiple biological mechanisms involved. There is apparently firm evidence that in general women who consume alcohol, even at the level of 1 drink per day, have higher blood levels of estrogen (estradiol) than women who do not drink. The authors recommend that in general women who do not drink should not start, and those who do drink should do so in moderation, which is generally recognized to be approximately 1 drink per day.
J. Am. Med. Assoc. 2001 286:2143
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