Over the last 4 decades, profound changes have occurred in breast cancer treatment, diagnosis and prevention, and radically new ways of conducting research have developed. Prognosis for the disease has improved markedly, patient quality of life has become a central concern and researchers and senologists are caught up in a whirlwind of new findings and concepts that has swept away notions thought consolidated just a few years ago.
In the recent 10 years breast cancer treatments' scenario is radically changed. Extraordinary new surgical approaches give more and more conservative solutions both for the breast and especially for the axilla avoiding dissection in more than 80% of early cases. Instrumental early diagnosis and clinical prediction are now able to identify very initial cases often in premalignant stage. Technology arrived in the operating theatre for the intraoperative radiotherapy treatments giving to the patients the better quality of life with the help also of the plastic surgeons. There are still near horizons to reach: modern neo-adjuvant and adjuvant treatments are going quickly from the laboratory to patient's bed. © 2007 Wiley-Liss, Inc.
The revolution in breast cancer treatment began in the 1970s with the large Milan I trial. This trial randomized 701 patients to either breast-conserving surgery (quadrantectomy, complete axillary dissection plus breast radiotherapy, QUART) or Halsted mastectomy.1 Eligible patients had infiltrating carcinoma up to 2 cm, without clinically evident axillary involvement (T1N0), and were randomized in the operating room after excisional biopsy had confirmed histology and tumor size. The results, which ushered in the era of conservative surgery for all types of cancer, showed no difference in survival between the 2 arms. The most recent analysis of the Milan I results, after more than 20 years of follow-up2 confirmed indistinguishable survival curves for the 2 arms (Fig. 1): 28 (7.9%) conservatively treated patients and 8 (2.3%) in the Halsted arm developed local recurrences, but these events had no impact on survival. The low rate of adverse events in the QUART arm was partly attributable to the quadrantectomy operation, which was developed with the aim of achieving local control (in contrast to lumpectomy). Earlier studies had indicated that intraductal spread was relatively frequent in breast cancer, and in quadrantectomy, the entire portion of the ductal tree (up to the nipple) involved by the carcinoma is excised.
Sentinel node biopsy
A second major development in the surgical treatment of breast cancer was sentinel node biopsy. The first major study in this area, conducted at the European Institute of Oncology (EIO), randomized 516 patients to compare sentinel node biopsy plus immediate axillary dissection, with sentinel node biopsy plus axillary dissection only if the sentinel node was positive. After more than 5 years of follow-up, no differences between the arms that did and did not receive complete axillary dissection were found, either in terms of axillary recurrences or distant metastases.3 The extensive EIO experience in regional node mapping in breast cancer (axillary sentinel node biopsy in more than 10,000; internal mammary chain (IMC) biopsy in more than 500 patients) shows that accurate information on breast cancer spread to regional nodes can avoid extensive nodal dissection in many patients.
The technique of sentinel node biopsy developed at the EIO involves the use of radioactive tracer, 5–10 MBq of technetium-99 m-labelled colloidal particles, scintigraphy and a γ-detecting probe. The sentinel node is often the only one detected, and has the greatest activity if other nodes subsequently become hot. During surgery, the γ-detecting probe is passed over the marked skin area to locate the sentinel node(s). A 2–3 cm skin incision is made and the node(s) isolated and removed using the probe as necessary to guide this procedure. All removed material is checked in the operating room for radioactivity before being sent for pathological examination.
The pathological examination developed at the EIO to examine sentinel nodes is more exhaustive than normally performed on lymph nodes. This led to the more frequent discovery of metastases, with improved staging accuracy as a consequence.4, 5, 6, 7, 8 Another result of extensive pathological examination of sentinel nodes is that micrometastases (<2 mm) and isolated tumor cells are found with greater frequency9; the clinical significance of such microinvolvement is unclear.
Use of radioactive tracer to localize the sentinel nodes occasionally picks out lymph nodes in the IMC.14 This lymphatic drainage pathway from the breast has been ignored in recent decades after randomized trials showed that IMC dissection did not improve survival.15, 16 Nevertheless, the long-term results of these trials did show that the metastatic status of the IMC was as important prognostically as axillary node status, and that the prognosis is very unfavorable if both axillary and IMC lymph nodes are involved.17, 18 According to the International Union Against Cancer staging classification, these cases migrated from N0 (17 cases) or N1 (50 cases) to N3. If internal mammary sampling had not been performed, they would have been understaged.19 The change of stage led to a modification of the postoperative treatment plan, with radiotherapy given to the IMC and systemic therapy also given in some cases.
Current policy at the EIO is to perform complete axillary dissection whenever the sentinel node is macrometastatic. There are 2 main reasons for this. First, metastatic nodes in the axilla may grow and may be inoperable when discovered. Second, the prognosis depends on the number of involved axillary nodes and level of invasion. However, if the sentinel node contains micrometastasis only it is not clear that complete axillary dissection is necessary. The ongoing trial of the International Breast Cancer Study Group (23-01) is designed to determine the prognostic significance of minimal (≤2 mm) metastatic involvement of sentinel nodes in breast cancer; it randomizes patients with minimal involvement to total axillary dissection or no further axillary treatment.
Ductal lavage is a new mini-invasive technique developed at the EIO, which recovers sufficient breast duct cells to identify premalignant and malignant cells more often than nipple aspiration.20 After insertion of a microcatheter into the nipple and infusion of saline, the cell-rich fluid is recovered after breast massage. An international study20 on over 500 high risk women compared ductal lavage with nipple aspirate in detecting abnormal breast epithelial cells. Atypical cells were found in 24% of the ductal lavage samples against 6% of the nipple aspirate samples. The incidence of atypical cells in high-risk women is being compared with that in low-risk women in an ongoing study.
Atypical duct hyperplasia, first described by Page and Rogers,21 has been regarded as a stage between benign duct hyperplasia and low-grade ductal carcinoma in situ (DCIS). However, the genetic changes found in atypical duct hyperplasia are identical to those in DCIS, suggesting the 2 entities may not be distinct. Approaches such as gene-expression profiling will increasingly be used to determine whether breast cell anomalies are premalignant.22
Breast cancer diagnosis
The mainstay procedures for breast cancer diagnosis today are mammography, ultrasonography (US), and increasingly MRI and PET. Mammography remains the most important diagnostic tool when the breast is not overly dense, and is considered the best available technique for detecting small, nonpalpable lesions in postmenopausal women.23 Physical examination is still important because about 11% of breast cancers do not show up on mammography. US is best for diagnosing small cancers in women with dense breasts, and for distinguishing solid from cystic lesions.24, 25 Although mammography shows up suspicious microcalcifications not frequently evident on US, the technique does not reliably show certain lobular invasive carcinomas, Paget's disease of the nipple, inflammatory carcinoma or small peripheral carcinomas.
Because of its expense, MRI is mainly used for problem-solving when mammography and US do not provide clear answers. Nevertheless, MRI may be a sensitive technique and particularly useful for example for screening high-risk BRCA-positive patients, identifying primary foci in nonpalpable lesions, revealing axillary metastases when there is no evidence of a primary, and for assessing response to neoadjuvant chemotherapy. In dynamic contrast-enhanced MRI, images are acquired before and after contrast injection. Malignant lesions usually uptake and eliminate contrast rapidly, and are thus distinguished from benign lesions characterized by slow-rising persistent enhancement.26 Although MRI is sensitive, the rate of false positive diagnoses remains high and MRI findings cannot be the sole indication for breast surgery.27
PET is mainly used to detect metastatic foci in distant organs, and increasingly to assess the status of axillary nodes preoperatively. However, the technique often fails to identify low-grade and small (less than 5 mm) lesions,28 a new program for axillary node management in breast cancer is being developed at the EIO using PET. PET is performed in all patients with clinically negative nodes. If axillary involvement is revealed, sentinel node biopsy is not required and axillary dissection is performed. If PET is negative and the primary is less than 1 cm, the risk of axillary metastases is so low that sentinel node biopsy may be avoided. If PET is negative and the primary is larger, then sentinel node biopsy is required. Those with micrometastases only in the sentinel node may be recruited to the ongoing 23-01 trial mentioned above, and randomized either to axillary dissection or no further axillary treatment.
Electron intraoperative therapy (ELIOT) is the application of high dose of electron radiation during surgery after removal of the primary. Data show that local relapses occur mainly at the resection site, and that relapses in other quadrants of the same breast are much rarer. ELIOT delivers high dose radiotherapy to a very limited area—the part of the breast involved by the tumor (Fig. 2)—while sparing adjacent and underlying tissues. The EIO pioneered the use of ELIOT, and since 1999 has used the technique on over 2,000 breast cancer patients. ELIOT as only radiation treatment is still being investigated in a prospective randomized trial against conventional radiotherapy in women with early-stage breast cancer treated by conservative surgery.29, 30 ELIOT has several advantages over conventional radiotherapy to the residual breast. It costs less, solves the problem of difficult access to radiotherapy centers and has a beneficial effect on patient quality of life. In addition, ELIOT does not irradiate the skin and contralateral breast, while irradiation to the lung and the heart is greatly reduced because of the surgical insertion of radiation shields under the breast. ELIOT is also be used to give booster doses.31 A booster dose of 10–15 Gy given intraoperatively extends surgery by only 10–20 min, yet reduces the length of the conventional radiotherapy course by 2 weeks, with improved patient wellbeing and again reduced costs.
Another trial, targeted intraoperative radiotherapy (TARGIT) is comparing a low-energy radiation source used intraoperatively with a conventional postoperative approach.32
An interesting use of ELIOT is in nipple-sparing mastectomy (and breast recontruction) in which the nipple-areola complex is spared but is treated intraoperatively with ELIOT. These are the cases of multicentric tumors or extensive intraductal carcinomas.
Another advantage of ELIOT is that it does not interfere with systemic therapy when this is indicated.
Radioguided occult lesion localization
Radioguided occult lesion localization (ROLL) is sophisticated surgical technique employing radioactive tracer and a γ-detecting probe for the intraoperative localization and removal of nonpalpable breast lesions. The technique, developed at the EIO, involves the injection of immobile radioactive tracer (as opposed to the mobile radiotracer used identify sentinel nodes) into the nonpalpable lesion under mammographic or ultrasonographic control. The γ-detecting probe is used intraoperatively to locate the lesion and guide its removal. ROLL is a simple and accurate technique, which aids complete lesion excision but minimizes the amount of healthy tissue removed.33
The much more extensive use of plastic surgery, whose aim would be to simultaneously remodel both breasts. Using this approach, the initial resection can be more extensive, as the contralateral breast can be remodeled to match, in the same surgical session.
When faced with a even a small retroareolar tumor, many surgeons prefer to perform a mastectomy because of the poor aesthetic result provided by a “central quadrantectomy”. A surgical technique for overcoming this drawback involves removal of the nipple–areolar complex plus an underlying cone of mammary parenchyma down to the pectoral fascia. A flap of breast tissue is then defined in the lower outer quadrant of the breast again down to the fascia, but a circle of skin attached to its apex is retained. The flap is rotated up to fill the central defect, with the skin coming to lie in the position of the areola.34
Approximately 35% of breast tumors are located in the lower (inner or outer) quadrants. For these, the quadrantectomy again begins with a radial incision, and axillary dissection is performed through a separate incision. Simple quadrantectomy at this site is often aesthetically unsatisfactory, because loss of tissue substance distorts and lowers the nipple. This problem can be corrected by a reconstruction involving inductive mastoplasty with an inferior cutaneous pedicle. For tumors located between the upper and lower outer quadrants, the quadrantectomy must remove equal portions of the 2 involved quadrants, with axillary clearance via a separate incision. For tumors situated astride, the 2 upper quadrants or in the upper inner quadrant, the classic radial incision is indicated if the lesion is fairly close to the areola and axillary dissection is by a separate incision. For intermediate or peripheral locations, however, a radial incision would extend almost subclavicularly and leave a highly visible scar. A good alternative here is to make a horizontal incision over the tumor site, which, however, mandates particularly careful breast reconstruction to avoid displacing the nipple too far superiorly. During reconstruction, the residual gland is detached from the fascia of the pectoralis major in depth, and from the skin tissue surrounding the areola superficially.
Adjuvant systemic treatments
Adjuvant systemic therapy is given in an attempt to eradicate micrometastatic disease, which may be present in all patients with invasive breast cancer. The efficacy of postoperative adjuvant therapies can only be verified by comparing long-term outcomes in randomized trials. A concern about such treatments is that these are given to a large proportion of patients who are either cured by local treatment, or whose small risk of relapse is adequately reduced by hormonotherapy. Patients selected for adjuvant chemotherapy are generally those hormone receptor negative tumors. Premenopausal women with receptor-positive cancer are usually offered tamoxifen, with or without suppression of ovarian function. Cytotoxic chemotherapy before hormonotherapy is recommended for patients at high risk of relapse.35
Nonsteroidal (anastrozole and letrozole) and steroidal (exemestane) aromatase inhibitors (inhibitors of the enzyme converting secondary male hormones to estrogen) are new and effective alternatives to tamoxifen in the treatment of postmenopausal women with hormone-responsive breast cancer. These drugs are usually given after 2–3 years of tamoxifen, cutting short the standard 5-year tamoxifen treatment. Aromatase inhibitors alone may be better than tamoxifen.36, 37
Overexpression of the epithelial growth factor receptor HER2/neu on cancer cell membranes is a strong predictor of response to trastuzumab, a monoclonal antibody that binds to the HER2/neu receptor, especially if given with one of several cytotoxic compounds.38, 39
Primary (preoperative, neoadjuvant, induction) chemotherapy was introduced 25 years ago in breast cancer treatment to elicit a rapid response before surgery in locally advanced cases and to render inoperable cases operable.40 More recently, the introduction of conservation treatments to substitute mastectomy among women with carcinomas of limited extent has led to a new indication for primary chemotherapy whose objective is to induce a reduction of the tumor mass to make the conservative surgical approach possible or easier. Most studies have shown a considerable response rate of primary breast carcinomas to neoadjuvant chemotherapy with objective responses around 50–70%, complete clinical remissions of 20–30% and a downgrading of primary carcinoma leading to breast conservation in 90% of cases, which were originally candidates for mastectomy.41 However, total pathological responses are rare and the survival rates are not improved by the treatment. An important advantage of primary chemotherapy is the ability to evaluate the degree of chemosensitivity of the tumor, information that is of great importance for further systemic treatments. The limiting factors of primary chemotherapy are (i) the fact that radical surgery must be postponed for 2–3 months while the tumor mass, although reduced in most cases, is still present with viable and actively proliferating cancer cells; (ii) the biological factors originally present in the primary carcinoma (ER, proliferation rate, grading, etc.) are modified by chemotherapy in an unpredictable way sometimes improving, sometimes worsening; (iii) the staging may be difficult to assess due to the disappearance of nodal metastases caused by the effect of chemotherapy. To avoid the last point, a sentinel node biopsy at the axilla may be performed before the beginning of chemotherapy.
The final decision on the type of surgery to perform after primary chemotherapy should be made in the operating room after careful evaluation of tumor regression, examination of the resection margins, assessment of tumor size in relation to breast size and assessment of microcalcifications. The cooperation of an experienced pathologist and of a skillful plastic surgeon is essential to obtain satisfactory results.
Cancer prevention and genetics
Cancer prevention is promising area of clinical oncology. It follows the example of cardiology, for example, where it is common practice to treat persons at increased risk of cardiovascular disease long before there is clinical evidence of such disease.
Cancer prevention may be primary, secondary or tertiary. In primary prevention, the aim is to prevent disease onset, targeting healthy cohorts with environmental, lifestyle or familial/genetic factors indicating increased risk. Secondary prevention treats populations with premalignant conditions or in situ neoplasia to block evolution to frank cancer. Tertiary interventions aim to protect against second primary cancers in patients cured of an initial primary. An essential aspect of prevention is the identification of a target population of high-risk subjects, thereby increasing the risk-benefit ratio of the intervention. Persons with familial and genetic factors indicating increased cancer risk constitute a primary target.
Knowledge of the human genome now makes a polygenic approach to cancer prevention possible, in which susceptible individuals can be identified by their genotype profile and disease prevented by targeting interventions to those at risk. The construction and use of genetic-risk profiles is likely to significantly improve the efficacy of screening programs for cancers, increasing the impact of molecular investigations.42
In women and their families genetically predisposed to developing breast cancer, there are 3 main strategies: intensive surveillance, pharmacological prevention and surgical prophylaxis, which is applied in a particular case depends on consultation with the individuals involved and may be revised as new information is acquired. The process of consultation is part of the wider process of counseling, the first step of which is family tree investigation of the proband and her family followed by risk assessment. This is followed by discussion of the meaning and utility of genetic tests, if indicated. A tailored follow-up program is then agreed, which in addition to surveillance may include preventive treatment.
MRI is becoming a routine examination for young women with suspected or confirmed mutations predisposing to breast cancer.26 High risk persons are also offered participation in clinical trials for early detection (e.g. ductal lavage)20 and risk reduction (chemoprevention, diet and lifestyle interventions). Confirmed carriers of BRCA1 or BRCA2 mutations may well be counseled about surgical prophylaxis involving bilateral mastectomy and ovariectomy.
Another aspect of cancer prevention is chemoprevention. Chemoprevention studies have demonstrated the need to study markers of biological and molecular risks, for example molecular pathways, levels of circulating proteins and the expression of histological markers. Such markers can be used as intermediate endpoints (surrogate endpoint biomarkers, SEBs) to test investigational agents, thus reducing study time, trial sample size and costs compared to trials using conventional clinical endpoints and permitting the screening of more such agents. Although there are good indications, this strategy is valid,43 no SEB has so far been shown correlate so well as, for example cholesterol, a marker of cardiovascular disease. Nevertheless, several SEBs appear promising including growth factors (e.g. the insulin-like growth factor family), hormones (estradiol, estrone, estrone sulfate, DHEA, prolactin), atypical breast cells in cytological samples and mammographic density studied using computerized techniques. The evaluation of the effectiveness of a breast cancer chemoprevention agent should also involve assessment of other health risks such as cardiovascular risk and bone fracture risk (in post menopausal women), as well as cancer. It is encouraging that one of the most effective cancer preventive agents (tamoxifen) may—at the right dose—have no adverse effects markers of cardiovascular and bone fracture risk, while still reducing markers of breast cancer.44 At the EIO, our efforts in cancer prevention have centered on various ways of performing risk assessment, evaluation of promising SEBs and novel chemopreventive strategies. Our main focus has been breast cancer, and we have conducted several successful clinical trials in this area over the last 10 years, including evaluations of the efficacy and safety of SERMs, retinoids and aromatase inhibitors in women at increased risk for breast cancer. The at-risk populations studied include healthy women with increased risk based on Gail's model or a family history of breast cancer, healthy women exposed to high hormone levels for long periods (high plasma IGFs in premenopausal women, and high sex hormones and long-term use of hormone replacement therapy in postmenopausal women), patients with intraepithelial neoplasia (IEN; atypical hyperplasia, lobular in situ neoplasia, DCIS) and patients with atypical cells in cytological specimens from the breast.
The synthetic retinoid fenretinide was administered for 5 years in a trial to prevent a second breast cancer. After a median of 8 years, there was no difference in the frequency of second breast cancer overall, although there was an indication of a risk reduction in premenopausal women. We analyzed the data in a subgroup of 1,739 of women of the fenretinide trial, aged 30–70 years, followed up in a single centre for a median of 14.6 years. We found 168 second breast cancers in the fenretinide arm and 190 in the control arm: 83 in the fenretinide arm and 126 in the observation arm in premenopausal women; 85 in the fenretinide arm and 64 in the observation arm in postmenopausal women. These findings amounted to a significantly reduced the risk of second breast cancer in premenopausal women taking fenretinide, most conspicuously in younger women. The reduction in risk persisted several years after cessation of treatment. Since adverse events were limited, a trial of fenretinide in young women at high-risk of breast cancer is justified.45
Over the last decade, the Italian Tamoxifen Trial and 4 other chemoprevention studies have confirmed the utility of tamoxifen as the most effective chemopreventive for ER + breast cancers—the most common form of the disease—currently available.46, 47
In an attempt to overcome the endometrial and venous thrombotic side effects of tamoxifen and optimize its risk-benefit ratio, we compared 1 mg/day and 5 mg/day doses with the standard dose (20 mg/day) in treated breast cancer patients, using SEBs of breast cancer, cardiovascular disease and bone fracture risk. At 120th of the standard daily dose, tamoxifen had a beneficial influence on wide spectrum of markers of breast carcinogenesis and cardiovascular risk (e.g. the ultrasensitive C-reactive protein) without increasing the risk of endometrial proliferative lesions and venous thrombosis. These findings provide a rationale for the wider use of low-dose tamoxifen in high risk cohorts.48
We also showed that low-dose tamoxifen combined with anastrozole did not impair anastrozole bioavailability (unlike in other studies in which tamoxifen at standard dose was used), but had beneficial effects on markers of bone turn-over like osteocalcin and C-telopeptide, suggesting an overall beneficial effect in postmenopausal patients.
Another important observation of our Tamoxifen Prevention Trial48 was that the protective effect of tamoxifen was more pronounced when combined with hormone replacement therapy. This is consistent with findings that the side effects of tamoxifen are rarer in younger, premenopausal women who appear to be protected by their own sex hormones. The observation suggests that risk-benefit ratio of tamoxifen is more favorable in premenopausal women and HRT users and provides a further reason for its wider use in breast cancer prevention. The situation in postmenopausal women is more complex, however, and requires evaluation of cardiovascular risk, bone fracture risk and quality of life issues that must be balanced against tamoxifen's protective effect against breast cancer.
We have also demonstrated positive effects on various biomarkers by low dose tamoxifen plus HRT (particularly when it is delivered transdermally rather than orally).49 To confirm the benefits of the combination of HRT and tamoxifen, we are currently conducting a large national placebo-controlled prevention trial in healthy postmenopausal HRT users who add to HRT a low dose (5 mg/day) of tamoxifen for 5 years: the HOT (hormone replacement therapy opposed by low dose tamoxifen) study. We are also investigating other possible breast cancer chemopreventive drugs in women with ER-positive intraepithelial neoplasia: raloxifene and low dose tamoxifen in premenopausal women and exemestane and celecoxib in postmenopausal women.
The new developments in breast cancer, prevention, diagnosis and treatment, many of which have been reviewed here, amount to a paradigm shift in which patient quality of life has emerged as central. Previously, the approach was to give the maximum tolerated treatment in the hope of arresting the disease, irrespective of the resulting morbidity; now the aim is to give the minimum treatment that will ensure disease control, taking care always to limit morbidity and preserve quality of life. The trend began with the introduction of breast-conserving surgery and sentinel node biopsy, and continues with more precisely targeted radiotherapy, and less aggressive chemotherapy and hormonotherapy. None of these changes would have been possible without major advances in our knowledge of natural history of breast cancer. These developments have encouraged large numbers of women to participate in early detection programs, so that their cancers are diagnosed increasingly early when the new treatments have the best chance of effecting a cure. Clearly, there is still much to do in the war against this killer disease, but it is reasonable to expect that the trend to reduced breast cancer mortality, seen in several developed countries, will continue and extend to other populations.