Breast Cancer

Adjuvant Endocrine Therapy
Types of Mastectomy
Pathology of Breast Cancer
Inflammatory Breast Cancer
Breast Cancer Staging
XRT on reconstructed Breast
6. Lumpectomy +/- XRT
BCT+XRT vs Mastectomy
XRT post Mastectomy
Locoregional RT after BCT
Management of Axilla
Internal mammary involvement
10. XRT post Neoadjuvant
Concurrent RT vs Sequential RT
Chemo-RT vs RT-Chemo
Boost vs No Boost Trial
Breast Conservative Therapy
Neoadjuvant Chemotherapy
Breast Cancer and Pregnancy
What do we know about DCIS
Management of high-risk population
XRT after reconstruction
Metastatic Breast Cancer
14. Adjuvant systemic therapy: How do we know TAMOXIFEN works??
15.Boost vs no Boost trial (EORTC-22881; EORTC-10882)
16.When not preserve Breast
17.So! If we preserve the breast, who has a higher risk to recur?
18. Three good things with Neoadj. Chemo:
19. In whom we can’t do the surgery as primary therapy:
20.Neoadjuvant Chemotherapy
21.Pre vs Post OP chemotherapy
23. Breast Cancer and Pregnancy
** LRF as first event (Node + patients operable Breast Ca NSABP 2004 Taghian Review )
24. Chemoprevention in LCIS

10. Lumpectomy +/- XRT
11. BCT+XRT vs Mastectomy
13. XRT post Mastectomy

21. XRT after reconstruction
22. Adjuvant systemic therapy:

37. St. Gallen Consensus Conference
38. Male Breast Cancer
39. Chemoprevention in LCIS
• Prospective, placebo-controlled clinical trial
• Tamoxifen reduced the incidence of breast cancer by 49%
o NSABP P2 (STAR) trial comparing tamoxifen and raloxifene
• Comparable efficacy in risk reduction was observed

o overview of the randomized trials
o 15 years of follow-up
o Tamoxifen for 5 years results
• 41% reduction in the annual rate of breast cancer recurrence (HR 0.59)
• 34% reduction in the annual death rate (HR 0.66) for women with ER-positive breast cancer.
• Independent of patient age or menopausal status
• Durable gain of benefit.
a. Improved survival through at least 15 years of follow-up.
• Shorter durations of tamoxifen therapy are also beneficial, but appear to have less impact than a 5-year treatment duration.
• After 5 years→ No approved benefit of survival
• Not effective in preventing recurrence of hormone-receptor–negative breast cancer

Major Studies Comparing Adjuvant Therapy Incorporating Aromatase Inhibitors against 5 Years of Tamoxifen
Timing/Setting Trial (Reference) AI No. of Patients Hazard Ratio for Disease-Free Survival Absolute Difference in Disease-Free Survival (%)
Upfront; year 0 ATAC (ref. 174)
ANA 9,366 0.87a
2.8 @ 5 y
BIG 1-98 (ref. 175)
LET 8,010 0.81 2.6 @ 5 y
Sequential; after 2–3 years of TAM IES (ref. 177)
EXE 4,742 0.68 4.7 @ 3 y
ARNO/ABCSG (ref. 176)
ANA 3,224 0.60 3.1 @ 3 y
Extended; after 5 years of TAM MA17 (ref. 179)
LET 5,187 0.58 4.6 @ 4 y
NSABP B33 (ref. 180)
EXE 1,598 0.68 2.0 @ 4 y
ANA, anastrozole; LET, letrozole; EXE, exemestane; TAM, tamoxifen, AI, aromatase inhibitor
aComparison for ANA vs TAM. The third arm of the trial, combined therapy with ANA plus TAM, yielded outcomes similar to TAM alone.

b. Aromatase Inhibitors (AIs)
o works by binding to the estrogen receptor, AIs function through inhibition of the aromatase enzyme that converts androgens into estrogens ⇒ profound estrogen depletion in postmenopausal women.
o Not appropriate for premenopausal patients, as residual ovarian function can lead to enhanced production of aromatase and thus overcome the effects of AIs.
c. Couple of options with AI:
o Primary up-front
o Sequential therapy after 2-3years
o Extended therapy after 5 years of tamoxifen
o In each instance, AI ⇒ improved outcomes compared to the control arm, which consisted of 5 years of tamoxifen therapy.
o Modest improvements in disease-free survival NOT OS
• As a result of a lower risk of
a. Distant metastasis
b. in-breast recurrences
c. contralateral tumors
• No differencein OS but
a. MA17 trial of letrozole after 5 years of tamoxifen, the addition of letrozole produced a statistically significant survival benefit in the subset of node-positive women
• So good to use AI at some point in post-menopausal women
a. Optimal use unknown
• Best timing for initiation of an AI vis-à-vis tamoxifen is not clear
• The Breast International Group 1-98 trial, which randomized patients to monotherapy with letrozole or tamoxifen or to a planned crossover, will eventually provide important information data on this point.
d. Similarly, the appropriate duration of AI treatment is not clear. The up-front trials174,175 limited treatment to a total of 5 years duration, and the sequential trials176,177 used AI therapy for only 2 or 3 years as part of a total of 5 years of adjuvant endocrine treatment. The studies of extended endocrine therapy beyond 5 years179,180 underscore the long natural history of hormone-receptor–positive breast cancer and demonstrate that antiestrogen treatments have ongoing benefits well beyond 5 years after diagnosis. For women who start an AI at the time of diagnosis, the appropriate duration of endocrine treatment is unknown, and studies are ongoing to address this question.
23. Because of these uncertainties, the selection of adjuvant endocrine therapy for postmenopausal women is surprisingly complicated. Postmenopausal women should consider an AI at some point in their treatment program and anticipate receiving an AI for up to 5 years, based on current data. AIs and tamoxifen have contrasting side-effect profiles, which may inform treatment selection. Tamoxifen is associated with rare risks of thromboembolism and uterine cancer.167,174,175 AI treatment is associated with accelerated osteoporosis and an arthralgia syndrome;182 patients on AI therapy require serial monitoring of bone mineral density.183 Both treatments are associated with menopausal symptoms such as hot flashes, night sweats, and genitourinary symptoms including sexual dysfunction. Symptomatically, patients may tolerate one class of agent better than another; those intolerant of either tamoxifen or AI therapy should be offered the alternative type of treatment. Because AI therapy is only effective in postmenopausal women, tamoxifen remains the treatment of choice in women who are pre- or perimenopausal or in whom there is question of residual ovarian function. In particular, women with chemotherapy-induced amenorrhea may have recovery of ovarian function and are not suitable candidates for AI treatment.184
24. Despite long-standing interest in ovarian suppression as adjuvant therapy, its role in addition to tamoxifen or chemotherapy remains unclear. Early studies of ovarian suppression were not limited to patients with hormone-receptor–positive tumors, meaning that these trials were often conducted in patients unlikely to benefit from endocrine treatment. In addition, many studies of ovarian suppression in the 1980s and 1990s failed to incorporate tamoxifen, as it was not appreciated that tamoxifen was beneficial in premenopausal women, so the benefits of ovarian suppression in addition to tamoxifen are not well understood. Finally, clinical trials that included chemotherapy for younger women were confounded by the high incidence of chemotherapy-induced menopause.185 Thus, despite the fact that multiple randomized trials have demonstrated that ovarian suppression can be effective adjuvant therapy for premenopausal women166 and have demonstrated that ovarian suppression is frequently at least as effective as adjuvant chemotherapy in preventing breast cancer recurrence,186 there remains little consensus on whether ovarian suppression adds meaningfully to results seen with tamoxifen with or without adjuvant chemotherapy.
25. Recent observations suggest that ovarian suppression is a critical question for younger women with hormone-receptor–positive breast cancer. Very young women–typically less than age 35—who do not routinely experience amenorrhea with adjuvant chemotherapy appear to have a substantially worse prognosis than patients who do enter menopause with chemotherapy.187 A randomized trial has compared chemotherapy alone, chemotherapy plus ovarian suppression and chemotherapy, and ovarian suppression plus tamoxifen as adjuvant treatment. The addition of tamoxifen clearly improved results compared to chemotherapy with or without ovarian suppression. In subset analyses, younger women (less than age 40) who were less likely to experience chemotherapy induced amenorrhea did appear to benefit from ovarian suppression in addition to chemotherapy.188 However, the study design does not directly address whether ovarian suppression would substantially add to tamoxifen-based treatment. The Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial compared tamoxifen alone versus tamoxifen with ovarian suppression in premenopausal women and did not show a substantial improvement in disease-free survival with the addition of ovarian suppression.189 However, in this study, only 40% of patients were known to have estrogen-receptor–positive breast cancer, and 80% of patients additionally received adjuvant chemotherapy, profoundly limiting the interpretation of the results. Ongoing trials are specifically testing the role of ovarian suppression in addition to tamoxifen for premenopausal patients.
26. Tamoxifen is metabolized by the cytochrome P-450 system into biologically active metabolites. Recent data have suggested that pharmacogenomic variation in P-450 alleles or the concurrent use of tamoxifen and P-450 inhibitors might affect tamoxifen metabolism, with clinically significant effects. Retrospective analyses of small adjuvant treatment trials have suggested that patients with inefficient tamoxifen metabolism owing to mutations in CYP2D6 enzyme, part of the P-450 complex, might derive less benefit from adjuvant tamoxifen than others.190,191 Patients taking certain medicines known to inhibit P-450, such as the selective serotonin reuptake inhibitors paroxetine and fluoxetine, also generate fewer active tamoxifen metabolites, which may interfere with clinical outcomes.192,193 Neither the full significance of pharmacogenomic allelic variation nor the adequacy of testing for such variation is well characterized at present. Patients on tamoxifen should probably avoid the aforementioned selective serotonin reuptake inhibitors in light of the potential pharmacological interaction.
b. How do we know TAMOXIFEN works??
c. NSABP B14
o Node - ; ER + (Tamoxifen vs none)
o Ipsilateral recurrence (4.3% vs 14.7%)
d. Stockholm Breast Cancer Study Group:
o Node - ; ER + ( Tamoxifen vs none )
o Ipsilateral recurrence ( 3% vs 12% )
e. NSABP B21
o Eligibility:
• < 1 cm
• Clear margins
• Node Negative
o lumpectomy + axillary dissection( Ipsilateral Breast Recurrence %)
• Tamoxifen(16.5%)
• XRT (9.3%)
• XRT+Tamoxifen(2.8%)
o XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status.
o Distant Metastasis : infrequent & not significantly different among the groups
o No difference in Survival
• 93%, 94%, and 93%,

Locally Advanced Breast ca

Estimates of Breast Cancer Extent of Disease at Diagnosis for 2001–2002
All Races (%) White (%) African American (%)
Tumor ≤2.0 cm 66 67 53
Tumor 2.1–5.0 cm 28 27 37
Tumor >5.0 cm 6 6 10
Lymph node–negative 64 65 56
Lymph node–positi
e 30 29 35
Distant metastasis 6 6 9

b. Involvement of cooper’s ligament ⇒ skin retraction
c. Infiltration and obstruction of lymphatic ⇒ skin edema
d. up to 35% of patients with clinical stage III cancer can show abnormal bone scan results
e. LABC fast growing usually ER NEG
f. Those neglected over long time usually ER +
g. 5-year survival rates
o IIIA :80%
o IIIB : 45%
LR rate and pattern in breast cancer:
h. LRF as first event (12.2%)
i. LRF+DM(19.8%)
j. DM only(43.3%)
40. LRF +/- DM According to Nodal Status
o LN+ (1-3) (13.0%)
o LN+(4-9) (24.4%)
o LN+ > 10 (31.9%)
41. LRF +/- DM according to Tumor size:
o Tumor size <2 cm(14.9%)
o 2.1-5.0 cm(21.3%)
o >5.0 cm(24.6%)
42. Time to Local Failure
a. The median times→ ( Isolated LR ) 2.0yrs & ( + DM ) 2.9yrs
b. The majority (71%) of LRF occurred within the first 4 years
c. 4-8 year (21.4%)
d. 8-12 year(6.5%)
e. > 12 year (1.0%)
1-3 LN+ 4-9 LN+ >=10 LN+
10yr risk <=2cm 2.1-5cm >5cm <=2cm 2.1-5cm >5cm <=2cm 2.1-5cm >5cm
LRF+/-DM 10% 15% 11% 20% 25% 30% 25% 35% 35%
DM 25% 35% 40% 40% 50% 55% 64% 70% 75%

Local Recurrence after Mastectomy

• Prognosis worse than recurrent in BCT
• In the Danish trial
o 5-year rate of distant metastatic disease after an isolated local-regional recurrence was 73%
• This rate is independent to previous chest wall RT
• A large series→analysis of the 535 patients who developed a postmastectomy recurrence after treatment in the Danish 82b and 82c randomized trials
o Factors to be associated with a poorer outcome
• Large initial primary tumor
• High number of positive lymph nodes
• Extracapsular extension
• Recurrence in the infraclavicular or supraclavicular regions
• Disease-free interval of <2 years
o M.D. Anderson
• Initial nodal status
• Time to recurrence
• Ability to use radiation to treat the recurrence
• If All of these factors→
o 5-year overall survival of 86%
• 1-2 unfavorable factor →
o The 5-year survival rate 48% (median survival time, 54 months)
• All three unfavorable factors
o died within 5 years of the recurrence (median survival, 16 months).
• Initial T stage→ no effect but Initial Node stage → effective
• Few data are available to quantify the benefits of systemic therapy for patients with local-regional recurrence. In one of the few series evaluating this issue, authors from British Columbia found in a nonrandomized study that use of chemotherapy at the time of recurrence reduced the probability of death from breast cancer, but this difference was not statistically significant compared with those who did not have chemotherapy at recurrence (p = 0.07). Finally, a randomized trial that investigated tamoxifen use versus no systemic therapy after salvage local therapy for patients with recurrent disease after mastectomy found an improvement in 5-year disease-free survival from 36% to 59% (p = 0.007) (8), supporting the use of systemic treatments in the management of patients with recurrent disease.
• Investigators from M.D. Anderson conducted a series of four prospective single-group protocols evaluating systemic therapies for patients with either local-regional recurrence or metastatic disease that was converted to “no evidence of disease” after surgery, radiation, or both (70). The findings suggest that for patients with anthracycline-naive disease, the introduction of doxorubicin at the time of recurrence can lead to improved survival and more recently the use of docetaxel also seemed to lead to favorable outcomes for patients who had previously had anthracycline treatment. The 3-year disease-free survival rate for such patients was 58%.
• The general management strategy for an isolated local-regional recurrence after mastectomy requires input from a multidisciplinary team. The initial evaluation should define the sites of disease involvement and determine whether the patient is able to undergo resection of all gross disease with negative surgical margins. Surgical therapy is recommended for patients with resectable disease, provided the patients can tolerate the surgery and the morbidity of the surgery is acceptable. After surgery, if the patients had not previously been given radiation therapy, they should receive comprehensive local-regional radiation. A study from Washington University found that patients who had radiation therapy to the chest wall and regional lymphatics had better outcomes than those in whom radiation fields were limited to the site of the recurrent disease (66). Finally, because patients with recurrent disease after mastectomy are at high risk of developing distant metastatic disease, those who have not been previously treated with anthracyclines or taxanes (or trastuzumab if the tumor is HER2/neu-positive) should strongly consider treatment with these agents (72). Patients with ER-positive disease should receive appropriate second-line endocrine therapy.
• Patients presenting with bulky unresectable disease should be considered for neoadjuvant chemotherapy if active systemic agents are available. If the disease responds favorably, some of these patients may become candidates for surgical resection, which then can be consolidated with comprehensive radiation. The prognosis for those whose disease fails to respond is very poor, and radiation treatments alone are unlikely to render such patients free of disease. Nevertheless, aggressive local-regional radiation is often used to help stabilize the disease and to avoid the significant adverse consequences of uncontrolled growth of local-regional disease. The dose of radiation to be used depends on the presence or absence of gross disease and whether patients have previously undergone radiation therapy. For
• P.1311

patients who have not had radiation therapy and do not have gross disease, we recommend comprehensive treatment to the chest wall and draining lymphatics to a dose of 50 to 54 Gy followed by a boost to the chest wall to 60 to 66 Gy. Hyperfractionated chest wall irradiation does not seem to provide any benefit over that of conventional therapy given once daily (4).
• Regional Nodal Relapse
• Patients with regional relapse have a less favorable prognosis than patients with intact breast or chest wall recurrences. In general, patients with isolated resectable disease in the low axilla should be treated with axillary dissection, comprehensive radiation to sites not previously treated including the chest wall, and systemic therapy. Most patients with recurrence in the supraclavicular fossa or internal mammary lymph nodes have unresectable disease. If active chemotherapy agents are available, it is reasonable to consider using neoadjuvant systemic treatment and consolidating with radiation at the point of maximal response. Woodward et al. (148) investigated the outcome of 140 patients with local-regional recurrence after mastectomy and doxorubicin chemotherapy and found that the 47 who had supraclavicular disease at the time of recurrence had a worse outcome than the remaining patients with recurrences in other sites (10-year disease-free survival of 5% vs. 39%, respectively; p = 0.003).

• Diagnosis and Biopsy
• The presence or absence of carcinoma in a suspicious clinically or mammographically detected abnormality can only be reliably determined by tissue sampling. The high sensitivity of MRI for cancer detection raised the possibility that this technique could replace biopsy in the evaluation of suspicious breast lesions. In a multi-institutional prospective study of 821 patients referred for breast biopsy, the sensitivity of MRI was 88.1% (95% CI, 84.6% to 91.1%) and the specificity was 67.7% (95% CI, 62.7% to 71.9%), indicating that an abnormal MRI does not reliably indicate the presence of cancer, and a nonworrisome MRI does not reliably exclude carcinoma.44
• A biopsy remains the standard technique for diagnosing both palpable and nonpalpable breast abnormalities. The available biopsy techniques for the diagnosis of palpable breast masses are fine needle aspiration (FNA), core cutting needle biopsy, and excisional biopsy. The advantages and disadvantages of each are listed in Table 43.2.7.
• Both FNA and core biopsy are office procedures. FNA is easily performed, but requires a trained cytopathologist for accurate specimen interpretation. The sensitivity of FNA ranges from 80% to 95%, and false-positive aspirates are seen in fewer than 1% of cases in most series. False-negative results are seen in 4% to 10% of cases and are most common in fibrotic or well-differentiated tumors.45 Although an FNA diagnosis of malignant cells is sufficient to proceed with definitive treatment, FNA does not reliably distinguish invasive cancer from ductal carcinoma in situ (DCIS), potentially leading to the overtreatment of gross DCIS.
• Core cutting needle biopsy has many of the advantages of FNA, but provides a histologic specimen suitable for interpretation by any pathologist. In addition, estrogen and progesterone receptor status and the presence of HER-2 overexpression can be routinely determined from core biopsy specimens, making core needle biopsy the diagnostic technique of choice for patients who will receive preoperative systemic therapy.
• P.1613

False-negative results due to sampling error may also occur with core cutting needle biopsy. If concordance between the core biopsy diagnosis and the clinical and imaging findings is not present, additional tissue should be obtained, usually by excisional biopsy.
• Table 43.2.7 Biopsy Techniques for Breast Lesions
• Technique • Advantages • Disadvantages
• Fine needle aspiration cytology • Rapid, painless, inexpensive. No incision prior to selection of local therapy. • Does not distinguish invasive from in situ cancer. Markers (ER, PR, HER-2) not routinely available. Requires experienced cytopathologist. False negatives and insufficient specimens occur.
• Core cutting needle biopsy • Rapid, relatively painless, inexpensive. No incision. Can be read by any pathologist, markers routinely available. • False-negative results, incomplete lesion characterization can occur.
• Excisional biopsy • False-negative results rare. Complete histology before treatment decisions. May serve as definitive lumpectomy. • Expensive, more painful. Creates an incision to be incorporated into definitive surgery. Unnecessary surgery with potential for cosmetic deformity in patients with benign abnormalities.
• ER, estrogen receptor; PR, progesterone receptor.

• When excisional biopsy is performed for diagnosis, a small margin of grossly normal breast should be excised around the tumor, orienting sutures should be placed, and the specimen should be inked to allow margin evaluation. This procedure allows an assessment of the completeness of the excision if carcinoma is found, sparing patients with negative margins further breast surgery and allowing re-excision to be limited to the involved margin surface(s). However, diagnosis by needle biopsy is the preferred initial method of evaluating almost all breast masses. A needle biopsy diagnosis permits a complete discussion of treatment options prior to the placement of an incision on the breast and allows the breast procedure and the axillary surgery to take place at a single operation. In addition, needle biopsy is a more cost-effective method of diagnosing benign lesions than surgical excision.
• Nonpalpable lesions can be biopsied with image-guided core needle biopsy or surgical excision after wire localization. Ultrasound guidance is used for lesions that are visualized with this modality; most calcifications require stereotactic mammographic guidance for biopsy. There is little role for FNA in the diagnosis of lesions detected by screening due to the high prevalence of in situ lesions. Concerns about the false-negative rate of image-guided core biopsy have been resolved with the availability of large, vacuum-assisted biopsy devices that increase the extent of lesion sampling, coupled with the development of clearly defined indications for follow-up surgical biopsy. In a study of 318 patients with mammographic abnormalities diagnosed by core biopsy between September 1997 and December 2001, the false-negative rate was 3.3%. For radiologists who had done more than 15 biopsies, the false-negative rate was 0.6%. All of the false negatives were recognized at the time, with no delay in the diagnosis of cancer.46 Indications for surgical biopsy following core biopsy are listed in Table 43.2.8. Although the finding of atypical ductal hyperplasia on a core biopsy is uniformly accepted as an indication for surgical biopsy, the need for surgical excision of all lesions showing atypical lobular hyperplasia or lobular carcinoma in situ remains controversial (discussed in the section Lobular Carcinoma in situ below). Papillary carcinoma in situ cannot always be readily distinguished from benign papillary lesions on a core biopsy, and radial scar may be difficult to distinguish from tubular carcinoma without complete removal of the lesion.
• The use of core biopsy for the diagnosis of mammographic abnormalities is cost effective and increases the likelihood that the patient will be able to undergo a single surgical procedure for definitive cancer treatment. In a prospective study of 1,550 consecutive patients undergoing biopsy for mammographic abnormalities, core biopsy reduced the number of surgical procedures needed for cancers presenting as both masses and calcifications as well as in patients requiring axillary staging and those treated by mastectomy.47 In a cost analysis using patients from this data set, core biopsy resulted in cost savings for all clinical scenarios. In spite of this, in a study of 5.5 million mammograms performed in two U.S. government–sponsored screening programs and the UK National Health Service between 1996 and 1999, 51% of the biopsies performed in the United States were surgical, compared to 23% in the United Kingdom.48
• Lobular Carcinoma In Situ
• In 1941 Foote and Stewart published their landmark study of LCIS, describing a relatively uncommon entity characterized by
• P.1614

an “alteration of lobular cytology.” Foote and Stewart chose the name to emphasize the morphologic similarities between the cells of LCIS and those of invasive lobular carcinoma (ILC). They hypothesized that LCIS represented a precursor lesion of invasive cancer, and, based on this, mastectomy was initially recommended. Subsequent studies, discussed below, have shown that the risk of subsequent breast cancer is bilateral. More recently, the term atypical lobular hyperplasia (ALH) has been introduced to describe morphologically similar, but less well-developed lesions. Some centers use the term, lobular neoplasia (LN) to cover both ALH and LCIS. Morphologically, LN is defined as “a proliferation of generally small and often loosely cohesive cells originating in the terminal duct-lobular unit, with or without pagetoid involvement of terminal ducts.”49
• Table 43.2.8 Indications for Surgical Biopsy after Core Needle Biopsy
• Failure to sample calcifications
Diagnosis of atypical ductal hyperplasia
Diagnosis of atypical lobular hyperplasia or lobular carcinoma in situa
Lack of concordance between imaging findings and histologic diagnosis
Radial scar
Papillary lesions
• aSee text.

• In the past, LCIS was most frequently diagnosed in women aged 40 to 50, a decade earlier than DCIS, but recent literature indicates that the incidence in postmenopausal women is increasing.50 Determining the true incidence of LCIS is difficult since there are no specific clinical or mammographic abnormalities associated with the lesion. LCIS is typically not associated with microcalcifications on mammography. The diagnosis of LCIS is therefore often made as an incidental, microscopic finding in a breast biopsy performed for other indications. The prevalence of LN in an otherwise benign breast biopsy has been reported as between 0.5% and 4.3%.51 LCIS is both multifocal and bilateral in a large percentage of cases.
• In an analysis of nine separate studies evaluating outcome following a diagnosis of LCIS, 172 patients who were treated by biopsy alone were identified. On follow-up averaging about 10 years, 15% of these patients had invasive carcinoma diagnosed in the ipsilateral breast and 9.3% had invasive carcinoma in the contralateral breast.52 This corresponds to an increased rate of development of invasive carcinoma of about 1% to 2% per year, with a lifetime risk of 30% to 40%. In this study (conducted prior to effective breast imaging), 5.7% developed metastatic breast cancer. Subsequent cancers are more often invasive ductal carcinoma than ILC, but the incidence of subsequent ILC is substantially increased compared to women without LCIS. Although the risk for development of breast cancer is bilateral, subsequent ipsilateral carcinoma is more likely than contralateral breast, supporting the view that ALH and LCIS act both as precursor lesions and as risk indicators. The relative risk for development of subsequent breast cancer is lower in women diagnosed with ALH compared with LCIS. Therefore, although LN is a helpful term for collectively describing this group of lesions, specific classification into ALH and LCIS is preferable in terms of risk assessment and management.
• LCIS is typically positive for ER and PR staining by immunohistochemistry (IHC) and negative for HER-2/neu staining. LN (and ILC) characteristically lacks expression of E-cadherin, an epithelial cell membrane molecule involved in cell–cell adhesion. E-cadherin negativity serves as a fairly reliable means of distinguishing ductal from lobular disease, both in situ and invasive. Pleomorphic LCIS is a relatively uncommon variant of LCIS characterized by medium to large pleomorphic cells containing eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasm. As with classic LCIS, it is usually estrogen-receptor positive and negative for E-cadherin; it also tests positive by IHC for gross cystic disease fluid protein-15. Pleomorphic LCIS can be associated with central necrosis and may be associated with mammographic microcalcifications. It is not clear at this time whether pleomorphic LCIS has a different natural history than classic LCIS.
• Genetic changes in LN have been evaluated in a number of studies using comparative genomic hybridization (CGH). In one study ALH showed gain at 2p11.2 and loss at 7p11-p11.1 and 22q11.1, and LCIS showed gain at 20q13.13 and loss at 19q13.2-q13.31.53 In both ALH and LCIS, there was loss at 16q21-q23.1, an altered region previously identified in invasive carcinoma. This genomic signature, common to LN and ILC, further suggests that LN is a precursor lesion in some women.
• Management of LN must address the bilateral risk, and options therefore include surveillance, chemoprevention, and prophylactic bilateral mastectomy. Surveillance is the strategy selected by most patients. Mammographic screening is the standard breast imaging for patients selecting surveillance. Breast MRI has been used, but there is no firm evidence supporting its efficacy; its value is being tested in a randomized clinical trial in Europe. Prophylactic mastectomy reduces breast cancer risk and mortality among high-risk women by approximately 90%. Chemoprevention with tamoxifen in patients with LCIS has been evaluated as part of the NSABP P1 study.28 In this prospective, placebo-controlled clinical trial, with a median follow-up of 54.6 months, tamoxifen reduced the incidence of breast cancer by 49% (P <.00001). Eight hundred twenty-six of the participants had a history of LCIS, and breast cancers were detected in 18 women randomized to placebo and eight to tamoxifen, consistent with the overall reduction in breast cancer risk seen with tamoxifen. However, with the small number of events, this difference was not statistically significant. Nearly 1,200 participants had a history of atypical hyperplasia, and tamoxifen reduced the incidence of breast cancer by 86% in this group (RR = 0.14; 95% CI, 0.03 to 0.47); however, the initial report of the study did not provide results subdivided by ALH versus ADH. In the NSABP P2 (STAR) trial comparing tamoxifen and raloxifene, comparable efficacy in risk reduction was observed.39 In this study 893 participants gave a history of LCIS, and their rates of subsequent breast cancer were similar with tamoxifen and raloxifene. This benefit with tamoxifen or raloxifene needs to be weighed against the possible side effects of treatment.
• Although the data are conflicting, it is generally recommended to perform an excisional biopsy after detection of LN on a core needle biopsy to rule out coexisting DCIS or invasive cancer. Some have advocated a more selective approach to LCIS on core biopsy based on whether or not there is concordance between the pathology and imaging findings. With LCIS, most reported cases of malignant findings on subsequent excision occur in the setting of either a suspicious mass lesion or calcifications that prompted the biopsy initially. The recent recognition that in some cases LCIS may be a precursor lesion has led to confusion as to whether it should be treated like DCIS (i.e., excised to negative margins and irradiated). At this time, there are no data indicating that the incidence of subsequent cancer is reduced with this approach. When LCIS is seen on an excision, it is not necessary to obtain negative margins of resection, and there is no established role for radiation therapy in patients with LN.