breast cancer: a review of the literature · women treated for breast cancer have about a 1%...

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JOURNAL OF INSURANCE MEDICINECopyright Q 2003 Journal of Insurance MedicineJ Insur Med 2003;35:85–101

REVIEW

Breast Cancer: A Review of the LiteratureRodney C. Richie, MD, FACP, FCCP; John O. Swanson, MD

This article presents a comprehensive review of the Breast Cancerliterature examining epidemiology, diagnosis, pathology, ‘‘benign’’breast disease, breast carcinoma in situ syndromes, staging, andpost-treatment surveillance among many topics. Breast cancer re-mains the most commonly occurring cancer in women. Breast cancerdetection, treatment, and prevention are prominent issues in publichealth and medical practice. Background information on develop-ments in these arenas is provided so that medical directors can con-tinue to update their approach to the assessment of breast cancerrisk.

Address: Texas Life Insurance Com-pany, 900 Washington Avenue,Waco, TX 76701.

Correspondent: Rodney C. Richie,Medical Director, Texas Life Insur-ance Company.

Key words: Breast cancer, ductalcarcinoma in situ, lobular carcino-ma in situ, breast cancer detection,breast cancer treatment, breast can-cer pathology.

EPIDEMIOLOGY

Breast cancer is the most commonly occur-ring cancer in women, comprising almost onethird of all malignancies in females. It is sec-ond only to lung cancer as a cause of cancermortality, and it is the leading cause of deathfor American women between the ages of 40and 55.1 The lifetime risk of a woman devel-oping invasive breast cancer is 12.6 % 2 oneout of 8 females in the United States will de-velop breast cancer at some point in her life.2

The death rate for breast cancer has beenslowly declining over the past decade, andthe incidence has remained level since 1988after increasing steadily for nearly 50 years.3Twenty-five percent to 30% of women withinvasive breast cancer will die of their dis-ease.1 But this statistic, as grim as it is, alsomeans that 70% to 75% of women with in-vasive breast cancer will die of something oth-er than their breast cancer. Hence, a diagnosisof breast cancer, even invasive breast cancer,is not necessarily the ‘‘sentence of death’’ that

many women (and their insurance compa-nies) imagine.

Mortality rates are highest in the veryyoung (less than age 35) and in the very old(greater than age 75).4 It appears that the veryyoung have more aggressive disease, and thatthe very old may not be treated aggressivelyor may have comorbid disease that increasesbreast cancer fatality.5

Although 60% to 80% of recurrences occurin the first 3 years, the chance of recurrenceexists for up to 20 years.6,7

PATHOLOGY OF BREAST CANCER

Ninety-five percent of breast cancers arecarcinomas, ie, they arise from breast epithe-lial elements. Breast cancers are divided into2 major types, in situ carcinomas and invasive(or infiltrating) carcinomas. The in situ car-cinomas may arise in either ductal or lobularepithelium, but remain confined there, withno invasion of the underlying basement mem-

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Table 1. Chances of a Woman Developing BreastCancer by Age

By Age Normal Risk Genetic Risk*

45556575

1 in 93 (1%)1 in 33 (3%)1 in 17 (6%)1 in 11 (9%)

42%72%80%84%

* Breast-related cancer antigen 1 and 2 (BRCA-1,BRCA-2). Data from American Cancer Society, CancerFacts and Figures 2000.

brane that would constitute extension beyondepithelial boundaries. As would be expectedwith such localized and confined malignancy,there is negligible potential for metastases.

When there is extension of the ductal orlobular malignancy beyond the basementmembrane that constitutes the epithelial bor-der, then the malignancy is considered inva-sive (or infiltrating) ductal or lobular carci-noma. The potential for metastases and ulti-mately death occurs in invasive disease.

RISK FACTORS FOR DEVELOPMENT OFBREAST CANCER

Breast cancer incidence is highest in NorthAmerica and Northern Europe and lowest inAsia and Africa. Studies of migration pat-terns to the United States suggest that geneticfactors alone do not account for the incidencevariation among countries, as the incidencerates of second-, third- and fourth-generationAsian immigrants increase steadily in thiscountry. Thus, environmental and/or life-style factors appear to be important deter-minants of breast cancer risk.5

Gender is by far the greatest risk factor.Breast cancer occurs 100 times more frequent-ly in women than men. In women, incidencerates of breast cancer rise sharply with age(see Table 1) until ages 45 to 50, when the risebecomes less steep.4 This change in slopeprobably reflects the impact of hormonalchange (menopause) that occurs about thistime. By ages 75 to 80, the curve actually flat-tens and then decreases.

Despite the steepness of the incidencecurve at younger ages, the more importantissue is the increasing prevalence of breastcancer with advancing age, and the take-home message for physicians and underwrit-ers alike is that any breast mass in a post-menopausal woman should be consideredcancer until proven otherwise.8

Genetics plays a limited but important roleas a risk factor for breast cancer. Only 5% to6% of breast cancers are considered heredi-tary.9 BRCA-1 and BRCA-2 account for an es-timated 80% of hereditary breast cancer, butagain, this only represents 5% to 6% of allbreast cancers. BRCA-1 and/or BRCA-2 posi-tive women have a 50% to 85% lifetime riskof developing breast cancer (see Table 1), anda 15% to 65% risk of developing ovarian can-cer, beginning at age 25.10

Familial breast cancer is considered a riskif a first-degree relative develops breast can-cer before menopause, if it affected bothbreasts, or if it occurred in conjunction withovarian cancer.11 There is a 2-fold relative riskof breast cancer if a woman has a single first-degree relative (mother, sister or daughter).There is a 5-fold increased risk if 2 first-de-gree relatives have had breast cancer.12

A woman’s hormonal history appears to bea risk factor, as the relative risk of breast can-cer seems to be related to the breast’s cumu-lative exposure to estrogen and progesterone.Early menarche (onset of menstruation , age13), having no children or having them afterage 30, and menopause after age 50 and es-pecially age 55—all these mean more men-strual cycles and thus greater hormone ex-posure.13

The Women’s Health Initiative (WHI), arandomized controlled trial of 16,608 post-menopausal women comparing effects of es-trogen plus progestin with placebo on chron-ic disease risk, confirmed that combined es-trogen plus progestin use increases the riskof invasive breast cancer.14 Hormone replace-ment therapy (HRT) users have a breast can-cer risk that is 53% higher for combinationtherapy and 34% higher for estrogen alone,especially if used for more than 5 years. Al-

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though earlier studies suggested that this in-creased risk of cancer was offset by the factthat the cancers induced by HRT were ofmore benign pathology and had a more fa-vorable prognosis,4 reevaluation of the WHIdata reveals this impression to be incorrect.Invasive breast cancers associated with estro-gen plus progestin use were larger (l.7 cm vs1.5 cm, p 5 0.04), were more likely to be nodepositive (26% vs 16%, p 5 0.03), and werediagnosed at a significantly more advancedstage (regional/metastatic 25.4% vs 16%, p 50.04). The percentages and distribution of in-vasive ductal, invasive lobular, mixed ductal,and lobular as well as tubular carcinomaswere similar in the estrogen plus progestingroup vs the placebo group.15

Over observation time as short as a year,there was a statistically significant increase inbreast density in the estrogen plus progestingroup, resulting in increased incidence of ab-normal mammograms (9.4% vs 5.4%,p,0.001).15 As noted by Gann and Morrowin a JAMA editorial, ‘‘the ability of combinedhormone therapy to decrease mammographicsensitivity creates an almost unique situationin which an agent increases the risk of de-veloping a disease while simultaneously de-laying its detection.’’16

Li et al reported that women using unop-posed estrogen replacement therapy (ERT)had no appreciable increase in the risk ofbreast cancer. However, use of combined es-trogen and progestin hormone replacementtherapy had an overall 1.7-fold (95% CI 1.3–2.2) increased risk of breast cancer, includinga 2.7-fold (95% CI 1.7–4.3) increased risk ofinvasive lobular carcinoma, a 1.5-fold (95%CI, 1.1–2.0) increased risk of invasive ductalcarcinoma, and a 2-fold (95% CI 1.5–2.7) in-creased risk of ER1/PR1 breast cancers.17

Other risk factors for breast cancer includealcohol, which has been linked to increasedblood levels of estrogen interfering with fo-late metabolism that protects against tumorgrowth. Women who drink .2 ounces of al-cohol per day are 40% more likely to developbreast cancer than women who drink no al-cohol.18

The Nurses’ Health Study found that inpostmenopausal women a weight gain ofmore than 45 pounds after age 18 was linkedas an independent risk factor for breast can-cer (fat tissue produces hormones that areconverted to estrogen).19 This association wasstronger in postmenopausal women who hadnever taken estrogen replacement therapy.The relative risk of developing breast cancerwas 1.6 with a 10–20 kg weight gain, and 2.0with a weight gain of more than 20 kg, com-pared to women with minimal weight gain.In contrast, among women taking estrogen,those who gained weight did not have an in-creased risk of breast cancer. The differing ef-fects of obesity and weight gain in premen-opausal and postmenopausal women isthought to be because obesity decreases es-tradiol and progesterone concentrations inpremenopausal women because of an in-creased frequency of anovulation.20 Thus, lesscirculating estrogen is available to target tis-sues such as the breast.

The Nurses’ Health Study also found thatpostmenopausal women who got at least 1hour of physical exercise per week were 15%to 20% less likely to develop breast cancerthan those who were completely sedentary.In regularly exercising women, participantsin a health-screening program in Norway, thereduction in risk was greater in premeno-pausal women than in postmenopausal wom-en (relative risk 0.38; 95% CI 0.19–0.79).21 Thereason for the reduction of risk in exercisingwomen may be related to delayed menarchein young girls involved in strenuous physicalactivity. Also, moderate levels of physical ac-tivity in premenopausal women are associat-ed with anovulatory cycles, which also areassociated with decreased risk.22

Women treated for breast cancer haveabout a 1% greater chance per year of devel-oping a new second cancer in either the treat-ed breast or the other breast. Therefore, pre-vious breast cancer is an accepted risk factorfor development of breast cancer.23 Ten per-cent of women with breast cancer develop asecond breast cancer, and women with breastcancer have a 3- to 7-fold increased relative


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risk of cancer developing in the oppositebreast.

Women who have had high doses of radi-ation to the chest before age 45—usually forHodgkin’s disease—are at significantly in-creased risk of breast cancer as adults. Radi-ation after age 45 does not confer increasedrisk. The most vulnerable ages appear to bethe prepubertal years of 10 to 14. These wom-en should have yearly mammograms andclinical breast exams beginning either 10years after the radiation treatments or by age35.24

RELATIONSHIP OF BENIGN BREASTDISEASE WITH BREAST CANCER

This is an issue of great concern for pa-tients, physicians and insurance companiesalike, as there are conditions that confer norisk of malignancy and others that definitelyconfer increased risk.

Breast biopsies conferring no significantlyincreased risk for malignancy include any le-sion with non-proliferative change.25,26 Theseinclude duct ectasia and simple fibroadeno-mas, benign solid tumors containing glan-dular as well as fibrous tissue. The latter isusually single but may be multiple. Solitarypapillomas are also benign lesions conferringno increased risk of future malignancy, de-spite the fact that they are often (in 21 of 24women in a single study27) with sanguineousor serosanguineous nipple discharge. Fibro-cystic change (cysts and/or fibrous tissuewithout symptoms) or fibrocystic disease (fi-brocystic changes occurring in conjunctionwith pain, nipple discharge, or a degree oflumpiness sufficient to cause suspicion ofcancer) does not carry increased risk for can-cer (other than the potential for missing amalignant mass).28

Some clinicians differentiate fibrocysticchange or disease into those of hyperplasia,adenosis, and cystic change because of theirdifferentiation into age distributions. Hyper-plasia characteristically occurs in women intheir 20s, often with upper outer quadrantbreast pain and an indurated axillary tail, as

a result of stromal proliferation. Women intheir 30s present with solitary or multiplebreast nodules 2–10 mm in size, as a result ofproliferation of glandular cells. Women intheir 30s and 40s present with solitary ormultiple cysts. Acute enlargement of cystsmay cause pain, and because breast ducts areusually patent, nipple discharge is commonwith the discharge varying in color from palegreen to brown.29

Conditions with increased risk of malig-nancy include ductal hyperplasia withoutatypia. This is the most commonly encoun-tered breast biopsy result that is definitely as-sociated with increased risk of future devel-opment of breast cancer and confers a 2-foldincreased risk. The number, size and shapeof epithelial cells lining the basement mem-brane of ducts are increased, but the histolo-gy does not fulfill criteria for malignancy.The loss of expression of transforminggrowth factor-b receptor II in the affected ep-ithelial cells is associated with an increasedrisk of invasive breast cancer.30

A number of other benign lesions also con-fer a roughly 2-fold increased risk for devel-opment of breast cancer. These include scle-rosing adenosis, where lobular tissue under-goes hyperplastic change with increased fi-brous tissue and interspaced glandular cells,diffuse papillomatosis which is the formationof multiple papillomas, and fibroadenomaswith proliferative disease, which are tumorsthat contain cysts greater than 3 mm in di-ameter, with sclerosing adenosis, epithelialcalcification, or papillary apocrine change.Radial scars are benign breast lesions of un-certain pathogenesis, which are usually dis-covered incidentally when a breast mass isremoved for other reasons. Radial scars arecharacterized by a fibroelastic core fromwhich ducts and lobules radiate.31

Atypical hyperplasia of either ductal or lob-ular cells, where the cells are uniform buthave lost their apical-basal cellular orienta-tion, confers a 4-fold increased risk unlessthere is also a family history of 1 or morefirst-degree relatives with breast cancer,where the risk increases to 6-fold. HER-2/


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Table 2. Breast Imaging and Reporting Data System (BI-RADS)*

Category Interpretation Probability of Malignancy

012345

incomplete; needs additional imagingnegative; nothing to comment onbenign findingprobably benign finding; short interval follow-upsuspicious abnormality; biopsy recommendedhighly suggestive of malignancy; action demanded

n/a0%0%

,2%2–75%.75%

* Orel SG, Kay N, Reynolds SC, Sullivan DC. BI-RADS categorization as a predictor of malignancy. Radiology.1999;211:845.

neu is a proto-oncogene with intrinsic tyro-sine kinase activity. Women with atypical hy-perplasia with over-expression of HER-2/neuhave a greater than 7-fold increased risk ofdeveloping invasive breast carcinoma, ascompared with women with non-prolifera-tive benign breast lesions and no evidence ofHER-2/neu amplification.32

Nipple discharge is often of concern towomen and their physicians as a sign of ma-lignancy, but the reality is that non-bloodynipple discharge and bilateral nipple dis-charge are usually of benign causation. Wom-en with papillomas often have bloody dis-charge. Nipple discharge is uncommon in in-vasive breast cancer and if present is invari-ably unilateral and is usually associated witha palpable mass.33

Similarly, breast pain is an uncommon pre-sentation of breast cancer. In a study of 987women referred for breast imaging becauseof breast pain alone, only 4 women (0.4%)were found to have invasive breast cancer, anumber that was not different from a controlasymptomatic group.34

DETECTION OF BREAST CANCER

As breast cancer rarely causes pain, a pain-less mass is much more worrisome for malig-nancy than is one causing symptoms. Mam-mography done yearly beginning at age 40 isthe current recommendation for women withno risk factors.35 The most commonly encoun-tered categorization of mammography find-ings is summarized in Table 2. Although

mammograms may detect malignancy assmall as 0.5 cm, 10% to 20% of malignancieselude detection by mammography, evenwhen they occur at a much larger size.36 In apatient with a solid, dominant mass (suspi-cious mass) the primary purpose of the mam-mogram is to screen the normal surroundingbreast tissue and the opposite breast for non-palpable cancers, not to make a diagnosis ofthe palpable mass.8 Thus, a negative mam-mogram is no guarantee of absence of malig-nancy, and a mass that does not disappear orcollapse with aspiration must be assumed tobe a malignancy and biopsied.

DIAGNOSING BREAST CANCER:THE BIOPSY

There are 3 methods of obtaining materialfrom a suspicious breast lump. Fine-needleaspiration is not a reliable means of diagno-sis, because it cannot distinguish ductal car-cinoma in situ from invasive cancer and itmay lead to a false-negative result.1 Fine nee-dle aspiration (FNA) is generally reserved forpalpable cyst-like lumps visible on a mam-mogram or ultrasound. False positives arenegligible but false-negative results occur in15% to 20%, leading to the recommendationthat if the cyst or lump doesn’t disappearwith FNA, further biopsy is mandatory.8

Core needle biopsy has generally replacedfine needle aspiration in all but obvious cysts.Core needle biopsies fail to identify areas ofinvasion in approximately 20% of cases whichare originally diagnosed as ductal carcinoma


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Table 3. Bloom-Richardson System With Nottingham Modification Scoring*

Description 1 2 3

Mitotic countTubule formationPleomorphism

few.75% of tumorminimal variation

(—)(—)(—)

many,10% of tumormarked variation

A total grade of 3 is most favorable, and a total grade of 9 is least favorable

* Elston C, Ellis I, eds. The Breast. Vol 13. Churchill Livingston; 1998.

in situ. Atypical ductal hyperplasia in a coreneedle biopsy has a relatively high incidenceof coexistent carcinoma (approximately 50%).This diagnosis, therefore, demands excisionalbiopsy.37

Seventy-five percent to 80% of excisionalbiopsies are expected to be benign. Of the re-maining 20% to 25% that reveal cancer, a sec-ond surgery is often needed to ensure re-moval of all cancerous tissue.

Axillary lymph node involvement is themost important routinely-available predictorof relapse and of survival.38 See later discus-sion on cyclin E measurements and DNA mi-croarrays that may challenge this statementin the future. Axillary recurrence or tumor in-volvement in internal mammary or supracla-vicular lymph nodes always indicates a poorprognosis.39 Sentinel lymph node biopsy is abiopsy of level I axillary lymph nodes. It hasa positive predictive value approaching100%, with a sensitivity of 89% and a speci-ficity of 100%.40 Three percent of positive sen-tinel nodes, however, are found in non-axil-lary regions. There appears to be a 15% in-cidence of ‘‘skip’’ metastases, defined as me-tastases to level II and III axillary nodeswithout involvement of level I nodes.38 Thus,the cost of performing sentinel node biopsyalone is reflected in a study in which the 10-year survival rate of 85% for stage I breastcancer patients who have full axillary dissec-tion falls to 66% when axillary dissection wasnot performed.41 A more complete discussionof sentinel lymph node biopsy can be foundin a recent issue of this journal.42

High nuclear grade (high nucleus-to-cyto-plasmic ratio), high mitotic index and poorlydifferentiated all connote poor prognosis (see

Table 3 for the most commonly used and use-ful histopathologic scoring system). Infiltrat-ing ductal carcinoma is by far the most com-mon type of invasive breast cancer, with rel-atively poorer survival. (See Figures 1 and 2)Tubular, medullary, mucinous, and papillarycancers have a more favorable prognosis, butaccount for only 6% of invasive cancers.39 Per-itumoral lymphatic and blood vessel invasionconnotes a much poorer prognosis.

Estrogen and/or progesterone receptor-positive tumors have a better prognosis anda better response to hormone treatment thanreceptor-negative tumors. Flow cytometrymeasures DNA Index (or DNA content), withdiploid cancer cells (normal DNA content,DNA index of 1) having a better prognosisthan those with aneuploidy.43 S-phase frac-tion refers to the number of cells actively syn-thesizing DNA. Tumors with high S-phasecells have a poorer differentiation and poorerprognosis.44

Tumor marker CA 15–3 is increased inmany women with metastatic breast cancer.HER-2/neu oncoprotein (also called c-erbB-2) is associated with shorter survival, shortertime-to-relapse, and an overall worse prog-nosis.1 This tumor marker is especially im-portant with the introduction of trastuzumabfor treatment. CA 27.29 is the first FDA-ap-proved (in June 1996) blood test for breastcancer recurrence.

A recent study45 found that the hazard ra-tio for breast cancer death in patients withhigh levels of total cyclin E in the tumor washigher than any other biological marker, in-cluding the presence of lymph node metas-tases (7 times higher), hormone-receptor sta-tus, and levels of HER-2/NEU. Among 114


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patients with Stage I breast cancer, none ofthe 102 patients with low levels of cyclin E inthe tumor had died of breast cancer 5 yearsafter diagnosis, whereas all 12 patients witha high level of low-molecular-weight cyclin Ehad died of breast cancer within that period.The hazard ratio for death in breast cancerpatients with high total cyclin E levels ascompared to those with low levels was 13.3,8 times as high as the hazard ratio for otherclinical and pathologic risk factors.

More recently, DNA-microarray datashowed the gene-expression profile is a morepowerful predictor of outcome for young pa-tients with breast cancer than the previouslystandard systems based on clinical and his-tologic criteria. Patients with a poor-progno-sis signature had an overall 10-year survivalrate of 54.6%; those with a good-prognosissignature had an overall 10-year survival rateof 94.6%. These data seem to indicate thatcurrently used criteria misclassify a signifi-cant number of patients. These data indicatehematogenous metastasis to distant sites maybe independent of lymphogenic metastases,and that such tumorigenesis is an early andinherent genetic property of breast cancer.46

If verified, these studies should accuratelyidentify patients most likely to benefit fromadjuvant treatment.47

INTRADUCTAL (DUCTAL) CARCINOMAIN SITU (DCIS)

Intraductal (or ductal) carcinoma in situ(DCIS) is the proliferation of malignant epi-thelial cells confined to ducts, with no evi-dence of invasion through the basementmembrane. Prior to mammography, DCISwas an uncommon diagnosis. With the intro-duction of routine mammography, the age-adjusted incidence of DCIS rose from 2.3 to15.8 per 100,000 females, a 587% increase.New cases of invasive breast cancer increased34% over the same time period.48

About 85% of all intraductal cancers, oftenless than 1 cm, are discovered by the appear-ance of clustered microcalcifications on mam-mography. Other conditions, including scle-

rosing adenosis and atypical ductal hyperpla-sia, may also present on mammography withmicrocalcifications. Morphology of the micro-calcifications is the most important factor indifferentiating benign from malignant calci-fication. Findings suggesting malignancy in-clude heterogenous clustered calcifications,fine linear branching calcifications, or calcifi-cations in a segmental distribution. Magnifi-cation views of benign findings often showmultiple clusters of finely granular microcal-cification, whereas those associated withDCIS usually appear as coarser microcalcifi-cations.49

For women with poorly differentiatedDCIS, the microscopic extent of disease cor-relates well with the radiographic extent. Incontrast, the mammographic appearance ofwell-differentiated DCIS can substantiallyunderestimate the microscopic extent. Resid-ual microcalcifications on the post-surgerymammogram indicates residual tumor with apositive-predictive value of 65% to 70%.50 Thelikelihood of residual cancer increases to 90%if greater than 5 microcalcifications are seenon post-operative mammography.51

Occult invasion is more common if the le-sion is clinically palpable compared to onefound only by mammography. In 70 womenwith palpable DCIS, invasive cancer wasfound in 6 of 54 (11%), vs none of 16 withnon-palpable DCIS.52 If DCIS diagnosis ismade by needle biopsy (note that patholo-gists may have difficulty distinguishing DCISfrom highly atypical hyperplasia), areas of in-vasive cancer are found in 20% of cases atsubsequent surgical excision.37

Axillary node involvement in DCIS is dis-tinctly uncommon. In a National Center DataBase review of 10,946 patients with DCISwho underwent axillary node dissection be-tween 1985 and 1991, only 3.6% had axillarymetastases.53 In another series of 189 womenwith DCIS all of whom underwent axillarynode dissection, none had positive nodes.54

Some experts have argued that presence ofaxillary lymph node metastases in DCISmeans that the pathologist missed the stro-


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Figures 1 and 2. Low-power (Fig. 1) and high-power (Fig. 2) views demonstrating poorly differentiated infiltrating ade-nocarcinoma. The disorganized pattern is characteristic of a poorly differentiated cancer. Photomicrographs courtesy of E.Morrison, MD, Waco, TX.

mal invasion on initial reading of the patho-logic material.

Comedo-type DCIS (Figures 3 and 4) ismore malignant than other types of DCISand is probably mid-way between DCIS and

invasive cancer. Invasive breast cancer was ul-timately found in 12 of 19 cases (63%) ofDCIS with comedo necrosis, vs 4 of 36 (11%)without comedo necrosis.55

An on-going controversy among breast


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Figures 3 and 4. Low-power (Fig. 3) and high-power (Fig. 4) views show ductal carcinoma in situ, comedo-type (comedo-carcinoma). The tumor is contained within the basement membrane. Central necrosis is characteristic of comedocarcinoma.Photomicrographs courtesy of E. Morrison, MD, Waco, TX.

surgeons and pathologists is the so-called mi-cro-invasive DCIS lesion. The American JointCommittee on Cancer (AJCC) defines micro-invasion as the extension of cancer cells be-yond the basement membrane into adjacent

tissues, with no focus more than 0.1 cm ingreatest dimension. Lesions that fulfill suchcriteria are staged as T1mic, a subset of T1breast cancer.56 Ideally, the term microinva-sion in the breast should be applied in the


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same way as it is in the cervix, ie, to identifythose invasive lesions of such limited extentthat have virtually no risk of metastases. Un-fortunately, the available data are inadequateto permit the reproducible identification ofsuch a subset.

In considering treatment of DCIS, mastec-tomy is nearly curative (98%).57,58,59 Breast-conserving therapy (‘‘lumpectomy’’) is al-most as curative if certain criteria are met: thelesion is ,3 cm, the histologic margins arenegative, and the nuclear grade is low or in-termediate, or at least certainly not highgrade.60 Most commonly, breast-conservingsurgery is followed by radiation. The rate oflocal failure in the treated breast is 16% at 15years, with the median time to local failurebeing 5.0 years (mean 5.7 years, range 1.0–15.2 years).61

The importance of age and margin statusin treating DCIS was revealed in a study of418 women who underwent breast-conserv-ing surgery (‘‘lumpectomy’’) and breast ra-diation. Recurrence occurred in 48 (11%)within 10 years. Recurrence developed in24% of women who retrospectively had pos-itive margins, 12% in women with unknownmargin status, and 9% of women with nega-tive margins. The likelihood of local recur-rence is statistically related to age of thewoman at initial diagnosis and surgery, withrecurrences of 31% for those less than 39years of age, 13% for ages 40–49, 8% for ages50–59, and 6% for those older than age 60 (p5 0.0001).61

When local recurrence does occur follow-ing lumpectomy and radiation for DCIS,roughly half of the women again have DCISand half have invasive ductal carcinoma. Sal-vage therapy for recurrence usually consistsof mastectomy (88%) without adjuvant che-motherapy or tamoxifen (69%), and at 8 yearspost salvage treatment in 1 series, 92% of pa-tients were alive and 88% were free of anyevidence of recurrent disease. Favorable prog-nostic factors after salvage treatment wereDCIS as the histology of the local recurrenceand mammography only as the method ofdetection of the local recurrence.62

Interestingly, a diagnosis of DCIS vs themore ominous invasive ductal breast cancerdoes not automatically imply a simpler sur-gical solution. In 1 series, contraindications tobreast preservation surgery were present in33% of women with DCIS, compared to only10% of women with stage I invasive ductalcarcinoma.63

Two randomized trials have comparedlumpectomy alone for DCIS with lumpecto-my with radiation.64,65 Both trials favoredlumpectomy with radiation in regard to re-currence of malignancy (whether the recur-rence was DCIS or invasive ductal disease),but overall survival of the 2 groups was sim-ilar (95% vs 94%), a reflection of the efficacyof salvage mastectomy. There appears to bea select group of patients with DCIS whohave low histologic grade, absence of come-do-type necrosis and small tumor size, whocan be managed with lumpectomy alone.66

The time course to local failure is usually pro-longed, and when local failure occurs, inva-sive cancer is present in the same one-half ofcases as occurs with lumpectomy with radi-ation therapy.62,67,68

Tamoxifen is indicated for women withDCIS who have undergone either lumpecto-my or lumpectomy with radiation. In a trialto specifically address this issue, 1804 womenwith DCIS undergoing breast conservationtherapy were randomly assigned to receiveeither tamoxifen (20 mg daily for 5 years) orplacebo. After a mean follow-up of 62months, tamoxifen reduced the rate of inva-sive recurrence from 9 to 5 per 1000 patients(relative risk reduction 0.56, p 5 0.03) andreduced the rate of recurrent DCIS from 11%to 9% per 100 patients (relative risk reduction0.82, p 5 0.043). Overall, the ipsilateral re-currence of either local or invasive cancer wasreduced from 13% to 8% at 5 years in thetamoxifen group.65

LOBULAR CARCINOMA IN SITU (LCIS)

As it is clinically undiagnosable (it is nevera palpable mass and it has no distinguishingmammographic features), the true incidence


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Table 4. TNM Definitions and Staging

TNM Description

Tis

T1T1aT1bT1c

Carcinoma in situTumor 2 cm or less in greatest dimension

0.5 cm or less.0.5 cm but # 1 cm.1 cm but # 2 cm

T2T3T4

Tumor . 2 cm but # 5 cmTumor . 5 cmTumor of any size with direct extension to

chest wall, skinN0N1

No regional lymph node metastasesMetastases to moveable ipsilateral axillary

lymph nodesN2 Metastases to fixed ipsilateral axillary lymph

nodesN3 Metastases to ipsilateral internal mammary

lymph nodesM0M1

No distant metastasesDistant metastases (including supraclavicular

lymph nodes)

TNM StageStage Description

0IIIAIIBIIIAIIIBIV

Tis, N0, M0T1, N0, M0T0, N1, M0 or T1, N1, M0 or T2, N0, M0T2, N1, M0 or T3, N0, M0T0–T2, N2, M0 or T3, N1, M0T4, any N, M0, or any T, N3, M0any T, any N, M1

of LCIS is unknown.69 LCIS incidence inbreast masses removed has varied from0.05% to as high as 10%,70,71,72 and the inci-dence of LCIS is 10-fold higher in white com-pared to African-American women in theUnited States.73 This diagnosis is alwaysmade incidental to a needle biopsy or resect-ed mass done for fibrocystic change, fibro-adenoma, or a mass suspected as being can-cer.74 LCIS is more often detected in premen-opausal than postmenopausal women, sug-gesting a hormonal influence in thedevelopment or maintenance of these le-sions.75,76

LCIS requires no specific therapy per se.Although the cells of LCIS are in fact small,well-differentiated neoplastic cells, they donot behave as a true malignant neoplasm inthat these cells may distend and distort theterminal-lobular units, but invasion of andthrough the basement membrane does not oc-cur, so the lesion never results in invasivebreast malignancy.

Rather, the clinical significance of LCIS isthat it serves as an important marker for sub-sequent invasive breast cancer, in a magni-tude of risk of approximately 1% per year forthe remainder of the woman’s life (7- to 10-fold higher risk of invasive breast cancer thanthe average US woman27), with the invasivecancer occurring with equal frequency in ei-ther breast. Subsequent invasive cancers arealso more often of the infiltrating ductaltype.75

The recommended management of LCIS iscareful follow-up and semiannual physicalbreast exam and yearly mammography. TheNSABP tamoxifen prevention trial (NSABPprotocol P1) included 826 women with LCIS.At 4 years of follow-up, invasive breast cancerwas less common in the tamoxifen arm (2%vs 4% with placebo, 5.7 vs 13 per 1000 wom-en, a 56% risk reduction).77 However, manyexperts do not recommend tamoxifen in thisgroup, citing the adverse effects of tamoxifen(hot flashes, an estrogen antagonist effect,and in postmenopausal women the increasedoccurrence of endometrial cancer and venous

thromboembolism) and costs (tamoxifen isgiven in 20 mg tablets daily for 5 years).

STAGING AND PROGNOSISOF BREAST CANCER

At initial diagnosis, over 50% of breast can-cers are stages 0 or I,78 and 75% are Stage 0,I, or II. (Table 4)79

The quantity of lymph node involvementhas a profound impact on survival. Stage IIAcancer (T0-T1, N1) with only 1 involvedlymph node has a 10-year disease-free sur-vival of 71% and a 20-year disease-free sur-vival of 66%. If 2 to 4 lymph nodes are in-volved, the 10-year disease-free survival is62% and the 20-year disease-free survival is56%.79


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Table 5. Standard Adjuvant Chemotherapy Regimens

StandardRegimens Components

AC (w or w/o T) Adriamycin, cyclophosphamide,Taxol

CMF Cyclophosphamide, methotrexate,fluorouracil (5-FU)

CEF Cyclophosphamide, epirubicin, fluo-rouracil (5-FU)

CAF Cyclophosphamide, adriamycin,fluorouracil (5-FU)

SURGICAL TREATMENTOF BREAST CANCER

The Consensus Development Conferenceon the Treatment of Early-Stage Breast Can-cer (June 1990, NCI) has concluded that breastconservation treatment is an appropriatemethod of primary therapy for the majorityof women with Stage I and Stage II breastcancers. This treatment is preferable in manycases because it provides survival equivalentto total mastectomy and axillary dissectionwhile preserving the breast.80

Subsequent studies have confirmed thatthere is no difference in long-term survivalbetween surgical removal of the breast (mas-tectomy) and excision of the tumor mass andradiation therapy to residual breast tissue(breast conservation therapy).81–83

Breast-conserving surgery includes lump-ectomy, re-excision, partial mastectomy,quadrantectomy, segmental excision, andwide excision. Axillary lymph nodes are re-moved for evaluation through a separate in-cision. The most common breast-removal pro-cedure is a modified-radical mastectomy,which involves making an elliptical incisionaround an area including the nipple and bi-opsy scar, removing that section, and tunnel-ing under the remaining skin to remove thebreast tissue and some lymph nodes. Radicalmastectomy, which removes the entire breast,chest wall muscles, and all axillary lymphnodes, is rarely done today because it offersno survival advantage over a modified radicalmastectomy. A simple, or total mastectomy,removes the entire breast but none of the ax-illary lymph nodes. This is usually done forwomen with DCIS, or prophylactically forwomen at especially high risk for developingbreast cancer. A newer procedure is the skin-sparing mastectomy, which involves removingthe breast tissue through a circular incisionaround the nipple and replacing the breastwith fat taken from the abdomen or back.

ADJUVANT THERAPIESFOR BREAST CANCER

Radiation adjuvant therapy is routine afterbreast-conserving surgery (eg, lumpectomy)

to prevent recurrence of cancer in the breast,and it may be used after mastectomy to pre-vent recurrence on the chest wall and axilla.Radiation therapy is generally given 5 days aweek over a 5- or 6-week time span, with caretaken to try to avoid damage to the heart orlungs. The only usual changes with breast ra-diation are skin erythema and possibly sometransient lymphedema.

Systemic adjuvant chemotherapy is neverrecommended for non-invasive, in situ cancer(DCIS). The most commonly used standardadjuvant chemotherapy regimens are listed inTable 5.

Hormone adjuvant therapy helps to pre-vent recurrence by blocking the effects of es-trogen, which is known to stimulate cancercell growth. Hormones are most effective inwomen whose primary tumor has hormonereceptors (ie, estrogen-receptor or progester-one-receptor positive). Tamoxifen is the stan-dard first choice of most experts.84 Other hor-monal therapeutic agents include aromataseinhibitors, which interfere with the enzymearomatase, which plays a critical role in theproduction of estrogen in postmenopausalwomen. Examples of this class include anas-trozole, letrozole and exemestane.85,86

A recent study of women who had com-pleted 5 years of tamoxifen therapy and wereassigned to either no therapy or continuingtherapy with letrozole was prematurely end-ed when preliminary results revealed a great-er than 40% reduction in recurrent breastcancers in the letrozole arm. Unanswered


97

questions are whether women should take le-trozole for 5 years (the original study design)or indefinitely, and whether women shouldtake letrozole (or one of the other aromataseinhibitors) instead of tamoxifen initially. Anearlier head-to-head comparison of anastro-zole and tamoxifen found that it was some-what more effective in reducing the risk of arecurrence than tamoxifen.99

Biological adjuvant therapy includes tras-tuzumab, which blocks the action of agrowth-promoting protein called Her-2/neuthat is found in larger-than-normal amountsin about 30% of breast cancers.87 Trastuzum-ab more specifically targets cancer cells andthus has fewer side effects than standard che-motherapy, although it may have some effectson normal heart tissue when used with che-motherapy.88 The drug has been approved formetastatic breast cancer and is currently un-der study as a first-line agent in combinationwith other chemotherapy.89

PATTERNS OF RELAPSE

The rate of local recurrence at 8 to 10 yearshas varied from 4% to 20%, with no differ-ences between women who underwent mas-tectomy vs those who underwent breast-con-serving therapy. However, the mortality im-plication of recurrence between the 2 groupsis considerable. Women treated initially withbreast-conservation therapy can present withlocoregional recurrence in the preservedbreast tissue. This may represent regrowth ofthe previous tumor or a second primary tu-mor. These patients can often be treated withmastectomy for curative intent. Women whohave undergone a mastectomy as a primarytreatment will usually manifest locoregionalrecurrence as a mass in the chest wall or over-lying skin. This carries a much graver prog-nosis, since distant metastatic disease is al-ready present in 25%–30% of these cases.90

Breast cancer survivors are at increasedrisk for developing a second primary breastcancer compared with the general population(approximately 0.5% to 1% of women peryear develop contralateral breast cancer).91

Patients who have undergone breast conser-vation therapy are at similar risk for devel-oping a second primary breast cancer in thepreserved breast as in the contralateral breast.

Finally, in addition to locoregional recur-rence and second primary breast cancer, re-lapse may occur with the presence of distantmetastases.

RECOMMENDED SURVEILLANCE INBREAST CANCER SURVIVORS

One trial randomly assigned breast cancersurvivors to either a specialist or a familyphysician, and found no differences betweenthe 2 groups in measured outcomes, includ-ing time to diagnosis of recurrence, anxiety,or health-related quality of life.92 A subse-quent economic analysis of this study foundthe quality of life as measured by frequencyand length of patient visits and costs werebetter when follow-up was provided by thefamily physician as compared to the special-ist.93

Routine history and physical examinationand regularly scheduled mammograms arethe mainstay of care for the breast cancer sur-vivor.94 Recurrence of breast cancer is morefrequently discovered by the patient (71%)than by her physician (15%).6 Women shouldbe encouraged to perform breast self exami-nation monthly. Mammograms should bedone at 6 and 12 months after surgery andthen yearly thereafter.

Several tumor-associated antigens, includ-ing CA 15-3 and CEA, may detect breast can-cer recurrence, but not with sufficient sensi-tivity and specificity to be routinely used byeither clinicians95 or insurance underwriters.A newer marker, CA 27.29, showed promisein one well-designed study of 166 womenwith stage II and III breast cancer. The sen-sitivity and specificity of this test were 58%and 98%, respectively. Recurrence was de-tected approximately 5 months earlier thanwith routine surveillance.96 However, im-provement in survival or quality of life usingthis marker has not yet been proven.

Neither routine chest x-rays nor serial ra-


98

dionucleotide bone scans have been found tobe useful in detecting metastatic disease inasymptomatic women.97,98

CONCLUSION

Although breast cancer is a major cause ofmorbidity and mortality in women, and thusis of understandable concern to life under-writers, basic understanding of the diseaseoften allows for aggressive underwriting insome cases. Women with DCIS and LCIS whohave been correctly managed should still beeligible for optimistic ratings, whereas under-writing women with cumulative risk factorsdescribed in this treatise, as well as unfavor-able pathology and especially the presence ofaxillary metastases, calls for ever increasingcaution.

Of particular note to underwriting depart-ments is the newer reports of the discrimi-nating power of measurements of cyclin Eand analysis of the levels of expression ofthousands of genes simultaneously with theuse of DNA microarray technology in iden-tifying women with stage I and II breast can-cers with both much better, and those withmuch worse, prognoses than is now availablewith knowledge of estrogen-receptor statusand the presence or absence of lymph nodemetastases.

In the section Risk Factors for Developmentof Breast Cancer, we have reviewed the dataavailable at the time of this writing on thecontroversial role of hormone replacementtherapy (HRT) in post-menopausal women.Although some controversial points remain,there does appear to be mounting evidencethat HRT that includes both estrogen andprogestin does entail risks that need to beconsidered in underwriting decisions.

Perhaps the most significant finding in ourreview was that 70% to 75% of women withinvasive breast cancer actually die of some-thing other than their breast malignancy. Al-though there are certainly red flags thatshould raise serious concern in underwritingthese women, there are many ‘‘breast cancersurvivors’’ who are just that: they apparently

have survived their disease. But only a firmunderstanding of all of the issues describedin this review will allow for the selection ofthese insurable cases.

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