INTRODUCTION

Interest in prognostic factors has been stimulated by the success of systemic adjuvant therapy for early-stage, cancer of the breast. Patients destined for recurrence can be selected for systemic adjuvant therapy, while patients who will not have a recurrence can be spared the morbidity of a treatment that offers no benefit.

For lawyers this factors may help the lawyer to evaluate whether the delay in diagnosis was material.

2 factors are important doubling time and cancer maturity. Doubling time reflects how fast the tumor grew between the time mammography was erroneously read as benign and the ultimate removal of the tumor. Cancer maturity referrs to the tendency of tumors to be less differentiated as they grow bigger. Understanding prognostic factors are thus of prime importance in projecting damages.

The enclosed article is based largely on Tumor-Related Prognostic Factors for Breast Cancer William L. Donegan, MD CA Cancer J Clin 1997;47:28-51 and on Retsky, Swartzendruber, Wardwell, Bame. Computer model challenges breast cancer treatment strategy. Cancer Investigation, 12(6): 559-67, 1994.

HISTOLOGIC TYPES OF CANCER

Ductal Carcinoma in Situ

Ductal carcinoma in situ (DCIS) represents a small, but important, group of preinvasive breast cancers that can almost always be cured by local-regional therapy. DCIS made up 6.3 percent of 169,260 carcinomas reported to the National Cancer Institute's Surveillance registry between 1973-1987. Only one percent of these early cancers are associated with metastasis to axillary nodes, and almost all (98 percent) are cured by local-regional therapy regardless of their size. , systemic adjuvant therapy is unnecessary.

Microinvasive Carcinoma

Invasive carcinoma carries with it the clear potential for metastasis and a diminished opportunity for cure. The term "microinvasive" is loosely used to describe the process of invasion in its earliest beginnings and to suggest that a tumor is still highly curable. As a group, invasive carcinomas 5 mm or less in diameter have widely divergent rates of metastasis to regional lymph nodes, ranging from three to 28 percent

A few special histologic types of invasive carcinoma pose a smaller risk of dissemination and death than other types of invasive ductal carcinoma. These types are pure mucinous, pure tubular, pure medullary, and pure papillary carcinoma.

In a large study, Rosen et al found that patients with special histologic types measuring 1.0 cm or less in diameter had a 10-year recurrence-free survival of 100 percent. The 10-year survival for all patients with tumors measuring 3.0 cm or less was 91 percent. Five-year relative survivals.

Histologic and Nuclear Grade

A number of additional histologic features of invasive ductal and lobular carcinomas have prognostic value when considered in isolation. They include histologic grade, nuclear grade, tumor borders as stellate or circumscribed, peritumoral lymphatic and blood vessel invasion,27,28 and necrosis within the tumor.29-31 Many of these lose, however,relevance in multivariate analyses.

Histologic grade is currently based on the degree of tubule formation, number of mitoses, and nuclear pleomorphism in routine sections. These are combined as the Bloom-Richardson (B-R) grade or Scarff-Bloom-Richardson grade. Grades from 1 to 3 indicate progression from well differentiated (low or good grade) to poorly differentiated (high or poor grade).

Histologic and nuclear grade are subordinate to node status and tumor size as prognostic features, but both are significant predictors of overall mortality for node-positive and node-negative patients. In a multivariate analysis by Fisher et al,neither histologic grade nor any of nine additional pathologic variables related univariately to prognosis had independent predictive value for 15-year survival of 620 stage I and II patients treated with radical mastectomy after the number of positive axillary nodes, tumor size, and nipple involvement were taken into account.

Poor histologic and nuclear grade may indicate responsiveness to adjuvant chemotherapy. Adjuvant chemotherapy has been observed to produce a greater improvement in prognosis among node-positive and node-negative patients with poorly differentiated tumors than among such patients with well-differentiated tumors. This may diminish the difference in outcome between well-differentiated and poorly differentiated cases treated with chemotherapy.

Among node-negative patients, the prognostic influences of nuclear and histologic grades are clearly evident. Treatment failures are few among the small group of histologic grade 1 cases. In an analysis of 1,157 node-negative patients, Fisher et al found that nuclear grade was a more important determinant of outcome than estrogen receptor or progesterone receptor status. Histologic grade was second only to tumor diameter as a predictor of disease-free survival among aneuploid tumors

Investigators reported a disease-free survival of 100 percent for a small group of node-negative patients with nuclear grade 1 tumors or with histologic grade 1 aneuploid tumors.

Tumor Angiogenesis

Tumor angiogenesis as a prognostic assay is predicated on the evidence that ingrowth of blood vessels is a necessity for sustained tumor growth and metastasis. Interest in neovascularity as a prognostic factor was stimulated by the work of Judah Folkman on tumor angiogenesis and by the potential for treatment with antiangiogenic agents. The reliability of this test is however questionable . In a large study Axelsson et al concluded that microvessel assay in its present state was unsuited for general application in the management of patients.

ANATOMIC STAGING

The anatomic extent of a cancer determined clinically or histologically is a classic and reliable indicator of prognosis, but an imprecise one. The general staging categories include:

• localized confined to breast tissue,
• regional direct invasion to extramammary tissues or metastasis to regional lymph nodes
• and distant metastasis beyond regional tissues.

. According to a statistical report from the NCI, the five-year relative survivals of localized and regional cases diagnosed during the years 1960 through 1964 were 84 and 53 percent, respectively. Gardner and Feldman reported ten-year survival rates of 54, 28, and five percent respectively for local , regional and distant metastasis for 1,024 patients diagnosed before 1981.

The five-stage TNM staging system is an improvement over general staging. It categorizes noninvasive carcinomas, which are highly curable, as stage 0. For staging invasive carcinomas, it places emphasis on size of the primary tumor and the extent of nodal metastasis. Excluding the incurable cases with distant metastasis (stage IV), the remaining stages of invasive carcinoma (stages I, IIA, IIB, IIIA, and IIIB) have an increasing likelihood of treatment failure and death. Five-year survivals for stages I to IIIB are 90, 80, 65, 50, and 40 percent, respectively.

The probability of metastasis to regional nodes (both axillary and internal mammary) and to distant sites increases progressively as tumors enlarge. As continuous variables the number of nodal metastases and tumor size allow more precision for assessment of prognosis than does anatomic staging.

METASTASIS TO REGIONAL LYMPH NODES

Axillary Lymph Nodes

Analyses regularly indicate that the presence or absence of metastasis to axillary lymph nodes is the single most influential predictor of post treatment recurrence and death. In the absence of systemic adjuvant therapy, the chance of recurrence within 10 years is 24 percent for patients without nodal metastasis on histologic examination and 76 percent for patients with nodal metastasis. While axillary metastasis is the most important determinant of prognosis in operable cases, the fact that a quarter of patients without axillary metastasis are not cured by local-regional therapy and some patients with metastasis are alive and well after many years (at 10 years, 30 percent overall and 17 percent for patients with metastasis to four or more nodes) indicate that they are an imperfect sign of systemic disease.

More prognostic information is derived from axillary lymph nodes than the fact of involvement alone. The most important information is the number of involved nodes. The absolute number of involved nodes provides a prognostic continuum that is directly related to the prospects for recurrence and indirectly related to survival. In one large study of 1,741 cases, the 10-year survival of patients with 0, 1 to 3, 4 to 9, and 10 or more involved nodes was 75, 62, 42, and 20 percent, respectively.

The total number of nodes examined, and by inference the percentage of nodes involved, does not alter the prognostic importance of the absolute number of nodes that contain metastases, provided that sampling is sufficient to detect all positive nodes. Surgical removal or pathologic examination that is too limited is likely to provide misleading information. A level II axillary dissection is considered necessary to obtain reasonably accurate information.

The size of metastases, the growth of metastases through the capsule of the lymph nodes, and the highest axillary level reached by the metastases can be related individually to prognosis, but all are interrelated in a complex manner and generally tend to be a function of the total number of involved nodes. Metastasis to increasing numbers of nodes results in larger metastases, extracapsular growth of metastases, and a higher axillary level of involvement. For example, extracapsular growth is seen only with macrometastases and influences prognosis adversely only when three or more nodes are involved. When the number of nodes with metastases is constant, the level of axillary involvement has no additional predictive value. Micrometastases <2 mm in diameter) are more favorable than macrometastases (>2 mm), and micrometastases rarely involve more than three nodes.

Internal Mammary Lymph Nodes

Internal mammary lymph nodes are also a primary lymphatic drainage basin of the breast. They are not routinely examined for pathologic staging, but they are involved in nine percent of cases when no metastases are found in axillary nodes, unmasking a high-risk group of "node-negative" cases. For this reason, histologic proof that they are free of metastasis provides additional evidence that a tumor is locally confined. Metastasis to these nodes has the same overall prognostic importance as metastasis to axillary nodes. However, they are less accessible for examination, and their small number provides less potential for quantifying prognosis.

Supraclavicular Lymph Nodes

Metastasis to supraclavicular nodes implies extensive involvement of axillary nodes, but it can occur in the absence of axillary involvement, suggesting passage through internal mammary nodes or blood-borne passage. The prognosis for patients with metastasis to this site is equated in the current TNM staging system with general dissemination of cancer (i.e., stage IV).

Tumor Size

The importance of tumor size as a prognostic variable in cases of invasive carcinoma is robust enough to survivemeasurements derived variously from clinical estimates, mammograms, and gross and histologic sections. In many analyses it is second only to axillary node status as an independent prognostic factor. Tumor size is directly related to an increasing probability of regional metastasis, an increasing average number of involved axillary lymph nodes, and an increasing probability of recurrence and death.

The favorable prognosis of nonpalpable invasive carcinomas relative to palpable ones and of screening-detectedversus nonscreening-detected cancers is easily explained by their smaller size. In one report cancers 0.1 to 5 mm and 6 to 10 mm in diameter produced axillary metastasis in only 7.7 and 12.5 percent of cases, respectively.However, the incidence of positive nodes can range up to 21 percent for both of these size groups.15 Tumors of equal size are prognostically similar whether they are palpable or not and regardless of how they are detected.

The influence of primary tumor size on prognosis can be appreciated in both node-negative and node-positive cases. This relationship probably reflects increasing vascular and lymphatic dissemination with progressive tumor growth. Of particular interest are node-negative cases, where tumor size provides a readily available means foridentifying patients at low and high risk for recurrence.

Tumors 1.0 cm or less in diameter have an especially low risk of recurrence. The five-year disease-free survival of node-negative patients with tumors 1.0 cm or less in diameter is 92 to 96 percent. A large study at Memorial Sloan-Kettering Cancer Center found a 10-year relapse-free survival of 91 percent.

 These and other studies support the contention that patients with the combination of node-negative disease and a tumor diameter of 1 cm or less represent a favorable subset of patients who would not benefit significantly from systemic adjuvant therapy.88 As failure rates are high enough in any case with macrometastasis to axillary lymphnodes to justify systemic adjuvant therapy, investigations have largely focused on the ability of other biologicvariables to further define the prognosis of node-negative individuals, a group that is increasing due to more widespread use of screening mammography.

Steroid-Hormone Receptor Proteins

Intracellular steroid-hormone receptor proteins, primarily estrogen receptor (ER) and progesterone receptor (PR), have received intensive study both as indicators of prognosis and as guides to hormone and endocrine therapy. About 50 to 85 percent of breast cancers contain measurable amounts of ER. The frequency with which tumors contain ER and the concentration of ER increase with patient age, both reaching their highest levels in postmenopausal patients. The presence of ER implies that normal cellular mechanisms for processing estrogen have been maintained despite malignant change, particularly if PR is present.

The clinical importance of ER relates principally to the fact that its presence identifies hormone-sensitive tumors. About 50 to 60 percent of patients with significant amounts of ER in their tumors respond favorably to hormone or endocrine therapy. A higher percentage respond if ER levels are high and if

both ER and PR are positive. Patients with ER-positive tumors have prolonged disease-free survival after primary treatment, superior overall survival, and longer survival after recurrence compared with patients with ER-negative tumors, and this advantage is independent of axillary node status.

The indications are that ER status is a weak prognostic indicator and that PR status provides no important advantage. Both are probably more reflective of growth rate than of metastatic potential. ER status alone or in combination with axillary status fails to identify a node-negative or a node-positive subset that has a rate of recurrence low enough to exclude systemic adjuvant therapy.

The pS2 protein appears to identify a subset of ER-positive tumors with a particularly favorable outlook. pS2 protein is an estrogen-regulated secretory protein of unknown function, but it probably indicates a more intact cellular estrogen-processing mechanism. After adjustment for tumor size, lymph node status, and ER status, negative pS2 status is still associated with early recurrence and death. Positive pS2 status in ER-positive patients indicates improved prognosis in both node-negative and node-positive patients. In patients with ER-positive/PR-positive tumors, positive pS2 status was associated with a five-year survival of 97 percent versus 54 percent for negative pS2 status.

Ploidy and S-Phase Fraction

Flow cytometry with laser-stimulated DNA fluorescence makes automated measurement of the DNA content of individual cells and the number of cells in each phase of the cell cycle readily available. It is possible to determine whether the DNA of each cell is normal (diploid versus nondiploid) compared with a control and to determine the fraction of cells actively synthesizing DNA.

Normally, diploid cells are in the resting phase (G0) or in the first gap phase of the cell cycle (G1). Cells with twice the normal DNA content are in either the G2 or early mitotic phase (M), and cells with intermediate amounts of DNA are in the synthesis phase (S). About 32 to 51 percent of tumors are diploid. The remainder are aneuploid to various degrees. The degree of departure from normal DNA content is calculated as the DNA index (i.e., the DNA content of the predominant cell population divided by diploid DNA content). By definition, a diploid tumor has a DNA index of 1.0. Standardization of S-phase fraction (SPF) and ploidy has been a continuing challenge. It is not possible to obtain measurements in 10 to 20 percent of tumors, and contaminating debris and nonneoplastic cells are potential sources of error.

Results generally confirm that patients with diploid tumors or tumors with a low SPF have more favorable disease-free survival and observed survival than patients with aneuploid tumors or tumors with a high SPF, however, the differences may be small. SPF evaluation allows for stratification of node-negative patients with diploid tumors into high- and low-risk groups. Clark et al reported that patients with diploid tumors with a low SPF (<6.7 percent) had a five-year disease-free survival of 90 percent. Patients with diploid tumors with a high SPF had a poor prognosis comparable to patients with aneuploid tumors.

In multivariate analyses, tumor size and SPF often emerge as independent determinants of prognosis in node-negative patients, permitting these prognostic factors to be combined to advantage. Bosari et al were able to identify three discrete prognostic groups based on tumor size, SPF, and ploidy. Only 12 percent of patients with small (>2.0cm), diploid tumors with a low SPF (<5 percent) had recurrence within nine years.

An international consensus group met in 1992 to consider the clinical use of DNA cytometry in carcinoma of the breast. The group concluded that operable breast cancers that were diploid, even up to a DNA index of 1.3, had a favorable prognosis compared with aneuploid tumors but that the advantage was small and tended not to survive as a prognostic determinant in multivariate analyses because of the correlation of ploidy with more powerful prognostic factors. SPF, however, was believed to have an important association with recurrence and mortality for both node-positive and node-negative breast cancers. This association was generally independent of other prognostic factors, although its strong correlation with tumor grade often caused it to lose significance as an independent prognostic variable, particularly when grading was expertly performed. Its practical utility lay in being less subjective than grading.

Mitotic Index and Thymidine Labeling Index

Mitotic index (MI) and thymidine labeling index (TLI) measure cellular proliferative activity directly on histologic sections. The MI is measured as the number of mitoses per specified number of high-power microscopic fields (usually 10 fields) in routine sections. It requires no special technology but varies with field selection. Baak et al were able to correlate increasing MI with decreasing cancer-specific survival.

TLI is a direct measure of cells in S phase of the cell cycle. Some investigators have found close correlation between the TLI of primaries and their metastases. High values are associated with high MIs, poor histologic differentiation, and young age. In a large, multivariate analysis, TLI ranked fourth behind nodal status, tumor size, and nuclear size as an indicator of relapse-free survival. Among node-negative patients, it is superior to tumor size but not to ER status.

Cathepsin-D

Cathepsin-D (CD) is an estrogen-dependent lysosomal protease that is synthesized by normal tissues andoverexpressed and secreted by some breast cancers. CD is suspected of facilitating invasion and metastasis of breast cancer, and indeed, levels of CD tend to be higher in node-positive cases of breastcancer. Overexpression of CD in breast cancer is associated with high risk of recurrence and poor survival, largely because of its relationship with node status. Its value as a prognosticators remains uncertain.

Urokinase Plasminogen Activator

Urokinase plasminogen activator (uPA) is one of several proteases that have been implicated in the process of invasion and metastasis. Investigations in human breast cancer indicate that high levels of uPA are correlated with a short disease-free interval and poor survival. As a prognostic marker, uPA level is independent of tumor size, node status, and ER status. The level of uPA has proved to be a discriminant for disease-free survival and observed survival in patients with positive nodes and those who are ER positive. It is also a discriminant for disease-free survival in patients with negative nodes. In node-negative patients and in patients with ER-positive tumors, low levels have been associated with five-year disease-free survivals of about 90 percent and 95 percent, respectively..

conclusions

Traditional pathologic features (i.e., nodal status, tumor size, and tumor differentiation) continue to provide guides for prognosis and are information that is routinely available. ER and PR are also important, but are more important for guiding selection of hormone treatment than for determining prognosis. Newer prognostic indicators relating to the proliferative rates of tumors are increasingly available and are potentially helpful, but for the most part their role is uncertain.

 ER and PR are the prime examples of prognostic indicators capable of identifying patients likely to respond to aparticular form of therapy (i.e., hormone therapy). Poor histologic grade may indicate a higher potential for response to chemotherapy. The overexpression of c-ERBB2 may be a potential indicator of resistance to chemotherapy and hormone therapy. It is possible that reliable markers for resistance or sensitivity to specific chemotherapeutic agents will be forthcoming, information that could have a constructive influence on treatment planning.

Patients with an excellent prognosis include women with DCIS and women with negative axillary nodes whose invasive carcinomas are less than 1.0 cm in diameter or who have special histologic types of carcinoma less than 3.0 cm in diameter. On the other hand, patients with any number of metastases to regional lymph nodes and node-negative patients with tumors more than 2.0 cm in maximum diameter have recurrence rates high enough to derive a substantial benefit from systemic therapy.

Node-negative patients with tumors 1.0 to 2.0 cm in diameter have an intermediate prognosis with average five-year disease-free survivals of about 85 percent. It is in this group that measures of proliferation such as histologic or nuclear grade, SPF, and ER status may have the most value in deciding for or against systemic therapy.

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DOUBLING TIME

A tumor consists of some normal tissue plus cancer cells that are descendants of one cell that had undergone a malignant transformation. The number of cells is described by the equation 2n where n is the number of doublings that have taken place. Tissue density is approximately a billion cells per cubic centimeter (cc). A billion is approximately 2 30. Ignoring the normal cells, a 1 cc tumor started as a single cancer cell that has divided 30 times. Data show the time for a breast cancer to double in volume is 25 days to at least 1000 days with a typical value of about 100 days. Depending on breast tissue density and structure, mammography is usually capable of finding breast tumors at approximately 1 cc. Combining this information, we can estimate the usual preclinical time of breast cancer as 30 doublings at 100 day doubling time or a total of 8 years.

If left untreated, a primary breast cancer 1 liter (1000 cc) in size is typically lethal. That size is 40 doublings of a single cell. Thus the possible observation times in breast cancer is limited to between the 30th and 40th doublings or at most only the last 25% of the growth history of a tumor.

Exponential growth, the simplest possible growth, is cellular division with a constant dividing time. One cell divides into two and then four, etc., with each doubling taking the same time. This growth is easily recognizable when graphed. It is a straight line on a semi-log scale (logarithmic on the vertical scale and linear on the horizontal scale).

Exponential growth cannot continue indefinitely since it is boundless. Beyond a size where the tumor is a few percent of the host size, the host cannot fully sustain the tumor. At that point exponential growth gradually slows. Growth that is exponential at small time and limited to an asymptotic level at large time is called Gompertzian growth.

. According to the 1991 American Cancer Society Textbook of Clinical Oncology , Gompertzian growth accurately describe the growth of breast cancer. When cancer is found in a patient, the tumor lies high on the growth phase of the Gompertz curve and is thus relatively slowly growing. Debulking the tumor by surgical removal and radiation puts any residual tumor in the smaller thus faster growing section of the Gompertz curve and makes it more sensitive to chemotherapy.

Due to limitations of human experimentation, there is little hard data. Publications that use Gompertzian kinetics directly or indirectly. There is much well documented evidence to support temporary dormancy in the natural history of breast as well as other cancers. A 4.5 cm. tumor with a constant doubling time of 7200 days leads to the impossible result that the tumor started growing 655 years earlier. The tumor must have grown faster initially and then slowed and finally faster again. That is impossible to explain by Gompertzian growth.

Because of the variability in cancer growth doubling time is of limited value to a treating onclogist. There are, however, aspects of this subject which may be of interest to attorneys. One issue facing the attorney trying to establish if a delayed diagnosis made any difference in outcome to a patient is whether the tumor grew appreciably between the time it could have been detected and when it was actually detected. If growth is continuous and deterministic as in the Gompertzian model, then every day of delay produces a measurably worse prognosis. If growth is discontinuous and erratic, then some periods of time delay in diagnosis produce no worsening of prognosis while other periods of time delay will produce significant worsening of prognosis.

To the attorneys representing either the plaintiff or the accused in a case of delayed diagnosis of breast cancer, it often cannot be established with absolute certainty whether survivability was compromised due to delay. However the probability and the likely extent of damage to survivability can be calculated. For example if after applying the prognostic characteristics cited earlier, one finds that the long term prognosis of the patient as diagnosed is 28% chance of long term survival. One can possibly state with some degree of certainty that if the patient were diagnosed 10 months earlier, the chance of survival would have been 41% to 65%.